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{ "abstract": "Subglottic hemangioma is a potentially life-threatening manifestation of the PHACES syndrome. The disease process has been treated with corticosteroids, oral chemotherapeutic agents, endoscopic airway interventions, tracheostomy, and even laryngotracheal reconstruction. Oral propranolol has emerged as an effective therapy and in many cases has led to complete regression of hemangioma during the proliferative phase. There have been several reports of patients showing signs of reproliferation after discontinuing propranolol therapy. This article illustrates a patient who has had multiple episodes of reproliferation of subglottic hemangioma after weaning from propranolol therapy.", "affiliations": "Division of Otolaryngology, Department of Surgery, Texas A&M College of Medicine/Scott and White Memorial Hospital Program, Temple, Texas.;Division of Otolaryngology, Department of Surgery, Baylor Scott and White McLane Children's Hospital, Temple, Texas.", "authors": "Holdgraf\|Randall W\|RW\|;Kress\|Melissa\|M\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1080/08998280.2017.1415547", "fulltext": null, "fulltext_license": null, "issn_linking": "0899-8280", "issue": "31(2)", "journal": "Proceedings (Baylor University. Medical Center)", "keywords": "PHACES syndrome; propranolol; subglottic hemangioma", "medline_ta": "Proc (Bayl Univ Med Cent)", "mesh_terms": null, "nlm_unique_id": "9302033", "other_id": null, "pages": "194-196", "pmc": null, "pmid": "29706817", "pubdate": "2018-04", "publication_types": "D002363:Case Reports", "references": "19858157;20674045;25721095;20643720;22082463;18676554;16172341;15510009", "title": "The PHACES syndrome: Multiple episodes of reproliferation of subglottic hemangioma.", "title_normalized": "the phaces syndrome multiple episodes of reproliferation of subglottic hemangioma" }	[ { "companynumb": "US-PFM-2019-06245", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile haemangioma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.25", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.6 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.0 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.67 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.67", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile haemangioma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "803", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stridor", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug titration error", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Holdgraf RW, Kress M. The PHACES syndrome: multiple episodes of reproliferation of subglottic hemangioma. Bayl Univ Med Cent Proc. 2018;31:194-6", "literaturereference_normalized": "the phaces syndrome multiple episodes of reproliferation of subglottic hemangioma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20955276, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "The objective of this manuscript is to describe the challenges of Cardio-Cerebral Infarction (CCI) treatment and to highlight the variable approaches in management. CCI is a rare clinical presentation of simultaneous acute ischemic stroke (AIS) and acute myocardial infarction (AMI) and poses a therapeutic challenge for practitioners. Each disease requires timely intervention to prevent irreversible damage; however, optimal management remains unclear. We describe three cases of CCI. All three patients presented with symptomatic left MCA (M1) occlusion, with ST elevation myocardial infarction (STEMI) and left ventricular apical thrombus. Fibrinolysis and mechanical thrombectomy (MT) were discussed in all cases, but only one patient received alteplase (0.9 mg/kg) and none underwent MT. Percutaneous intervention (PCI) was done in only one case. The two patients that did not receive thrombolysis were treated with modified therapeutic heparin (no bolus), and all received antiplatelet therapy. Ultimately, all three patients passed away. CCI poses a clinical challenge for physicians including (1) optimal strategies to enable swift mechanical reperfusion to both the brain and myocardium; (2) difference in dosage of thrombolytics for AIS versus AMI; (3) risk of symptomatic intracerebral hemorrhage following administration of anticoagulation and/or antiplatelet therapy; and (4) caution with use of thrombolytics in the setting of acute STEMI due to the risk of myocardial rupture. In the absence of high quality evidence and clinical guidelines, treatment of CCI is highly individualized.", "affiliations": "Department of Neurology and Neurocritical Care, The Ohio State University, 395 West 12th Avenue, 7th Floor, Columbus, OH, 43210, USA. [email protected].;Department of Neurology and Neurocritical Care, The Ohio State University, 395 West 12th Avenue, 7th Floor, Columbus, OH, 43210, USA.;Department of Neurology and Neurocritical Care, The Ohio State University, 395 West 12th Avenue, 7th Floor, Columbus, OH, 43210, USA.", "authors": "Ibekwe\|Elochukwu\|E\|http://orcid.org/0000-0002-0339-6384;Kamdar\|Hera A\|HA\|;Strohm\|Tamara\|T\|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.1007/s10072-021-05628-x", "fulltext": null, "fulltext_license": null, "issn_linking": "1590-1874", "issue": null, "journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology", "keywords": "Acute ischemic stroke; Alteplase; Cardio-cerebral infarct; Cerebral ischemia; Myocardial infarct", "medline_ta": "Neurol Sci", "mesh_terms": null, "nlm_unique_id": "100959175", "other_id": null, "pages": null, "pmc": null, "pmid": "34590206", "pubdate": "2021-09-29", "publication_types": "D016428:Journal Article", "references": "32281601;23247304;24495655;11023929;24703066;27105568;28220330;31555206;20977759;31318627;15769776;31662037;31893142;22552166;16974058;29018137;28886621;842403;31277605;10475182;24363753;31327296;25692111;31971093;15956123;25306124;30484009;23151669;32829200;18715661;28302386;16505298;28450663;6465861;29270151;33530272;31436141;33045929;27333833;33446625;19608993", "title": "Cardio-cerebral infarction in left MCA strokes: a case series and literature review.", "title_normalized": "cardio cerebral infarction in left mca strokes a case series and literature review" }	[ { "companynumb": "US-BOEHRINGERINGELHEIM-2021-BI-130511", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "Unknown,ASKED BUT UNKNOWN,ASKED BUT", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.2 MG BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Acute myocardial infarction", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "Unknown,ASKED BUT UNKNOWN,ASKED BUT", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WITH INFUSION AT 28.7 MG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ischaemic stroke", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "Unknown,ASKED BUT UNKNOWN,ASKED BUT", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.9 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".9", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cerebrovascular accident", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.9%", "drugenddate": null, "drugenddateformat": null, "drugindication": "Oedema", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Ibekwe E, Kamdar H, Strohm T. Cardio-cerebral infarction in left MCA strokes: a case series and literature review. Neurological Sciences. 2021;:-.", "literaturereference_normalized": "cardio cerebral infarction in left mca strokes a case series and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211006", "receivedate": "20211006", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19925099, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" } ]
{ "abstract": "ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT.\n\n\n\nTwenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 ≤ age < 18; n = 10).\n\n\n\nThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection.\n\n\n\nABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases.", "affiliations": "Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.", "authors": "Honda\|Masaki\|M\|;Sugawara\|Yasuhiko\|Y\|;Kadohisa\|Masashi\|M\|;Shimata\|Keita\|K\|;Sakisaka\|Masataka\|M\|;Yoshii\|Daiki\|D\|;Uto\|Keiichi\|K\|;Hayashida\|Shintaro\|S\|;Ohya\|Yuki\|Y\|;Yamamoto\|Hidekazu\|H\|;Yamamoto\|Hirotoshi\|H\|;Inomata\|Yukihiro\|Y\|;Hibi\|Taizo\|T\|", "chemical_list": "D000017:ABO Blood-Group System; D005938:Glucocorticoids; D007518:Isoantibodies; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.1097/TP.0000000000002197", "fulltext": "\n==== Front\nTransplantationTransplantationTPTransplantation0041-13371534-6080Lippincott Williams & Wilkins TP50148210.1097/TP.000000000000219700025Original Clinical Science—LiverLong-term Outcomes of ABO-incompatible Pediatric Living Donor Liver Transplantation Honda Masaki MD, PhD1Sugawara Yasuhiko MD, PhD1Kadohisa Masashi MD1Shimata Keita MD1Sakisaka Masataka MD, PhD1Yoshii Daiki MD, PhD1Uto Keiichi MD1Hayashida Shintaro MD1Ohya Yuki MD, PhD1Yamamoto Hidekazu MD, PhD1Yamamoto Hirotoshi MD, PhD1Inomata Yukihiro MD, PhD1Hibi Taizo MD, PhD11 Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.Correspondence: Yasuhiko Sugawara, MD, PhD, Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. ([email protected]).10 2018 24 9 2018 102 10 1702 1709 2 10 2017 14 2 2018 17 2 2018 Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.2018Wolters Kluwer Health, Inc. All rights reserved.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Background\nABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT.\n\nMethods\nTwenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 ≤ age < 18; n = 10).\n\nResults\nThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection.\n\nConclusions\nABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases.\n\nThe authors of this single-center retrospective study demonstrate that ABO incompatible (ABOi) LDLT is a feasible option for pediatric end-stage liver disease patients by comparing the clinical outcomes between ABOi and non-ABOi pediatric LDLT recipients as well as assessing the safety and efficacy of a rituximab-based desensitization protocol. Supplemental digital content is available in the text.\n\n OPEN-ACCESSTRUESDCT\n==== Body\nLiver transplantation has been established as an effective treatment for end-stage liver disease. Although considerable progress of perioperative care and the refinement of surgical techniques have been achieved, chronic donor shortage has been a serious problem globally. In several countries, living donor liver transplantation (LDLT) remains a major modality because of the limited availability of deceased donor organs for sociocultural reasons. Furthermore, liver grafts from ABO-incompatible (ABOi) donors have been used to increase the possibilities of transplantation.1,2 Pediatric patients who suffer from liver disease are no exception to this issue.\n\nAdvanced strategies in ABOi LDLT through innovation of B-cell desensitization using intravenous immunoglobulin, intrahepatic portal and/or arterial infusion therapy, plasma exchange (PE), splenectomy, and anti-CD20 monoclonal antibody, rituximab have expanded the donor pool effectively over the last 2 decades.3-7 Indeed, recent studies using the induction of rituximab have demonstrated the dramatically improved survival rate in ABOi pediatric and adult LDLT.1,8-11 However, the incidence of antibody-mediated rejection (AMR) remains an issue that has not yet been completely resolved. In addition, several reports showed that concerns still remain in the incidence of high prevalence rates, such as biliary stricture and infectious complications.1,8,12\n\nTo date, few studies have reported the detailed B-cell desensitization protocol and long-term outcomes of ABOi pediatric LDLT in rituximab era. Therefore, safety and efficacy of the rituximab based protocol for ABOi pediatric LDLT are unclear. The aims of our single-center study are to analyze the long-term outcomes of pediatric patients who underwent ABOi LDLT and to assess the adequacy of the immunosuppressive protocol against the ABO-barrier.\n\nMATERIALS AND METHODS\nStudy Population\nBetween December 1998 and March 2016, 444 patients underwent 463 LDLT at Kumamoto University Hospital. Of these, 160 pediatric LDLT recipients younger than 18 years were analyzed retrospectively by reviewing the clinical records. Data were collected and analyzed in December 2016. All patients were of Asian ethnic origin. In the study population, 29 recipients underwent ABOi LDLT. The characteristics of study population are shown in Table 1. All our LDLT protocol received an approval from the institutional review committee. This study was performed according to the Ethical Guidelines for Clinical Research published on April 1, 2009, by the Ministry of Health, Labour and Welfare of Japan.\n\nTABLE 1 Patients characteristics (n = 160)\n\nSurgical Procedure\nThe transplant procedures in our institution have been described previously.13,14 Briefly, hepatic and portal veins were reconstructed under a surgical loupe, and hepatic arteries were reconstructed under a microscope. Duct-to-duct biliary reconstruction was a routine procedure except for the recipients with biliary atresia. Absolute indication of graft size reduction was that the estimated graft-to-recipient weight ratio (GRWR) was greater than 4.0%. Even if the preoperative GRWR was less than 4.0%, the reduction was considered to ensure a size match.\n\nBasic Immunosuppressive Regimen\nThe immunosuppressive regimen consisted of tacrolimus combined with low-dose steroids. The target trough levels of tacrolimus were between 10 and 15 ng/mL in the first 2 weeks, around 10 ng/mL in the next 2 weeks, and between 5 and 10 ng/mL thereafter. Steroids were initiated with an injection of 10 mg/kg of methylprednisolone before graft perfusion during surgery. Recipients received the intravenous injection of 1 mg/kg of methylprednisolone during postoperative day (POD) 1-3, 0.5 mg/kg during POD 4-6, and 0.3 mg/kg at POD 7. Subsequently, they were changed to oral administration of prednisolone and were tapered off until around 3 to 6 months. When acute cellular rejection (ACR) was suspected by a liver function test, patients were initially treated by increasing the dose of tacrolimus. If a liver function test showed no improvement or ACR as proven by liver biopsy, high-dose methylprednisolone (10 mg/kg) was administered at 3 days as a steroid pulse therapy and then the dose was tapered (over 7-10 days totally).\n\nImmunosuppressive Protocol for ABOi Pediatric LDLT\nWe have performed a total of 29 cases of ABOi pediatric LDLT, of which 10 cases were 2 years or older. A target trough level of tacrolimus was the same as that of non-ABOi cases as described above. Steroids were administered as same as non-ABOi cases until 1 month after LDLT, and tapered off taking twice as much time. Oral administration of mycophenolate mofetil (MMF) (10 mg/kg twice a day) was started POD 1. In patients younger than 2 years, preoperative PE was performed in 6 of 8 cases by 2010 to decrease the antidonor blood group antibody to less than 16, and in 11 cases since 2010, additional prophylaxis protocol was not performed (Figure 1). All of patients who were 2 years or older received single dose of rituximab 2 weeks before LDLT (3 of them received at different timings). The dose of rituximab was 300 mg/m2 for 1 patient, 375 mg/m2 for 6 patients, and 500 mg/body for 3 patients. Of these, the first consecutive three patients received additional B-cell desensitization using preoperative PE, infusion therapy, and splenectomy. From 2010, we have used a protocol without additional B-cell desensitization except for rituximab. Acetaminophen (10 mg/kg) and d chlorpheniramine maleate (0.04 mg/kg) were orally administered before administration of rituximab to prevent adverse events. The diagnosis of AMR was made based on the clinical course, immunological assays, and histopathological findings.15,16 C4d immunostaining was performed case by case if AMR was suspected.17\n\nFIGURE 1 Protocol of the pediatric ABOi LDLT at Kumamoto University Hospital.\n\nEvaluated Factors\nAs patient characteristics, clinical data including age at transplant, sex, primary disease, donor age, donor sex, graft type, GRWR, blood loss, cold ischemia time (CIT), warm ischemia time (WIT), and operation time were assessed. Moreover, incidence for bacterial infection, cytomegalovirus infection, fungal infection, vascular complication, biliary complication, ACR, AMR, and graft survival were compared between ABOi and non-ABOi LDLT group. Bacterial infection was defined as elevated inflammatory parameters accompanied by infected foci, and cytomegalovirus infection was evaluated by the antigenemia test. Fungal infection was diagnosed with identification in culture or image findings accompanied by the increase of β-d glucan. Vascular and biliary complications were defined as those requiring some intervention. Rituximab-treated group was further evaluated in detail including pediatric end-stage liver disease (PELD) score (under 12 years of age) or model for end-stage liver disease score, blood type combination, lymphocyte crossmatch test (flow cytometry), peak titer of Immunoglobulin M (IgM) and G (IgG) isoagglutinin against donor erythrocyte antigens at admission, at LDLT, and after transplantation, proportion of CD19+ lymphocyte cells (%) before rituximab treatment and at LDLT, and adverse events of rituximab treatment. The clinical course before and after AMR onset was described separately in detail.\n\nStatistical Analysis\nContinuous variables were expressed as mean values ± standard deviations. Statistical analysis was performed using the Mann-Whitney U test or Wilcoxon signed-rank test as appropriate for continuous data, whereas categorical variables were compared using either the χ2 test (without the Yates correction) or Fisher exact test as appropriate. The cumulative graft survival was estimated using the Kaplan-Meier product limit method. The log-rank (Mantel-Cox) test was used for comparison of the curves. A P value less than 0.05 was considered statistically significant; all tests were 2-tailed. All statistical analyses were performed using the GraphPad Prism 7 (GraphPad Software).\n\nRESULTS\nClinical Characteristics\nAmong 160 pediatric LDLT recipients, 29 recipients underwent ABOi LDLT (Table 1). The mean age at transplant was significantly lower in ABOi group (3.0 ± 5.2 years vs 4.6 ± 5.6 years, P = 0.040). The mean follow-up period was 60.6 ± 45.4 months in ABOi group and was 83.8 ± 55.6 months in non-ABOi group. The most common indication for ABOi LDLT was biliary atresia (51.7%). There were no significant differences in donor-related factors including donor age and sex between ABOi and non-ABOi groups. The most used graft type was left lateral (75.9%), and mean GRWR was 3.2 ± 3.9 in ABOi group. Operation-related factors including graft type, GRWR, CIT, WIT, operation time, and blood loss also showed no significant differences.\n\nPostoperative Outcomes and Graft Survivals\nThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and ACR between ABOi and non-ABOi group (Table 2). Meanwhile, 2 (6.9%) patients developed AMR in ABOi group but not in non-ABOi group (P = 0.036). Next, to elucidate the impact of rituximab treatment, we compared the clinical outcomes between rituximab-treated and non–rituximab-treated ABOi group. Rituximab-treated 10 patients were classified into 2 groups based on the additional B-cell desensitization protocol as described. Reflecting excessive immunosuppression, rituximab-treated ABOi group (until 2010, n = 3) showed a higher incidence of bacterial and fungal infection compared with rituximab-treated ABOi group (from 2010, n = 7) and non–rituximab-treated ABOi group (n = 19) (Table 3). The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, respectively, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively (P = 0.375, Figure 2A). Rituximab-treated ABOi group showed comparable graft survival rate (80.0%, 80.0%, 66.7% at 1, 3, and 5 years with a mean follow-up of 40.7 ± 27.4 months) compared with the non-ABOi and non–rituximab-treated ABOi group (P = 0.328, Figure 2B). During the study period, mortality rate in non–rituximab-treated ABOi group was 15.8%, and in rituximab-treated ABOi group was 30.0%. The cause of death in the former group was heart failure (in related to the primary disease, glycogen storage disease type IV), pulmonary hypertension (in related to the primary disease, mitochondrial DNA depletion syndrome), and interstitial pneumonia (Table S1, SDC,\nhttp://links.lww.com/TP/B555). The cause of death in the latter group was AMR in 2 patients and the other was multiple organ failure related to complications of the primary disease (progressive familial intrahepatic cholestasis type 1 [PFIC1]) including bleeding from the ileostomy, severe malnutrition, and chronic renal failure.18\n\nTABLE 2 Clinical outcomes between ABOi and non-ABOi group\n\nTABLE 3 Clinical outcomes between rituximab-treated and non–rituximab-treated ABOi group\n\nFIGURE 2 Cumulative graft survival rate of pediatric LDLT recipients. (A) Comparison between ABOi and non-ABOi group. Log-rank test, P = 0.375. (B) Comparison between ABOi (age < 2), ABOi (2 ≤ age < 18), and non-ABOi group. Log-rank test, P = 0.328.\n\nSafety and Efficacy of Rituximab for ABOi Pediatric LDLT\nTo analyze the detailed clinical course in related to the rituximab administration for pediatric patients, we reviewed the 10 rituximab-treated ABOi LDLT recipients whose age was 2 years or older (Table 4). Mean age at LDLT was 8.6 ± 5.5 and male-female ratio was equivalent. The most common indication for rituximab-treated ABOi LDLT was graft failure (40.0%). The original disease was PFIC1 in case 2 (104 months from first LDLT), acute liver failure in case 3 (36 months from first LDLT), and biliary atresia in cases 8 and 10 (163 and 192 months from first LDLT, respectively). The cause of graft failure was chronic rejection in cases 2, 3, 8, and unknown in case 10. Cases 1 to 3 had received PE and splenectomy and/or infusion therapy during the perioperative period. The lymphocyte crossmatch test was positive for T and B cells in case 1, and for B cells in cases 5 and 10. The median titers of IgM and IgG isoagglutinin at LDLT were 1:16 (1:1–1:256), 1:8 (1:1–1:256), respectively. CD19+ lymphocyte counts were decreased significantly after rituximab administration (24.9 ± 9.8% to 0.49 ± 0.46%, P < 0.001). Case 2 experienced rebound elevation of the CD19+ lymphocyte counts (19.4%) and received 375 mg/m2 rituximab 10 days after LDLT. When rituximab was administered, 1 case of headache, rash, cough was observed, but both of symptoms were mild, and it was not necessary to stop the treatment. In addition, although significant elevation of body temperature was observed after rituximab treatment (36.7 ± 0.4°C to 37.6 ± 0.4°C, P < 0.001), which improved promptly within 1 day.\n\nTABLE 4 Detailed outcomes of rituximab-treated ABOi pediatric LDLT patients\n\nIn rituximab-treated group, 2 patients (cases 1 and 9) developed AMR. In case 1, both T and B were positive in the preoperative lymphocyte crossmatch test. Although the elevation of antidonor type IgM and IgG could not be observed after LDLT, the patient repeated cholangitis from the early stage of posttransplant and showed the distinctive AMR phenotype with intrahepatic biliary complications. The patient received high-dose intravenous immunoglobulin administration and percutaneous transhepatic biliary drainage against multiple biloma, however eventually died of graft failure 5 months after LDLT. As previously reported, case 9 developed streptococcal infection 13 days after rituximab, and LDLT was postponed.19 CD19+ lymphocyte count decreased to 0.1% at 9 days after rituximab administration, but the number just before LDLT increased to 1.2%. The patient showed an increased ascites, a marked increase of hepatic enzyme levels, and decreased platelet levels on POD 5. Both of the IgM and IgG antidonor antibody titers increased to 1:1024, and the CD19+ lymphocyte count increased to 4.1%. The liver histology showed hepatocyte ballooning, portal inflammation, sinusoidal congestion, and complement component 4d positivity in the vascular endothelium. Therefore, in this case, it was speculated that streptococcal infection resulted in reactivation of B cells, which might make a foothold to trigger AMR. Despite treatment with PE, intravenous immunoglobulin, steroid pulse therapy, and readministration of rituximab, the patient died with graft failure accompanied by renal failure and acute respiratory distress syndrome 1 month after LDLT.\n\nDISCUSSION\nIn Japan, ABOi grafts have been used in 13.8% of pediatric LDLT from 1989 to 2013.20 Thus, even in pediatric patients, ABOi LDLT has been implemented as an important option to compensate for the shortage of donors. In our institution, 18.1% of pediatric LDLT was performed using ABOi grafts and their clinical outcomes and graft survival were comparable to non-ABOi grafts. We evaluated the clinical outcomes and the adequacy of the immunosuppressive protocol in ABOi pediatric LDLT.\n\nPrevious literatures have reported that infants show better outcomes in ABOi LT.2,21 One possible reason is the different immune responses of infants to ABOi graft. Infants do not produce isohemagglutinins, therefore, their anti-A and -B antibody titers remain low levels in early childhood.22 Additionally, the activation of complement system is suppressed in infants.23 Taken together, infants have less mediators in related to the AMR. In accordance with these mechanisms, ABOi pediatric LDLT recipients who are younger than 2 years in our study cohort did not develop AMR. Therefore, we believe that it is unnecessary to use rituximab in ABOi pediatric LDLT younger than 2 years.\n\nWe have used the rituximab-based protocol in 10 pediatric ABOi LDLT recipients for B-cell desensitization. The pretransplant therapy could be performed safely without severe adverse events and reduced their CD19+ lymphocyte counts effectively just before LT. However, regardless of the desensitization, we experienced 2 cases (cases 1 and 9) of AMR. Case 1 developed the distinctive AMR phenotype with intrahepatic biliary complications without the elevation of anti-donor type IgM and IgG. Characteristically, case 1 had shown positive lymphocyte crossmatch for T and B cells before LDLT. Importantly, Hori et al24 have shown that a positive lymphocyte crossmatch has a negative impact on LDLT possibly because of the wide expression of HLA antigens. As such background might affect clinical course of case 1, advanced immunological strategies must be considered for lymphocyte crossmatch-positive recipients. Case 9 showed specific clinical course suggesting the streptococcal infection after rituximab administration resulted in reactivation of B cells, which might trigger AMR.19 In the light of experience, we think that additional desensitization therapy should be considered if the reactivation of B cells is suspected before ABOi LDLT.\n\nPlasmapheresis is a standard procedure to reduce donor specific antibody titers, but the titer required to prevent AMR is not defined. Egawa et al1 observed no significant relationships between plasmapheresis and clinical outcomes after ABOi adult LDLT from a Japanese multicenter study. The study also revealed that local infusion, splenectomy, antilymphocyte antibody, and intravenous immunoglobulin had no significant impact on overall survival or AMR incidence in rituximab-treated ABOi LDLT recipients. As these results indicate, we believe that the most important key to prevent AMR in ABOi LT is inhibition of new antibody production. Additionally, the procedure, such as catheter insertion for local infusion, or splenectomy increases the risk of bleeding and infection. Based on this policy, we have used a protocol based on the administration of rituximab (patients who were 2 years or older), tacrolimus, steroids, and MMF without PE, local infusion, and splenectomy since 2010 in ABOi LDLT.25\n\nFrom the viewpoint of rituximab dose, it is widely accepted that a single maximum dose of rituximab with efficacy and safety is 375 mg/m2 for the B-cell lymphoma treatment.26 Recently, Egawa et al27 suggested that the dose in 300 mg/m2 or less of rituximab single administration would be insufficient for prevention of AMR in ABOi adult LDLT. Indeed, 1 patient who had received 300 mg/m2 of rituximab showed rebound elevation of the CD19+ lymphocyte counts after LDLT in our study cohort. Thus, the use of rituximab at sufficient dose is recommended, whereas it is worth mentioning that careful attention must be paid to the prevention of infectious diseases.\n\nThe optimal treatment strategy for AMR after LDLT remains unclear so far. Based on a combination of calcineurin inhibitor, corticosteroid, plasmapheresis, and B cell–modulating therapies, use of thymoglobulin is also considered as an option to disrupt key T-cell and B-cell interactions.28 In addition, in some cases, AMR can be induced by isohemagglutinin production from plasma cells which do not express CD20. In such a case, treatment with bortezomib, which is a proteasome inhibitor, can be considered as another option.29,30 Recently, eculizumab, which is a monoclonal antibody that blocks the complement pathway, is successfully used for the treatment of AMR after pediatric LT.31 In this report, eculizumab was used for recipient showing refractory AMR associated with C1q-binding donor specific antibody. Of course, retransplantation that does not miss the time should always be considered.\n\nThe precise role of donor-specific antibodies (DSA) after LT is unclear, whereas evidence is increasing that DSA, especially those with higher mean fluorescence intensity, are associated with both acute and chronic liver allograft rejections.32-35 In our study cohort, case 1 in rituximab-treated ABOi group developed AMR which did not seem to be involved in antiblood type antibodies, therefore, involvement of DSA should be taken into consideration as the cause of AMR. For the impact of DSA on humoral immunity in post-LT follow-up, more detailed investigation will be needed, including intervention of immunosuppressive protocols. It is also worth noting that detrimental aspect of DSA might differ between deceased donor LT and LDLT.36\n\nIt has been well accepted that hypogammaglobulinemia is a crucial risk factor for development of infection.37 As a reminder, rituximab and immunosuppressive drugs, such as steroids and MMF, are known to induce iatrogenic hypogammaglobulinemia. Although ABOi pediatric LDLT recipients did not develop the recurrent infections related low IgG levels in our cohort, serum IgG levels, in particular, rituximab-treated ABOi LDLT recipients, should be monitored at least until the recovery of B cells. Proper IgG supplementation has to be done in case a serum IgG level is below 500 mg/dL with recurrent or severe infections.\n\nOur study has some limitations. First, it was a retrospective single-center cohort study of a relatively small patient population. However, we believe that the data from our cohort are reliable because the treatment practices, immunosuppressive strategy, and surgical techniques are standardized. Prospective and multicenter studies are needed to clarify the feasibility of our protocol. Second, the observation period in ABOi group, in particular in rituximab-treated group, is shorter compared with the non-ABOi group. This difference is affected by the time of approval of rituximab, but we believe that an observation period of over 40 months on average is sufficient to evaluate the long-term posttransplant outcomes. Third, our study population does not contain acute liver failure patients in rituximab-treated group. The timing of rituximab administration is known to be related to the rebound elevation of isohemagglutinin titers,38 therefore, further investigation will be needed to detect the minimal time interval from rituximab administration to ABOi LDLT.\n\nIn conclusion, ABOi LDLT is a feasible option for PELD patients. Rituximab-based protocol is a promising procedure for preventing AMR in ABOi pediatric LDLT recipients who are 2 years or older. However, we need to keep in mind that the current protocol does not completely prevent the onset of AMR in several cases, and further research is required in the future.\n\nSupplementary Material\nSUPPLEMENTARY MATERIAL\n The authors declare no funding or conflicts of interest.\n\nM.H., Y.S., H.Y, and Y.I. participated in the study concept and design, analysis and interpretation of data, and critical revision of the article. M.H., M.K., S.K., M.S., D.Y., K.U., S.H., Y.O., H.Y., and H.Y. participated in data collection. M.H., T.H., and Y.S. participated in the writing of the article.\n\nSupplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).\n==== Refs\nREFERENCES\n1 Egawa H Teramukai S Haga H \nImpact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study . Am J Transplant . 2014 ;14 :102 –114 .24279828 \n2 Stewart ZA Locke JE Montgomery RA \nABO-incompatible deceased donor liver transplantation in the United States: a national registry analysis . Liver Transpl . 2009 ;15 :883 –893 .19642117 \n3 Tanabe M Shimazu M Wakabayashi G \nIntraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation . 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Liver Transpl . 2007 ;13 :579 –588 .17394164\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0041-1337", "issue": "102(10)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D001402:B-Lymphocytes; D001787:Blood Group Incompatibility; D002648:Child; D002675:Child, Preschool; D058625:End Stage Liver Disease; D005240:Feasibility Studies; D005260:Female; D005938:Glucocorticoids; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D007518:Isoantibodies; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "0132144", "other_id": null, "pages": "1702-1709", "pmc": null, "pmid": "29620615", "pubdate": "2018-10", "publication_types": "D016428:Journal Article", "references": "24279828;28002655;20096431;26887781;26372830;14966415;22410063;25538710;17929298;28938311;28583540;16048608;16498648;10071029;19642117;26896194;23293980;28060025;4432260;2333747;21672151;25689881;17394164;12131697;26038872;27273869;22681986;24801413;14755773;27597379;23928408;27436684;27016995;11133748;19667930;21342448;20477975;27570428", "title": "Long-term Outcomes of ABO-incompatible Pediatric Living Donor Liver Transplantation.", "title_normalized": "long term outcomes of abo incompatible pediatric living donor liver transplantation" }	[ { "companynumb": "JP-TEVA-2018-JP-977186", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "36 DAYS PRIOR TO LDLT", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING POST-OPERATIVE DAY 4-6", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090402", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IMMUNE GLOBULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNE-GLOBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG DAILY; ON POST-OPERATIVE DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING POST-OPERATIVE DAY 1-3", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT POST-OPERATIVE DAY 7", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HONDA M, SUGAWARA Y, KADOHISA M, SHIMATA K, SAKISAKA M, YOSHII D, ET AL. LONG-TERM OUTCOMES OF ABO-INCOMPATIBLE PEDIATRIC LIVING DONOR LIVER TRANSPLANTATION. TRANSPLANTATION 2018?102(10):1702-1709.", "literaturereference_normalized": "long term outcomes of abo incompatible pediatric living donor liver transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181121", "receivedate": "20181121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15642367, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "JP-TEVA-2018-JP-977185", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING POST-OPERATIVE DAY 1-3", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "POST-OPERATIVE DAY 7", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "365", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG DAILY; ON POST-OPERATIVE DAY 1", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IMMUNE GLOBULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSES WERE ADMINISTERED", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNE-GLOBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING DAY 4-6", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090402", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transplant failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HONDA M, SUGAWARA Y, KADOHISA M, SHIMATA K, SAKISAKA M, YOSHII D, ET AL. LONG-TERM OUTCOMES OF ABO-INCOMPATIBLE PEDIATRIC LIVING DONOR LIVER TRANSPLANTATION. TRANSPLANTATION 2018?102(10):1702-1709.", "literaturereference_normalized": "long term outcomes of abo incompatible pediatric living donor liver transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20181121", "receivedate": "20181121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15642366, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "A 42-year-old woman underwent renal transplantation in 200X. After the transplant, she received tacrolimus as immunosuppressant therapy. Eleven years after the transplant, diffuse large B-cell lymphomas were detected in the duodenum and terminal ileum. Wireless capsule endoscopy (WCE) revealed multiple lymphoma lesions in the entire small intestine. The patient achieved complete response through the administration of R-CHOP therapy and discontinuation of immunosuppressant therapy. Post-transplant lymphoproliferative disorder (PTLD) is a rare complication and WCE may be useful for diagnosing PTLD of the small intestine.", "affiliations": "Department of Gastroenterology, Oita University Hospital.", "authors": "Sonoda\|Akira\|A\|;Katsuta\|Makoto\|M\|;Yada\|Mika\|M\|;Mizukami\|Kazuhiro\|K\|;Okamoto\|Kazuhisa\|K\|;Ogawa\|Ryo\|R\|;Okimoto\|Tadayoshi\|T\|;Kodama\|Masaaki\|M\|;Murakami\|Kazunari\|K\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11405/nisshoshi.112.729", "fulltext": null, "fulltext_license": null, "issn_linking": "0446-6586", "issue": "112(4)", "journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology", "keywords": null, "medline_ta": "Nihon Shokakibyo Gakkai Zasshi", "mesh_terms": "D000328:Adult; D053704:Capsule Endoscopy; D005260:Female; D006801:Humans; D007410:Intestinal Diseases; D007421:Intestine, Small; D016030:Kidney Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D011183:Postoperative Complications", "nlm_unique_id": "2984683R", "other_id": null, "pages": "729-35", "pmc": null, "pmid": "25843462", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of lymphoproliferative disorder in the entire small intestine after renal transplantation detected by wireless capsule endoscopy.", "title_normalized": "a case of lymphoproliferative disorder in the entire small intestine after renal transplantation detected by wireless capsule endoscopy" }	[ { "companynumb": "GXJP2015JP000856", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040194", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4.5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "42", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "158.3", "reaction": [ { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diffuse large B-cell lymphoma stage IV", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AKIRA SONODA, MAKOTO KATSUTA, MIKA YADA, KAZUHIRO MIZUKAMI, KAZUHISA OKAMOT ET AL.. A CASE OF LYMPHOPROLIFERATIVE DISORDER IN THE ENTIRE SMALL INTESTINE AFTER RENAL TRANSPLANTATION DETECTED BY WIRELESS CAPSULE ENDOSCOPY. JOURNAL OF JAPANESE SOCIETY OF GASTROENTEROLOGY. 2015;112:729-735", "literaturereference_normalized": "a case of lymphoproliferative disorder in the entire small intestine after renal transplantation detected by wireless capsule endoscopy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150622", "receivedate": "20150622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11209480, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "BACKGROUND\nRadioactive iodine-131 (RAI) is an established treatment for patients with Graves' hyperthyroidism. RAI is reported to be associated with a 20-30% incidence of development or exacerbation of Graves' ophthalmopathy (GO). This study compares the progression of GO in patients who had evidence or no evidence of GO before RAI therapy.\n\n\nMETHODS\nForty-eight patients were studied. One group had no evidence whereas the other group had evidence of GO before RAI treatment. All underwent RAI therapy. Group A (27 patients, 18 women, nine men, age: 19-68 with a mean of 49 years) had pre-existing exophthalmos. Group B consisted of 21 patients (13 women, eight men, age: 30-63 with a mean of 43 years) developed exophthalmos after treatment. All patients underwent RAI therapy and followed by ophthalmologists.\n\n\nRESULTS\nThe average administered dose in group A was 24.3 mCi (range: 10-36.2 mCi) compared with group B: 25.4 mCi (range: 13-35.9 mCi), P=0.60. Ten (37%) of the 27 patients in group A experienced worsening of symptoms post-treatment. There was no significant difference between the administered dose of RAI in patients with worsening symptoms, 25.1 mCi versus patients with stable symptoms, 24.5 mCi (P=0.82). However, group A developed GO symptoms earlier than group B (4.5 vs. 9.5 months), P=0.02.\n\n\nCONCLUSIONS\nRAI is known to exacerbate ophthalmopathy. Our study showed it was not dose-dependent. Patients without a previous history of GO were observed to have a significantly delayed period for the development of symptoms.", "affiliations": "Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.;Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.;Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.;Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.;Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.", "authors": "Khiyani\|Neeraj\|N\|;Dadparvar\|Simin\|S\|;Gish\|Aaron\|A\|;Intenzo\|Charles M\|CM\|;Malmud\|Leon S\|LS\|", "chemical_list": "D007457:Iodine Radioisotopes; C000614965:Iodine-131", "country": "England", "delete": false, "doi": "10.1097/MNM.0000000000001008", "fulltext": null, "fulltext_license": null, "issn_linking": "0143-3636", "issue": "40(5)", "journal": "Nuclear medicine communications", "keywords": null, "medline_ta": "Nucl Med Commun", "mesh_terms": "D000328:Adult; D000368:Aged; D004307:Dose-Response Relationship, Radiation; D005260:Female; D049970:Graves Ophthalmopathy; D006801:Humans; D006980:Hyperthyroidism; D015994:Incidence; D007457:Iodine Radioisotopes; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "8201017", "other_id": null, "pages": "455-460", "pmc": null, "pmid": "30855542", "pubdate": "2019-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Does the dose of iodine-131 influence the incidence of Graves' ophthalmopathy?", "title_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy" }	[ { "companynumb": "US-CURIUM-201900190", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. 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DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338091, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-CURIUM-201900191", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338101, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-CURIUM-201900189", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338093, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]
{ "abstract": "Long-term outcome of ustekinumab in Crohn's disease (CD) has not been evaluated.\n\n\n\nTo evaluate the long-term efficacy and safety of ustekinumab and identify the predictive factors of ustekinumab failure-free persistence in a cohort of anti-TNF refractory CD patients.\n\n\n\nWe performed a retrospective multicentre cohort study including all consecutive CD patients who began subcutaneous ustekinumab and presented a clinical response (defined as a significant improvement of CD-related clinical symptoms assessed by the patient's physician leading to continued ustekinumab) during the first year of treatment. Primary outcome was treatment failure defined as withdrawal of treatment due to loss of response, intolerance or need for surgery.\n\n\n\nEighty-eight of the 122 (72%) CD patients beginning ustekinumab from March 2011 to December 2014, responded to ustekinumab and were followed up until November 2016. Median time on ustekinumab was 26.6 (13.4-34.4) months. Forty-seven patients (54%) continued ustekinumab with a clinical response and 38 (43%) stopped treatment (32 for failure, five for remission and one for pregnancy). Endoscopic response was observed in 82% of patients with endoscopic evaluation and mucosal healing in 39%. Ustekinumab failure-free persistence rates were 78% at 12 months, 66% at 24 months and 55% at 36 months. No predictive factor of ustekinumab failure-free persistence was identified. One severe adverse event was observed (anal adenocarcinoma).\n\n\n\nIn this cohort of refractory CD patients receiving long-term ustekinumab therapy, more than 50% of patients continued ustekinumab treatment with no loss of response, intolerance or surgery and with a good safety profile.", "affiliations": "Lille, France.;Clichy, France.;Lausanne, Switzerland.;Lyon, France.;Reims, France.;Paris, France.;Paris, France.;Strasbourg, France.;Marseille, France.;Clermont-Ferrand, France.;Créteil, France.;Amiens, France.;Saint Etienne, France.;Nancy, France.;Nice, France.;Rennes, France.;Paris, France.;Colombes, France.;Paris, France.;Bordeaux, France.;Lille, France.", "authors": "Wils\|P\|P\|;Bouhnik\|Y\|Y\|;Michetti\|P\|P\|0000-0003-4982-7327;Flourie\|B\|B\|;Brixi\|H\|H\|;Bourrier\|A\|A\|;Allez\|M\|M\|;Duclos\|B\|B\|;Serrero\|M\|M\|;Buisson\|A\|A\|0000-0002-6347-409X;Amiot\|A\|A\|0000-0001-6676-1222;Fumery\|M\|M\|;Roblin\|X\|X\|0000-0002-7929-4878;Peyrin-Biroulet\|L\|L\|0000-0003-2536-6618;Filippi\|J\|J\|;Bouguen\|G\|G\|0000-0002-7444-5905;Abitbol\|V\|V\|;Coffin\|B\|B\|;Simon\|M\|M\|;Laharie\|D\|D\|0000-0002-4753-6676;Pariente\|B\|B\|0000-0003-1442-0244;\|\|\|", "chemical_list": "D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab", "country": "England", "delete": false, "doi": "10.1111/apt.14487", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "47(5)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003424:Crohn Disease; D004351:Drug Resistance; D004724:Endoscopy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D011247:Pregnancy; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab", "nlm_unique_id": "8707234", "other_id": null, "pages": "588-595", "pmc": null, "pmid": "29315694", "pubdate": "2018-03", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Long-term efficacy and safety of ustekinumab in 122 refractory Crohn's disease patients: a multicentre experience.", "title_normalized": "long term efficacy and safety of ustekinumab in 122 refractory crohn s disease patients a multicentre experience" }	[ { "companynumb": "FR-JNJFOC-20180307561", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "USTEKINUMAB" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "761044", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": "201412", "drugenddateformat": "610", "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "USTEKINUMAB" } ], "patientagegroup": "5", "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Anal cancer", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILS P, BOUHNIK Y, MICHETTI P, FLOURIE B, BRIXI H, BOURRIER A, ET AL. LONG-TERM EFFICACY AND SAFETY OF USTEKINUMAB IN 122 REFRACTORY CROHN^S DISEASE PATIENTS: A MULTICENTRE EXPERIENCE. ALIMENTARY PHARMACOLOGY + THERAPEUTICS MAR-2018?47 (5):588-595.", "literaturereference_normalized": "long term efficacy and safety of ustekinumab in 122 refractory crohn s disease patients a multicentre experience", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20180309", "receivedate": "20180309", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14620514, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "BACKGROUND\nThe antiphospholipid syndrome is an acquired autoimmune thrombophilia, characterized by arterial and/or venous thrombosis. Rarely, this condition can have a catastrophic presenta tion, with high mortality, and presence of microangiopathy and involvement of three or more organs.\n\n\nOBJECTIVE\nTo describe the clinical presentation and evolution of a pediatric patient with catastrophic antiphospholipid syndrome, with a seronegative onset form, whose response to aggressive therapy was favorable.\n\n\nMETHODS\nAdolescent female, with a one-week history of pain, increased abdo minal volume and edema in the lower extremities. Generalized lupus erythematosus was diagnosed and the neoplastic process was ruled out. During its evolution, she presented various thrombotic events, initially with the presence of negative antiphospholipid antibodies, which were subsequently positive. The patient presented multisystemic failure secondary to multiorgan thrombosis, required hemodynamic and ventilatory support. It was managed with low molecular weight heparin, plas mapheresis, anticoagulation, immunosuppression and boluses of rituximab with excellent response.\n\n\nCONCLUSIONS\nWe consider this case interesting because it is an infrequent diagnosis in the pediatric age and whose suspicion, timely and aggressive intensive management, can change the poor progno sis and high mortality of these patients.", "affiliations": "Servicio de Medicina Interna Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Medicina Interna Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Banco de Sangre, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Hematología Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Medicina Interna Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.", "authors": "Vargas-Quevedo\|Ericka\|E\|;Ordoñez-Gutiérrez\|Eduardo\|E\|;Trejo-Gómora\|Jorge Enrique\|JE\|;Chávez-Aguilar\|Lénica Anahí\|LA\|;Peña-Vélez\|Rubén\|R\|", "chemical_list": "D017152:Antibodies, Antiphospholipid; D015415:Biomarkers", "country": "Chile", "delete": false, "doi": "10.4067/S0370-41062018000200236", "fulltext": null, "fulltext_license": null, "issn_linking": "0370-4106", "issue": "89(2)", "journal": "Revista chilena de pediatria", "keywords": null, "medline_ta": "Rev Chil Pediatr", "mesh_terms": "D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D015415:Biomarkers; D002648:Child; D005260:Female; D006801:Humans", "nlm_unique_id": "0404261", "other_id": null, "pages": "236-240", "pmc": null, "pmid": "29799892", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "\"Seronegative\" catastrophic antiphospholipid syndrome in pediatrics: Clinical case.", "title_normalized": "seronegative catastrophic antiphospholipid syndrome in pediatrics clinical case" }	[ { "companynumb": "MX-NOVAST LABORATORIES, LTD-MX-2018NOV000284", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040832", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL\\ASPIRIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G/24 HOUR", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ASPIRIN\\CARISOPRODOL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040832", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARISOPRODOL\\ASPIRIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ENOXAPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN SODIUM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VARGAS?QUEVEDO E, ORDONEZ?GUTIERREZ E, TREJO?GOMORA JE, CHAVEZ?AGUILAR LA, PENA?VELEZ R.. ^SERONEGATIVE^ CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME IN PEDIATRICS: CLINICAL CASE. REV?CHILE?PED. 2018?89(2):236?240", "literaturereference_normalized": "seronegative catastrophic antiphospholipid syndrome in pediatrics clinical case", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180807", "receivedate": "20180807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15249069, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "MX-TEVA-2018-MX-909382", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DABIGATRAN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, 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{ "abstract": "BACKGROUND\nPsoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors.\n\n\nMETHODS\nA 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis.\n\n\nCONCLUSIONS\nPatients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.", "affiliations": "Department of Neurology, University of California, San Francisco, California, USA. [email protected].;Division of Neuropathology, Department of Pathology, University of California, San Francisco, California, USA.;Division of Neuropathology, Department of Pathology, Duke University, Durham, North Carolina, USA.;Division of Neuropathology, Department of Pathology, University of California, San Francisco, California, USA.;Department of Neurology, Salinas Valley Memorial Healthcare System, Salinas, California, USA.;Department of Neurology, University of California, San Francisco, California, USA.;Department of Neurology, University of California, San Francisco, California, USA.;Department of Neurology, University of California, San Francisco, California, USA.", "authors": "Fan\|Joline M\|JM\|;Solomon\|David A\|DA\|;López\|Giselle Y\|GY\|;Hofmann\|Jeffrey W\|JW\|;Colorado\|Rene A\|RA\|;Kim\|Anthony S\|AS\|;Meisel\|Karl\|K\|;Halabi\|Cathra\|C\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12883-020-01681-9", "fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1681\n10.1186/s12883-020-01681-9\nCase Report\nCatastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report\nFan Joline M. [email protected] 1 Solomon David A. 2 López Giselle Y. 3 Hofmann Jeffrey W. 2 Colorado Rene A. 4 Kim Anthony S. 1 Meisel Karl 1 Halabi Cathra 15 1 grid.266102.10000 0001 2297 6811Department of Neurology, University of California, San Francisco, California USA \n2 grid.266102.10000 0001 2297 6811Division of Neuropathology, Department of Pathology, University of California, San Francisco, California USA \n3 grid.26009.3d0000 0004 1936 7961Division of Neuropathology, Department of Pathology, Duke University, Durham, North Carolina USA \n4 grid.430059.bDepartment of Neurology, Salinas Valley Memorial Healthcare System, Salinas, California USA \n5 grid.266102.10000 0001 2297 6811Weill Institute for Neurosciences, University of California, San Francisco, California USA \n21 3 2020 \n21 3 2020 \n2020 \n20 1062 9 2019 10 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nPsoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors.\n\nCase presentation\nA 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis.\n\nConclusion\nPatients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.\n\nKeywords\nAtherosclerosisStrokePsoriasisPsoriatic arthritisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPsoriasis is a common chronic inflammatory disorder affecting approximately 1.5–3% of the adult population [1, 2]. An additional 6–30% of patients with psoriasis also have psoriatic arthritis, which may reflect a more pronounced systemic disease [3–5]. Population cohort studies have identified both psoriasis and psoriatic arthritis to be individual risk factors for vascular disease [4–7]; however, the contribution of comorbid inflammatory diseases for clinical screening and management guidelines remains unknown. Here, we present an illustrative report of a fatal stroke in a young patient with severe psoriasis, psoriatic arthritis, and metabolic syndrome.\n\nCase presentation\nA 49 year-old Caucasian woman with psoriasis, psoriatic arthritis, multivessel coronary artery disease, hypertension, subclinical hypothyroidism, and diabetes mellitus presented with bilateral lower extremity weakness and severe anemia. Regarding her history of psoriasis, she initially developed diffuse psoriatic plaques and axial psoriatic arthritis at age 19. Her first severe psoriasis flare occurred at age 29. Chart review did not reveal recorded Psoriasis Area and Severity Index (PASI) scores but there was documentation of erythema and pustular psoriasis measured over 70% of her body surface area with elevated white blood cell count. Despite treatment with prednisone and acitretin, after 1 year she developed severe cutaneous flares of pustular psoriasis measuring up to 90% of total body surface area with spared regions in her legs, necessitating multiple hospitalizations. Her treatment was escalated to Geockerman therapy, methotrexate, and topical steroids, in addition to prednisone and acitretin. In subsequent years, her chronic psoriatic skin manifestations involved roughly 30% of her total body surface area, meeting criteria for severe psoriasis, and these skin manifestations were managed primarily with topical steroids. Plain films ultimately revealed active inflammatory spondylitis. Despite recommendations to start disease modifying therapy, the patient declined further treatment.\n\nSix years prior to the most recent presentation, the patient was diagnosed with metabolic syndrome. Risk factors measured at the time of diagnosis included a peak hemoglobin A1c level of 11.6%, body mass index of 36, triglycerides of 310, high density lipoprotein (HDL) of 34, and systolic blood pressures routinely measured between 140 and 160. For her modifiable risk factors of diabetes, dyslipidemia, and hypertension, she was prescribed insulin, statins, and antihypertensive agents, respectively. Her family history was notable for ischemic stroke in her mother though of unknown etiology and age. There were no known inflammatory disorders in the family. Three months prior to the most recent presentation, the patient was hospitalized for a non-ST elevation myocardial infarction (NSTEMI). Cardiac catheterization revealed severe right coronary artery (RCA) disease and in-stent thrombosis of a pre-existing stent within the left circumflex artery placed 6 years prior. She underwent re-stenting for her left circumflex artery and RCA and was subsequently treated with a dual antiplatelet therapy regimen with aspirin and clopidogrel.\n\nSubsequently, she presented with subacute bilateral lower extremity weakness and confusion. Her brain MRI revealed acute bilateral watershed infarcts, in addition to subacute left parietal and frontal gyrus infarcts. CT angiography of the head and neck revealed diffuse atherosclerotic plaques in the aortic arch and carotid bulbs, occlusion of the left internal carotid artery (ICA), and narrowing of the bilateral M1 segments of the middle cerebral artery (MCA). (Fig. 1a-c). There was reconstitution of flow in the left cavernous and supraclinoid segments of the ICA via an intact Circle of Willis. In addition to the bilateral MCA narrowing, there was mild narrowing of the right carotid artery and a single diminutive A1 segment which perfused bilateral anterior cerebral arteries (ACA) vessels.\nFig. 1 a Diffusion-weighted axial MRI showing bilateral anterior cerebral artery (ACA) and middle cerebral artery (MCA) distribution infarcts. b CTA axial MIP demonstrating mild irregular luminal narrowing of the right M1 segment and severe focal narrowing of the distal left M1 segment. c CTA sagittal MIP demonstrating calcified atherosclerotic plaque of the left carotid bulb and complete occlusion of the proximal cervical left internal carotid artery. d Diffusion-weighted axial MRI showing marked interval progression of infarcts involving the bilateral ACA and left MCA distributions\n\n\n\nThere were no known preceding hemodynamic changes or systemic illnesses. Possible etiologies of her multifocal infarcts included severe atherosclerosis and related artery-artery thromboembolic events, cardioembolic events, hypercoagulable state, infection, or vasculitis. Cardiac rhythm telemetry did not reveal atrial fibrillation. Transthoracic echocardiogram revealed normal left ventricular function, normal left and right atrial size, no thrombus, and no intra- or extra-cardiac shunt. Subsequent transesophageal echocardiogram (TEE) again did not reveal thrombus or valvular lesions. The TEE also demonstrated atheromatous plaque in the proximal descending aorta greater than 4 mm in thickness. Laboratory studies included hemoglobin (Hg) of 4.2 g/dL, an elevated erythrocyte sedimentation rate > 100 mm/hr. (normal 0–15 mm/hr) and lipoprotein (a) 133 nmol/L (normal < 75 nmol/L) but were otherwise unrevealing (Table 1). The cerebral spinal fluid (CSF) did not have infectious or inflammatory properties. Workup of anemia was consistent with alpha thalassemia and severe iron deficiency, also supported by peripheral blood smear.\nTable 1 Summary of serum and CSF studies obtained on present hospitalization\n\n\tData\tReference\t\nLipid profile\t\n Cholesterol, Total\t179\t< 200 mg/dL\t\n Triglycerides\t253\t< 200 mg/dL\t\n LDL\t114\t< 130 mg/dL\t\n Lipoprotein a\t133\t< 75 nmol/L\t\nHypercoagulation\t\n Beta-2-glycoprotein Antibody, IgG\t< 10.0\t< 20.1 CU\t\n Beta-2-glycoprotein Antibody, IgM\t< 5.0\t< 20.1 CU\t\n Protein C, Activity\t99\t76–146%\t\n Anti-Cardiolipin Antibody, IgG\t15.8\t< 20.1 CU\t\n Anti-Cardiolipin Antibody, IgM\t< 10.0\t< 20.1 CU\t\n Lupus Anticoagulant by HEXA\tNeg\tNeg\t\n RVVT Seconds\t30.9\t29.0–44.0 s\t\nCSF studies\t\n WBC\t1\t< 6 x10E6/L\t\n RBC\t44\t0 x10E6/L\t\n Glucose\t76\t40–70 mg/dL\t\n Protein\t13\t15–50 mg/dL\t\n IgG Index\t0.6\t0.3–0.6 Ratio\t\n Serum glucose\t164\t< 200\t\n Rapid HSV-1 PCR\tNeg\tNeg\t\n Rapid HSV-2 PCR\tNeg\tNeg\t\n VZV PCR\tNeg\tNeg\t\n VZV IgM\t0.03\t< 0.9\t\nAutoimmune/Endocrine\t\n Hemoglobin A1c\t6.4\t4.3–5.6%\t\n TSH\t0.64\t0.45–4.12 mlU/L\t\n Free T4\t13\t10–18 pmol/L\t\n CRP\t5.4 - > 36.9\t< 6.3\t\n ESR\t> 100\t0–15 mm/h\t\n Anti-Nuclear Antibodies\t< 40\t< 40\t\n Anti Proteinase 3 Ab\t< 10.0\t< 20.0 CU\t\n Anti Myeloperoxidase\t< 10.0\t< 20.0 CU\t\n GAD-65 Autoantibodies\t< 1.0\t< 1.0 U/mL\t\n Insulin Autoantibody\t< 0.4\t< 0.4 U/mL\t\n Islet Cell Antigen 512 Antibody\t< 0.8\t< 0.8 U/mL\t\n Rheumatoid Factor, serum\t< 40\t< 40 IU/mL\t\n Complement C3, serum\t101\t71–159 mg/dL\t\n Complement C4, serum\t26.4\t13–30 mg/dL\t\n Cryoglobulin\t< 0.12\t< 0.12 g/L\t\n Heterophile Agglutination\tNeg\tNeg\t\nInfectious\t\n Hepatitis B sAb\t< 5\tmIU/mL\t\n Hepatitis B cAb\tNeg\tNeg\t\n Hepatitis B sAg\tNeg\tNeg\t\n Hepatitis C Antibody\tNeg\tNeg\t\n HIV Ag/Ab\tNeg\tNeg\t\n\n\nDespite aggressive medical management, the patient clinically deteriorated. Repeat imaging revealed marked interval infarct progression involving multiple vascular territories (Fig. 1d). She underwent a left-sided decompressive hemicraniectomy as a life sustaining maneuver, and concomitant brain biopsy did not demonstrate evidence of vasculitis or infection. Clinical course was further complicated by sepsis, renal failure, and an acute generalized exanthematous pustulosis drug reaction to iodine contrast. In accordance with the patient’s prior wishes, she was transitioned to comfort-focused care and her family agreed to an autopsy.\n\nThe autopsy revealed eccentric, firm, yellow plaques involving all proximal intracranial vessels, consistent with severe atherosclerosis. There was an occlusive thrombus of the right ACA as well as diffuse arteriolar microthrombi. Elements of acute and chronic ischemic changes were seen on histology, including extensive ischemic neuronal necrosis. Diffuse, severe atherosclerosis was determined to be the cause of fatal burden of ischemic stroke (Fig. 2).\nFig. 2 Gross and microscopic pathology. a Gross pathology of aortic arch revealing extensive atheromas (black arrows). b Histopathology of the anterior cerebral artery. There is intimal thickening underlying the internal elastic lamina (blue arrow); the media and adventitia are distorted by fibrosis (blue dashed arrow). A recently-formed fibrin thrombus (black arrow) is adherent to a chronic and organized atherosclerotic plaque (red arrow). c Cross-sectional view of the left anterior descending coronary artery containing an intramural calcified nodule (black arrow). d Cross-sectional view of the basilar artery wall, demonstrating architectural distortion with cholesterol clefts (black arrow) and microcalcifications. e Left anterior descending artery with thickening of the intima and inflammatory infiltrate including T lymphocytes (red arrows) and macrophages (black arrows)\n\n\n\nDiscussion and conclusions\nWe present a case of a young patient with psoriasis and psoriatic arthritis, severe and diffuse atherosclerosis, and ultimately a fatal burden of ischemic infarcts of the brain. While the definitive contributions of the patient’s individual inflammatory conditions and anemia are unknown, we suggest that severe psoriasis and psoriatic arthritis enhance and accelerate progression of early presence of vascular risk factors and that recognition of this relationship provides another opportunity for risk factor stratification and treatment. Psoriasis and psoriatic arthritis have each been associated with cardiovascular risk factors and metabolic syndrome. This report illustrates that the burden and severity of comorbid inflammatory conditions and metabolic syndrome should prompt aggressive screening and management of vascular risk factors.\n\nPathophysiology\nThe pathophysiology of psoriasis involves the activation of effector T lymphocytes, including T helper cell type 1 and 17. Skin infiltration of activated T cells promotes antigen presentation and propagation of inflammatory cytokines [3]. A dysregulated Th1 system within the vessel wall intimal layer is implicated in the development of atherosclerosis and is a biologically plausible explanation for accelerated atherosclerosis in a chronic inflammatory state [8, 9]. The initial lesion responsible for atherogenesis is the fatty-streak, which is pathologically composed of monocytes and T lymphocytes [8, 10]. Endothelial cell activation leads to an enhanced local inflammatory response with upregulation of leukocyte adhesion molecules, increased of leukocyte recruitment, and expansion of the subendothelial fatty streak, leading to plaque formation [10, 11]. Progressive focal narrowing of vessels is punctuated by exposure of thrombogenic material when there is intimal layer plaque rupture or endothelial cell layer disruption. Thrombosis then leads to conditions such as unstable angina, myocardial infarction, or stroke [11, 12]. Fig. 2 illustrates extensive atheromas (2a) and chronic changes to the vessel wall layers (2c-d). Figure 2e illustrates the presence of T lymphocytes and macrophages within the thickened intima, which can be seen within the natural process of atherosclerosis [8, 10]. There is no evidence of excessive or patterned presence of inflammatory cells in pathology specimens, suggesting a chronic, cumulative process, and highlighting indirect and potentially synergistic roles of systemic inflammation in accelerating atherosclerosis.\n\nCirculation of inflammatory substances including low density lipoprotein (LDL) and lipoprotein (a) have also been directly implicated in vessel wall reactivity and plaque formation [3]. Studies have shown increased subclinical atherosclerosis and increased intima-medial thickness in patients with psoriatic arthritis, but without otherwise clear cardiovascular risk factors [13, 14], illustrating a more direct effect of systemic inflammation on the arterial wall. More severe subclinical atherosclerosis has also been seen in patients with psoriatic arthritis as compared to control populations and patients with cutaneous psoriasis alone [12]. The severity of atherosclerosis may increase with the added burden of inflammatory joint disease in patients with psoriasis.\n\nPsoriasis\nPopulation studies have demonstrated that patients with psoriasis have increased cardiovascular risk factors, including diabetes, hypertension, hyperlipidemia, and obesity, which are all features of metabolic syndrome [15–18]. Across observational studies, meta-analyses describe a 1.4–2.2 fold increased risk of developing metabolic syndrome in patients with psoriasis as compared to controls [18, 19]. In addition, the risk of developing metabolic syndrome has been shown to increase with psoriasis severity, with odds ratios (OR) of 1.22, 1.56, 1.98 for mild, moderate, and severe psoriasis, respectively [18]. Other studies have noted specific risk factors that are more prevalent in severe versus mild psoriasis, including diabetes (OR 1.39, 95% CI 1.22–1.58) and obesity (OR 1.47, 95% CI 1.32–1.63) [20]. These studies illustrate the relationship between the degree of systemic inflammation and development of metabolic syndrome.\n\nIn addition to the added risk conferred from elevated cardiovascular risk factors, population studies have also demonstrated that psoriasis independently leads to an increased risk of myocardial infarction or stroke [7, 18, 21, 22]. After adjusting for cardiovascular risk factors, studies demonstrate that mild and severe psoriasis confer a 1.29-fold risk (95% CI 1.02–1.63) and a 1.7-fold risk (CI 1.32–2.18) of myocardial infarction, as well as a 1.12-fold risk (95% CI, 1.08–1.16) and a 1.56-fold risk (95% CI 1.32–1.84) of stroke [23], respectively. These findings suggest a shared inflammatory pathway involved in the pathogenesis of psoriasis and atherogenesis [24].\n\nThe risk of cardiovascular risk factors and adverse events has also been noted to correlate with age of onset [22, 25]. The risk of incident myocardial infarction (MI) was found to be higher in younger patients with severe psoriasis as compared to older patients with late-onset psoriasis (HR 3.10 in a 30 year-old vs 1.36 in a 60 year-old) [25]. The difference in the disease activity of psoriasis is dependent on both genetic and environmental factors. Detection of specific human leukocyte antigens (HLA), such as type Cw6, has been differentially found in patients with early onset psoriasis as compared to late onset psoriasis, as one example of biological differences that contribute towards disease activity [26].\n\nPsoriatic arthritis\nOther studies have looked at the contribution of psoriatic arthritis as an independent risk factor for metabolic syndrome and adverse cardiovascular events. Patients with psoriatic arthritis have increased prevalence of hypertension (OR 1.31, 95% CI 1.26–1.47), hyperlipidemia (OR 1.23, 95% CI 1.18–1.29), diabetes (OR, 1.38, 95% CI 1.31–1.45), and obesity (OR 1.69, 95% CI 1.62–1.75) [4]. The prevalence of MI (OR 1.36-fold, 95% 1.04–1.77) and stroke (OR 1.26-fold, 95% CI 1.03–1.71) was also higher in patients with psoriatic arthritis as compared to controls [7, 27]. Notably, diagnosis of psoriatic arthritis did not confer a statistically significant elevation in mortality, as compared to controls [5]. Fewer studies have looked at the additive risk of accruing vascular risk factors in patients that have psoriatic arthritis in addition to cutaneous psoriasis. One study reports the elevated risk of vascular risk factors for patients with psoriatic arthritis to be 2.59-fold (95% CI 1.43–4.67) for cardiovascular disease, 2.42-fold (95% CI, 1.82–3.22) for hypertension, 1.9-fold (95% CI, 1.22–2.96) for diabetes, and 1.58-fold (95% CI, 1.19–2.09) for obesity [28, 29]. The presence of multiple inflammatory conditions may imply presence of multiple vascular risk factors.\n\nThere are many contributing factors toward atherosclerosis and vascular events, including conventional risk factors of dyslipidemia and hypertension, family history, ethnicity, and lifestyle [30]. The potential impact of anemia [31] and hemoglobinopathy [32] is also acknowledged but not definitive. In this report, however, we have focused on addressing the direct and indirect contributions of psoriasis and psoriatic arthritis.\n\nImmunosuppressive therapy\nMethotrexate and tumor necrosis factor inhibitors lead to 0.72-fold (95% CI 0.57–0.91) and 0.7-fold (95% CI 0.54–0.9) respective reduction of incident vascular events including MI and stroke in rheumatic diseases while agents such as cyclosporine, oral retinoids, steroids, and non-steroidal anti-inflammatory agents may confer increased risk [33, 34]. While fewer studies have been performed in patients with psoriasis and psoriatic arthritis, data suggests that disease modifying therapies, biologics, and anti-inflammatory agents may also lead to a reduced rate of cerebrovascular risk factors and events [35–39].\n\nIn conclusion, psoriasis and psoriatic arthritis have both indirect and direct causative roles in increasing the risk of vascular disease. Younger patients or those with multisystem disease need aggressive screening and treatment for active inflammatory disease along with vascular risk factor stratification. In patients with inflammatory conditions, we suggest screening for modifiable vascular risk factors and treating the risk factors in accordance with contemporary guidelines. Similarly, in young patients with vascular risk factors, we suggest reviewing systems for undiagnosed inflammatory disease in the appropriate clinical context. Studies are needed to help identify appropriate immunosuppressive therapy selection for synergistic risk factor reduction. Studies are also needed to help identify timing, cost-effectiveness, and patient selection for screening and treatment strategies.\n\nAbbreviations\nACAAnterior cerebral artery\n\nCIConfidence interval\n\nCTAComputerized tomography angiogram\n\nHDLHigh-density lipoprotein\n\nHgHemoglobin\n\nHLAHuman leukocyte antigens\n\nHRHazard ratio\n\nICAInternal carotid artery\n\nLDLLow density lipoprotein\n\nMCAMiddle cerebral artery\n\nMIMyocardial infarction\n\nNSTEMINon-ST elevation myocardial infarction\n\nOROdds ratios\n\nPASIPsoriasis Area and Severity Index\n\nRCARight coronary artery\n\nTEETransesophageal echocardiogram\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nJF, CH performed the data acquisition, analysis, and drafting of the manuscript. DS, GL, JH assisted with the analysis and interpretation of the pathology-specific data and the review of the manuscript. RC assisted with the data acquisition of the radiology images, figure creation, and the review of the manuscript. AK, KM, and CH assisted with the overall interpretation of the data and the review of the manuscript. All authors reviewed and approved of this manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nEthics approval and consent to participate\nNot applicable; see consent for publication.\n\nConsent for publication\nWritten informed consent was obtained from the next of kin for the publication of this case report, patient images, and lab data.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Tardif J-C Efficacy and safety of low-dose colchicine after myocardial infarction N Engl J Med 2019 381 26 2497 10.1056/NEJMoa1912388 31733140\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "20(1)", "journal": "BMC neurology", "keywords": "Atherosclerosis; Psoriasis; Psoriatic arthritis; Stroke", "medline_ta": "BMC Neurol", "mesh_terms": "D015535:Arthritis, Psoriatic; D050197:Atherosclerosis; D015897:Comorbidity; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D024821:Metabolic Syndrome; D008875:Middle Aged; D011565:Psoriasis; D012307:Risk Factors; D020521:Stroke", "nlm_unique_id": "100968555", "other_id": null, "pages": "106", "pmc": null, "pmid": "32199449", "pubdate": "2020-03-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23360868;31733140;29295598;9887164;27696731;19022533;22736087;15843671;28917453;22392612;18697777;23557749;21173301;25303139;17553036;25814357;25351522;24642015;22161801;4056119;17330278;17032986;21600738;21905258;23221331;26425147;21777216;17665475;18294316;17052489;25561362;22897416;16365254;21098427;30150978;23845149;19458634;8181179;11955534", "title": "Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report.", "title_normalized": "catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis a case report" }	[ { "companynumb": "US-TEVA-2020-US-1230735", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSORIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACITRETIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSORIASIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACITRETIN." } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Psoriasis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FAN J. CATASTROPHIC STROKE BURDEN IN A PATIENT WITH UNCONTROLLED PSORIASIS AND PSORIATIC ARTHRITIS: A CASE REPORT. 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{ "abstract": "BACKGROUND Myocardial bridging, although frequent, is often a forgotten cause of angina. It is a congenital anomaly in which the coronary artery tunnels through the myocardium with the overlying muscle, termed a myocardial bridge. The tunneled artery is prone to increased myocardial compression, mechanical load, endothelial damage, and vascular remodeling. During myocardial systole, the tunneled artery undergoes narrowing caused by myocardial compression, which leads to disruption of blood flow, thereby precipitating angina, arrhythmias, infarction, and sudden cardiac death. CASE REPORT Here, we present a case of a 29-year-old white woman who presented with atypical left-sided achy chest pain, occurring primarily at rest. Further evaluation showed mildly elevated troponins, with normal electrocardiogram, chest x-ray, and CTA chest. She subsequently underwent coronary angiography and was found to have myocardial bridging of her left anterior descending artery, with compression of up to 40% during systole. She was initially treated with diltiazem, but due to adverse effects was transitioned to metoprolol succinate, which she has tolerated well. CONCLUSIONS Myocardial bridging, although benign in nature, carries a vast array of complications requiring these patients to undergo prompt diagnosis and treatment. Vascular spasm, wall stress of the tunneled artery, and intensity of systolic constriction coupled with any delay in management can lead to ischemia, infarction, dysrhythmias, and death. Therefore, it is imperative that patients who have low clinical suspicion for atherosclerosis but who are presenting with anginal equivalents undergo coronary angiography to assess for myocardial bridging and receive immediate treatment.", "affiliations": "Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.;Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.", "authors": "Duymun\|Shahnaz\|S\|;Misodi\|Emmanuel\|E\|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D014336:Troponin; D008790:Metoprolol", "country": "United States", "delete": false, "doi": "10.12659/AJCR.923075", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32683394\n10.12659/AJCR.923075\n923075\nArtilces\nMyocardial Bridging: A Case Presentation of Atypical Chest Pain Syndrome in a Young Woman\nDuymun Shahnaz EF Misodi Emmanuel E Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, U.S.A.\nCorresponding Author: Shahnaz Duymun, e-mail: [email protected]’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n19 7 2020 \n21 e923075-1 e923075-5\n25 1 2020 30 4 2020 20 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 29-year-old\n\nFinal Diagnosis: Myocardial bridging\n\nSymptoms: Chest pain\n\nMedication: —\n\nClinical Procedure: Coronary angiography • CT scan • echocardiography\n\nSpecialty: Cardiology • General and Internal Medicine\n\nObjective:\nRare disease\n\nBackground:\nMyocardial bridging, although frequent, is often a forgotten cause of angina. It is a congenital anomaly in which the coronary artery tunnels through the myocardium with the overlying muscle, termed a myocardial bridge. The tunneled artery is prone to increased myocardial compression, mechanical load, endothelial damage, and vascular remodeling. During myocardial systole, the tunneled artery undergoes narrowing caused by myocardial compression, which leads to disruption of blood flow, thereby precipitating angina, arrhythmias, infarction, and sudden cardiac death.\n\nCase Report:\nHere, we present a case of a 29-year-old white woman who presented with atypical left-sided achy chest pain, occurring primarily at rest. Further evaluation showed mildly elevated troponins, with normal electrocardiogram, chest x-ray, and CTA chest. She subsequently underwent coronary angiography and was found to have myocardial bridging of her left anterior descending artery, with compression of up to 40% during systole. She was initially treated with diltiazem, but due to adverse effects was transitioned to metoprolol succinate, which she has tolerated well.\n\nConclusions:\nMyocardial bridging, although benign in nature, carries a vast array of complications requiring these patients to undergo prompt diagnosis and treatment. Vascular spasm, wall stress of the tunneled artery, and intensity of systolic constriction coupled with any delay in management can lead to ischemia, infarction, dysrhythmias, and death. Therefore, it is imperative that patients who have low clinical suspicion for atherosclerosis but who are presenting with anginal equivalents undergo coronary angiography to assess for myocardial bridging and receive immediate treatment.\n\nMeSH Keywords:\nCoronary AngiographyCoronary Vessel AnomaliesMyocardial Bridging\n==== Body\nBackground\nMyocardial bridging is a congenital variant of the coronary artery vasculature in which the vessel tunnels through the myocardium rather than running a typical epicardial course. The prevalence ranges anywhere from 0.5% to 85%, noted mostly on coronary angiography and autopsy [1]. It is primarily believed to be a benign finding, but it has been reported to cause myocardial ischemia, infarction, arrhythmias, and even sudden cardiac death [2]. These complications arise when the tunneled artery becomes compressed during systole and the stress and damage the vessel undergoes from the overlying muscle fibers and increased flow velocity. Treatment is therefore targeted towards decreasing the length and force of the contraction these arteries undergo. First-line therapy includes negative inotropic and chronotropic agents such as beta-blockers and calcium-channel blockers. Ivabradine and anti-platelet therapy could also be used if needed. If medical therapy fails to control symptoms, surgical intervention is warranted.\n\nCase Report\nWe present the case of a 29-year-old white woman with no significant past medical history who developed a sudden achy non-radiating pain in her left chest. It occurred while at rest and lasted approximately 30 minutes, with resolution after aspirin administration. She had associated left-hand pain and numbness but did not experience diaphoresis, dyspnea, nausea, lightheadedness, or headaches.\n\nShe had a Mirena IUD in place and had no known drug allergies. She had smoked one-half to one pack per day for 11 years but quit intermittently during her pregnancies. She drank alcohol occasionally but does not use any illicit drugs. Her family history was significant for a father with early coronary artery disease and stent placement in his early 40s.\n\nUpon admission, she was found to have an elevated troponin of 0.36, which remained relatively stable throughout her hospital stay. A urine drug screen was negative, minimizing the suspicion of drug-induced ischemia. D-dimer was obtained out of concern for a pulmonary embolus, but it was negative. Vasculitic pathology was considered; therefore, ESR and ANA were obtained, both of which were negative. CK and CK-MMB were both within normal limits, at 64 and 0.9, respectively, and a lipid panel was unremarkable. She was observed on a telemetry unit during her stay, without any major arrhythmias identified or worsening of symptoms.\n\nEKG revealed normal sinus rhythm and did not exhibit any acute ischemic changes (Figure 1). Chest radiography showed clear lungs without pleural effusions or consolidations. A CTA chest was obtained, which revealed clear lungs and no pulmonary embolus. The heart was normal in shape and size. No pericardial effusion or pulmonary vascular congestion were noted. An echocardiogram was performed, revealing a hyper-dynamic myocardium with an ejection fraction of 60–65%. Otherwise, echocardiography was unremarkable. She subsequently underwent a cardiac catheterization, which revealed a tubular zone of myocardial bridging of the left anterior descending artery with a mid-vessel lesion of 40% (Figure 2). She was started on aspirin and diltiazem and discharged home.\n\nUpon outpatient follow-up with cardiology, there was concern regarding diltiazem as she experienced episodes of lightheadedness and restless legs while taking the medication. Thus, she was switched to metoprolol succinate for therapy, which she has been tolerating well.\n\nDiscussion\nMyocardial bridging is a congenital anomaly described as tunneling of a coronary artery through the myocardium rather than running a typical epicardial course. Its prevalence ranges from 0.5% to 29.4% when detected by angiographic procedures; however, by autopsy, occurrences are noted to range from 5.4% to 85% [1]. Myocardial bridging most commonly involves the left anterior descending artery, as demonstrated in our patient, but there have been a few case reports of involvement of the right coronary artery. Typically a benign feature, symptoms usually do not appear until the third decade of life. Symptoms may include anginal equivalents, arrhythmias, and sudden cardiac death. The mechanism behind these symptoms lies in the disturbance of blood flow through the tunneled artery. There is enhanced myocardial compression in which the vessel enters into the myocardium, leading to a disturbance of blood flow to the rest of the myocardium. This disturbance mainly occurs during systole and is resolved in the diastolic phase. This transient hypoperfusion is thought to be the cause of presenting symptoms, myocardial ischemia, infarction, and sudden cardiac death. Our patient only described symptoms during rest; however, they can also occur with exertion.\n\nDuring rest, there is vasospasm of the tunneled artery, as well as mechanical trauma to the vessel wall. The inherent nature of the tunneled artery, coursing through the myocardium, causes the arterial wall to undergo an increased amount of oscillatory wall shear stress, prompting increased vascular cell adhesion molecule expression, reactive oxygen species production, and the development of pro-atherogenic endothelial cells. Together, the overexpression of these molecules and cells stimulate endothelial injury and plaque formation, leading to chest pain syndromes, dysrhythmias, ischemia, and death [3]. During exercise, ischemia is mediated by effort-induced tachycardia, which increases myocardial oxygen demand, contractility, and flow velocity, and reduces the coronary flow [4,5]. Symptoms and complications of myocardial bridging are associated with the degree of systolic narrowing, depth of tunneled artery, number of tunneled segments, and high heart rate [5,6].\n\nResting electrocardiograms rarely show any abnormalities in these patients; therefore, other modalities are needed to identify myocardial bridging. Coronary angiography remains the criterion standard of diagnosing the presence of myocardial bridging. The systolic compression of the tunneled artery is portrayed as a “milking effect” on coronary angiography, demonstrated as retrograde blood flow and subsequent antegrade flow with expansion of the vessel diameter during diastole. Other invasive studies such as intravascular ultra-sound and intracoronary Doppler sonography can be used for diagnosis. Intravascular ultrasound characterizes the length, thickness, and location of the myocardial bridge. It is seen as a “half-moon” sign, demonstrated by an echolucent area between the bridged artery and the epicardial tissue that persists throughout the cardiac cycle [3]. Intracoronary Doppler demonstrates a diastolic fingertip phenomenon specific for myocardial bridging, characterized by rapid diastolic blood flow followed by a plateau in the bridged segment [7].\n\nNoninvasive studies such as cardiac CT, cardiac MRI, and transthoracic echocardiography can also be used to diagnose myocardial bridging, but these are not the modalities of choice. Cardiac CT is a currently evolving method as an alternative to diagnosing coronary anomalies. It provides information regarding the lumen and walls of the coronary arteries and is effective in evaluating coronary anomalies, as well as atherosclerosis, stent patency, bypass grafts, and myocardial irregularities [8]. It offers the advantage of being noninvasive, using lower doses of radiation, and usefulness in treatment planning. Although is not the criterion standard for diagnosis, cardiac CT would have been a great option to diagnose myocardial bridging in our patient, given the low pretest probability of discovering significant coronary atherosclerosis on angiography as the cause of her presentation in light of her young age and minimal risk factors.\n\nOur patient, without any significant cardiac history or risk factors, was found to have a 40% lesion of the mid-LAD from myocardial bridging, likely due to the effects of shear stress of the tunneled artery from repetitive compression. It is unclear if her family history of early coronary disease had an impact on her coronary anomaly. Cerit found that patients with myocardial bridging have increased levels of inflammatory markers, neutrophil-to-lymphocyte ratio, and platelet activity [9]. It is well known that increased platelet activity and increased neutrophils play a key role in the development and destabilization of atherosclerotic plaques in cardiovascular disease. Although she did not exhibit any atherosclerosis on angiography, there may have been a genetic component of platelet and neutrophil activity contributing to her symptoms, especially given the history of early cardiovascular disease in her father.\n\nGiven the pathophysiology underlying myocardial bridging, treatment is focused on decreasing the compression of intramyocardial arteries via decreasing systolic contraction and prolonging the diastolic phase. First-line therapy includes negative inotropic and chronotropic agents such as beta-blockers and calcium-channel blockers, both of which were used in our patient. These agents lower transmural pressures, reducing the compression of the tunneled artery and prolonging diastole, thus mitigating symptoms. They have the added benefit of reducing heart rates, thus decreasing the frequency of systolic compression and increasing the diastolic period. Ivabradine has also been shown to have an effect on myocardial bridges by inhibiting the pacemaker current, thus decreasing heart rates and subsequently prolonging diastole [1]. If atherosclerosis is present, anti-platelet therapy can be used as an adjunct. Drugs to avoid include pure vasodilating agents such as nitrates, as they intensify systolic compression of the tunneled segment, leading to retrograde flow and thus worsening symptoms [3]. Intracoronary injection of dobutamine, epinephrine, and isoprotenerol was also shown to exacerbate vessel narrowing during systole and delay diastolic relaxation [5]. If symptoms persist despite medical therapy, intracoronary stenting or surgical myotomy can be considered, as these measures also counteract transmural pressures [10]. Minimally invasive coronary artery bypass grafting has also been reported as an option for the management of myocardial bridges [11].\n\nIn evaluating the cause of atypical chest pain syndromes in patients with low risk for atherosclerosis, as in this case, it is also important to consider other nonatherosclerotic causes of myocardial injury such as MINOCA (myocardial infarction with nonobstructive coronary arteries), microvascular angina, vascular spasm, coronary dissection, and coagulation disorders, as they can present similarly. MINOCA occurs in patients presenting with an acute myocardial infarction but in the absence of obstructing coronary disease, with no lesion greater than 50% and without another explanation for the presentation [12]. It is mostly seen in younger female patients presenting with NSTEMI, similar to our patient [13]. MINOCA was considered in this case, but with the angiographic findings of the existing myocardial bridge, we postulated that our patient’s presentation was due to the bridge. Microvascular angina, vascular spasms, and coronary dissection could also be considered; however, with no change in electrocardiography and the findings of myocardial bridging on angiography, our suspicion for other causes remained low. Nonetheless, it is imperative to perform complete imaging studies for diagnosing coronary anomalies in patients that have low pretest probability of atherosclerosis but who are presenting with anginal equivalents, as these anomalies can cause significant complications.\n\nConclusions\nMyocardial bridging is a frequent but often forgotten cause of angina and can be present in up to 25% of the population. Patients can present with a variety of symptoms, including angina and dysrhythmias, but the vast array of complications arising from myocardial bridging require these patients to undergo prompt coronary angiography. Vascular spasm, wall stress of the tunneled artery, and intensity of systolic constriction coupled with any delay in management can lead to ischemia, infarction, and sudden cardiac death. Therefore, it is imperative that patients for whom there is low clinical suspicion for atherosclerosis but who are presenting with anginal equivalents undergo coronary angiography to assess for myocardial bridging and receive immediate treatment for this coronary anomaly.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Electrocardiogram of our patient with myocardial bridging demonstrating normal sinus rhythm without any acute ischemic changes.\n\nFigure 2. Coronary angiography of our patient, demonstrating compression of the left anterior descending artery during systole (red circle).\n==== Refs\nReferences:\n1. Tarantini G Migliore F Cademartiri F Left anterior descending artery myocardial bridging J Am Coll Cardiol 2016 68 2887 99 28007148 \n2. Hostiuc S Rusu MC Hostiuc M Cardiovascular consequences of myocardial bridging: A meta-analysis and meta-regression Sci Rep 2017 7 1 14644 29116137 \n3. Corban M Hung OY Eshtehardi P Myocardial bridging: Contemporary understanding of pathophysiology with implications for diagnostic and therapeutic strategies J Am Coll Cardiol 2014 63 2346 55 24583304 \n4. Corrado D Thiene G Cocco P Frescura C Non-atherosclerotic coronary artery disease and sudden death in the young Br Heart J 1992 68 601 7 1467055 \n5. Dwyer J Coronary artery bridging as an etiology for non-atherosclerotic myocardial infarction: A review of literature and case history J Cardio Case Rep 2019 2 1 6 \n6. Mohlenkamp S Hort W Ge J Erbel R Update on myocardial bridging Circulation 2002 106 2616 22 12427660 \n7. Lovell MJ Knight CJ Invasive assessment of myocardial bridges Heart 2003 89 699 700 12807830 \n8. Hazirolan T Canyigit M Karcaaltincaba M Myocardial bridging on MDCT AmJ Roentgenol 2007 188 1074 80 17377050 \n9. Cerit L Assessment of indirect inflammatory markers in patients with myocardial bridging Cardiovasc J Afr 2017 28 182 85 27805707 \n10. Wan L Wu Q Myocardial bridge, surgery or stenting? Interact Cardiovasc Thorac Surg 2005 4 517 20 17670472 \n11. Ripa C Melatini MC Olivieri F Antonicelli R Myocardial bridging: A ‘forgotten’ cause of acute coronary syndrome – a case report Int J Angiol 2007 16 115 18 22477305 \n12. Tamis-Holland JE Jneid H Reynolds HR Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease Circulation 2019 139 891 908 \n13. Rakowski T De Luca G Sludak Z Characteristics of patients presenting with myocardial infarction with non-obstructive coronary arteries (MINOCA) in Poland: Data from the ORPKI national registry J Thromb Thrombolysis 2019 47 462 66 30565147\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "21()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D002637:Chest Pain; D017023:Coronary Angiography; D005260:Female; D006801:Humans; D008790:Metoprolol; D054084:Myocardial Bridging; D014336:Troponin", "nlm_unique_id": "101489566", "other_id": null, "pages": "e923075", "pmc": null, "pmid": "32683394", "pubdate": "2020-07-19", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "30565147;12807830;29116137;17377050;28007148;30913893;22477305;1467055;27805707;12427660;17670472;24583304", "title": "Myocardial Bridging: A Case Presentation of Atypical Chest Pain Syndrome in a Young Woman.", "title_normalized": "myocardial bridging a case presentation of atypical chest pain syndrome in a young woman" }	[ { "companynumb": "US-APOTEX-2020AP017156", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL BRIDGING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN [ACETYLSALICYLIC ACID]" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074943", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL BRIDGING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Restless legs syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUYMUN S, MISODI E.. MYOCARDIAL BRIDGING: A CASE PRESENTATION OF ATYPICAL CHEST PAIN SYNDROME IN A YOUNG WOMAN.. AMERICAN JOURNAL OF CASE REPORTS. 2020?21: E923075:1?5", "literaturereference_normalized": "myocardial bridging a case presentation of atypical chest pain syndrome in a young woman", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210906", "receivedate": "20210906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19791088, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]
{ "abstract": "Coronavirus disease 2019 (COVID-19) is a global pandemic, and it is increasingly important that physicians recognize and understand its atypical presentations. Neurological symptoms such as anosmia, altered mental status, headache, and myalgias may arise due to direct injury to the nervous system or by indirectly precipitating coagulopathies. We present the first COVID-19 related cases of carotid artery thrombosis and acute PRES-like leukoencephalopathy with multifocal hemorrhage.", "affiliations": "Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA. Electronic address: [email protected].;Mount Sinai Health System, Internal Medicine, 1000 10th Ave, New York 10019, NY, USA.;Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA.;Mount Sinai Health System, Neurology, 1000 10th Ave, New York 10019, NY, USA.;Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA.;Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA.", "authors": "Doo\|Florence X\|FX\|;Kassim\|Gassan\|G\|;Lefton\|Daniel R\|DR\|;Patterson\|Shanna\|S\|;Pham\|Hien\|H\|;Belani\|Puneet\|P\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clinimag.2020.07.007", "fulltext": null, "fulltext_license": null, "issn_linking": "0899-7071", "issue": "69()", "journal": "Clinical imaging", "keywords": "COVID-19; Carotid thrombosis; Infection; Leukoencephalopathy; Stroke", "medline_ta": "Clin Imaging", "mesh_terms": "D000086382:COVID-19; D002341:Carotid Artery Thrombosis; D018352:Coronavirus Infections; D006801:Humans; D056784:Leukoencephalopathies; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2", "nlm_unique_id": "8911831", "other_id": null, "pages": "94-101", "pmc": null, "pmid": "32707411", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "32133578;24632711;32469400;32299017;19940660;32167747;17885064;32338827;32305883;31986264;32268022;18356474;32275288;32229625;32299010;32228363;15141377;32240279;18403560;18390877;32385132;32291094;32142651;16252612", "title": "Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.", "title_normalized": "rare presentations of covid 19 pres like leukoencephalopathy and carotid thrombosis" }	[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP009238", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65490", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN ANHYDROUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VECURONIUM BROMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OXYGEN SATURATION DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VECURONIUM BROMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NITRIC OXIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "OXYGEN SATURATION DECREASED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NITRIC OXIDE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOO FX, KASSIM G, LEFTON DR, PATTERSON S, PHAM H, BELANI P.. RARE PRESENTATIONS OF COVID?19: PRES?LIKE LEUKOENCEPHALOPATHY AND CAROTID THROMBOSIS. CLINICAL IMAGING. 2021?69:94?101", "literaturereference_normalized": "rare presentations of covid 19 pres like leukoencephalopathy and carotid thrombosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210531", "receivedate": "20210531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19349929, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-2008USA002228", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPTIFIBATIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CAROTID ARTERY THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTEGRILIN" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOO FX, KASSIM G, LEFTON DR, PATTERSON S, PHAM H, BELANI P.. RARE PRESENTATIONS OF COVID?19: PRES?LIKE LEUKOENCEPHALOPATHY AND CAROTID THROMBOSIS. CLINICAL IMAGING. 2020?69 (2021):94?101", "literaturereference_normalized": "rare presentations of covid 19 pres like leukoencephalopathy and carotid thrombosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200813", "receivedate": "20200813", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18146441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "This retrospective analysis of data from heroin users screening for clinical research, sought to determine if more naloxone is needed to precipitate opioid withdrawal among those who regularly use heroin with fentanyl, as opposed to those who use heroin without fentanyl.\n\n\n\nOver the course of three to five screening visits, participants completed assessments of drug use, along with urine toxicology tests at each visit. To test for opioid dependence, 29 participants completed a modified Wang test (score: 0-150) during which an intramuscular dose of naloxone (0.2-0.4 mg) was administered and the severity of withdrawal was quantified.\n\n\n\nThe severity of opioid withdrawal was compared between individuals whose urine toxicology regularly tested positive for fentanyl (N = 15), and those only positive for other opioids (N = 14). No significant differences were found in demographic or drug use between the fentanyl-positive (mean: age 41.1 years, 9.1 bags heroin/d) and fentanyl-negative (42.0 years, 10.0 bags heroin/d) groups. Intramuscular naloxone-precipitated robust withdrawal in both samples (P < .01) with no significant difference (P = .8) in the severity (fentanyl positive [100.6 ± 13.4]; fentanyl negative [82.7 ± 9.6]).\n\n\n\nThese data suggest that a standard naloxone dose can be equally effective at precipitating withdrawal in individuals using heroin with fentanyl compared to heroin without fentanyl. These data contribute to our understanding of how naloxone antagonizes the effects of fentanyl and may have significant implications for the clinical laboratory and opioid overdose. A prospective clinical laboratory study with the proper opioid maintenance controls is needed to provide a more definitive finding. (Am J Addict 2019;00:00-00).", "affiliations": "Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.", "authors": "Jones\|Jermaine D\|JD\|0000-0003-4476-2800;Sherwin\|Elliana\|E\|;Martinez\|Suky\|S\|;Comer\|Sandra D\|SD\|", "chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D005283:Fentanyl", "country": "England", "delete": false, "doi": "10.1111/ajad.12979", "fulltext": null, "fulltext_license": null, "issn_linking": "1055-0496", "issue": "29(1)", "journal": "The American journal on addictions", "keywords": null, "medline_ta": "Am J Addict", "mesh_terms": "D000328:Adult; D005260:Female; D005283:Fentanyl; D006556:Heroin Dependence; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D010865:Pilot Projects; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome; D055815:Young Adult", "nlm_unique_id": "9208821", "other_id": null, "pages": "51-56", "pmc": null, "pmid": "31782591", "pubdate": "2020-01", "publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.", "references": "26095483;29042317;18397839;28859052;28687187;30861160;30204554;28068563;27560775;2763981;4422361;720211", "title": "Naloxone-Induced Withdrawal in Individuals With and Without Fentanyl-Positive Urine Samples.", "title_normalized": "naloxone induced withdrawal in individuals with and without fentanyl positive urine samples" }	[ { "companynumb": "US-SPECGX-T202000419", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "COCAINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COCAINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040517", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAMORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JONES JD, SHERWIN E, MARTINEZ S, COMER SD. NALOXONE-INDUCED WITHDRAWAL IN INDIVIDUALS WITH AND WITHOUT FENTANYL-POSITIVE URINE SAMPLES.. 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NALOXONE-INDUCED WITHDRAWAL IN INDIVIDUALS WITH AND WITHOUT FENTANYL-POSITIVE URINE SAMPLES.. THE AMERICAN JOURNAL ON ADDICTIONS. 2020?29(1):51-6", "literaturereference_normalized": "naloxone induced withdrawal in individuals with and without fentanyl positive urine samples", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200224", "receivedate": "20200224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17452493, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "US-SPECGX-T202000420", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHADONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040517", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHADONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIAMORPHINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEROIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "JONES JD, SHERWIN E, MARTINEZ S, COMER SD. NALOXONE-INDUCED WITHDRAWAL IN INDIVIDUALS WITH AND WITHOUT FENTANYL-POSITIVE URINE SAMPLES.. THE AMERICAN JOURNAL ON ADDICTIONS. 2020?29(1):51-6", "literaturereference_normalized": "naloxone induced withdrawal in individuals with and without fentanyl positive urine samples", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200224", "receivedate": "20200224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17452473, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "Introduction Fetal exposition to valproate can lead to a cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. Case Report In this report we describe 2 cases of fetal valproate syndrome. In the first case, the gravida had a valproate medication before and during pregnancy with additional folic acid. She delivered a male premature infant at 25+2 weeks of gestation due to preterm labor and rupture of the membranes. Physical examination showed even in the premature infant typical signs of fetal valproate syndrome with trigonocephaly, epicanthal folds, broad root of the nose, low-set ears, thin upper lip and anteverted nares. In the second case, the gravida was under antiepileptic therapy with valproate and lamotrigine before and during pregnancy without any prophylaxis with folic acid. Sonographic examination during pregnancy diagnosed a spina bifida, Chiari II malformation and clubfeet. A female newborn was delivered at 39+4 weeks of gestation. Besides the prenatally detected anomalies, facial dysmorphism including microcephaly, low-set ears, thin upper lip and shallow philtrum were seen after birth. Conclusion Valproate, a widely used anticonvulsant medication, is known for its teratogenic effects. The risk of congenital anomalies is even higher in combination with other antiepileptic drugs. Therefore, the avoidance of valproate or at least supplementation with a high dose prophylactic folic acid before and during pregnancy is highly recommended for women with epilepsy.", "affiliations": "Neonatology, University Children's Hospital, Würzburg, Germany.;Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.;Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.;Neonatology, University Children's Hospital, Würzburg, Germany.", "authors": "Wiedemann\|Katharina\|K\|;Stüber\|Tanja\|T\|;Rehn\|Monika\|M\|;Frieauff\|Eric\|E\|", "chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid; D005492:Folic Acid; D000077213:Lamotrigine", "country": "Germany", "delete": false, "doi": "10.1055/s-0043-107619", "fulltext": null, "fulltext_license": null, "issn_linking": "0948-2393", "issue": "221(5)", "journal": "Zeitschrift fur Geburtshilfe und Neonatologie", "keywords": null, "medline_ta": "Z Geburtshilfe Neonatol", "mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D002585:Cesarean Section; D004359:Drug Therapy, Combination; D004827:Epilepsy; D005260:Female; D005492:Folic Acid; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D000077213:Lamotrigine; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011262:Pregnancy Trimester, Second; D012307:Risk Factors; D013577:Syndrome; D014635:Valproic Acid", "nlm_unique_id": "9508901", "other_id": null, "pages": "243-246", "pmc": null, "pmid": "29073690", "pubdate": "2017-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Fetal Valproate Syndrome - Still a Problem Today!", "title_normalized": "fetal valproate syndrome still a problem today" }	[ { "companynumb": "PHHY2019DE016978", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 DF, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 DF, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Preterm premature rupture of membranes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature delivery", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STIIBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. 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FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. 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FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z-GEBURTSHILFE-NEONATOL 2017?221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190131", "receivedate": "20190131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15897484, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "DE-BION-006744", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "073484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": ".9", "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY. Z GEBURTSHILFE NEONATOL. 2017 OCT;221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20171113", "receivedate": "20171113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14182364, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "DE-TEVA-2019-DE-1007462", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "76941", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MILLIGRAM DAILY; 1/2-0-1 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM DAILY; 1-0-1 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z-GEBURTSHILFE-NEONATOL 2017?221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190206", "receivedate": "20190206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15925777, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "DE-CIPLA LTD.-2017DE20075", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "090035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemangioma of bone", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z GEBURTSHILFE NEONATOL. 2017?221(5):243 TO 246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180220", "receivedate": "20171115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14189447, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" }, { "companynumb": "DE-GLAXOSMITHKLINE-DE2019GSK014579", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "020241", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spina bifida", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low set ears", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arnold-Chiari malformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital oral malformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Microcephaly", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Talipes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysmorphism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ill-defined disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE. 2017?221 (5):243-246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190128", "receivedate": "20190128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15880557, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "DE-CIPLA LTD.-2017DE20073", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X0.4 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3X600 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature rupture of membranes", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature labour", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z GEBURTSHILFE NEONATOL. 2017?221(5):243 TO 246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180220", "receivedate": "20171115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14189448, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" }, { "companynumb": "DE-ABBVIE-18P-062-2270871-00", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "018081", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningomyelocele", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital anomaly", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Talipes", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysmorphism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Spina bifida", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Microcephaly", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paralysis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrial septal defect", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac aneurysm", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low set ears", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital flaccid paralysis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral ventricle dilatation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arnold-Chiari malformation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head circumference abnormal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, ET AL. FETAL VALPROATE SYNDROME STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE. 2017 OCT?221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20180409", "receivedate": "20180307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14610306, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "DE-NUVO PHARMACEUTICALS INC-2085930", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "204418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE SODIUM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": ".9", "reaction": [ { "reactionmeddrapt": "Haemangioma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypospadias", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prominent epicanthal folds", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low set ears", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hypermobility syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dysmorphism", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pericardial cyst", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Inguinal hernia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. 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FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. 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FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY. Z GEBURTSH NEONATOL. 2017;221:243-246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20171114", "receivedate": "20171114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14186132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "DE-CIPLA LTD.-2017DE20078", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arnold-Chiari malformation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z GEBURTSHILFE NEONATOL. 2017?221 (5):243 TO 246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180220", "receivedate": "20171228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14331535, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "DE-BION-006745", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1-0-1 DOSAGE", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "073484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5-0-1 DOSAGE", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "2.5", "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY. Z GEBURTSHILFE NEONATOL. 2017 OCT;221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20171113", "receivedate": "20171113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14182051, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "DE-SUNRISE PHARMACEUTICAL, INC.-2079045", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature labour", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature rupture of membranes", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. URL: HTTP://DOI.ORG/10.1055/S-0043-107619.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 17272251, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]
{ "abstract": "The aim of this study was to evaluate the incidence of a variety of infectious complications in patients with CLL regarding the duration of CLL and the type of treatment. We present the retrospective analysis of patients with CLL treated at our institution in years 2004-2016. We collected data about the type of infection, pathogenes, treatment and severity of infections surpassed in connection with administration treatment. In the study one hundred and ten patients were evaluated. The average age of patients was 61.7 years (range 34.5-91.9 years). Fludarabine was the most widely used regimen, followed by bendamustine and alemtuzumab. We recorded 393 episodes of infections, of which 114 (29%) were severe and life threatening of degree 3-5, and 279 (71%) of degree 2. The most common infections were the upper respiratory tract infections together with sinusitis (45.03%), pneumonia (26.20%), CMV reactivation occured in 8.14%, infections of the skin was in 7.6 %. Most infections have occurred with the administration of monoclonal antibody alemtuzumab, these patients were at significantly higher risk of infection [RR 2.59 (1.30 to 5.17)] than patients receiving obinutuzumab [RR 0.63 (0.48 to 0.82)] (p = 0.0001). On the contrary, the safety profile of BCR signaling pathway inhibitors was very acceptable [RR 1.17 (0.70 - 1.96)]. The number of infections have decreased during the first 12 months of treatment with ibrutinib. In the study group we recorded 19 deaths, 8 (7.27%) of them were of infectious etiology. The risk of infectious complications is lifelong in patients with CLL, it can be minimized by early detection and aggressive management. Novel targeted agents used in therapy of CLL have a good safety profile, even the risk of infection is decreased during administration.", "affiliations": null, "authors": "Demitrovicova\|L\|L\|;Mikuskova\|E\|E\|;Oravcova\|I\|I\|;Cingelova\|S\|S\|;Drgona\|L\|L\|;Mladosievicova\|B\|B\|", "chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074323:Alemtuzumab; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine", "country": "Slovakia", "delete": false, "doi": "10.4149/neo_2017_320", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-2685", "issue": "64(3)", "journal": "Neoplasma", "keywords": "chronic lymphocytic leukemia; infectious complications; inhibitors of BCR signaling monoclonal antibodies.", "medline_ta": "Neoplasma", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000069461:Bendamustine Hydrochloride; D006801:Humans; D007239:Infections; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008875:Middle Aged; D011014:Pneumonia; D012141:Respiratory Tract Infections; D012189:Retrospective Studies; D012852:Sinusitis; D014740:Vidarabine", "nlm_unique_id": "0377266", "other_id": null, "pages": "474-481", "pmc": null, "pmid": "28503927", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": null, "title": "Infectious complications in chronic lymphocytic leukemia- a retrospective analysis: single institution experience.", "title_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience" }	[ { "companynumb": "SK-MYLANLABS-2019M1012711", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALEMTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OBINUTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OBINUTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBRUTINIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBRUTINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204104", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE HYDROCHLORIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OFATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFATUMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IDELALISIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDELALISIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cholecystitis infective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterocolitis infectious", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ear infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeria sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L, MIKUSKOVA E, ORAVCOVA I, CINGELOVA S, DRGONA I, MLADOSIEVIGOVA B.. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA.. 2017?64(3):474-81", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20190214", "receivedate": "20190214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15963778, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "SK-FRESENIUS KABI-FK201706792", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L,MIKUSKOVA E,ORAVCOVA I,CINGELOVA S,DRGONA L,MLADOSIEVICOVA B. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA 2017;64(3):474-481.", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20170809", "receivedate": "20170809", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13851148, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "SK-ACCORD-105870", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE/CYCLOPHOSPHAMIDE MONOHYDRATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IDELALISIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDELALISIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OBINUTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OBINUTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BENDAMUSTINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE/BENDAMUSTINE HYDROCHLORIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OFATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFATUMUMAB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IBRUTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBRUTINIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALEMTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia fungal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterocolitis infectious", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cholecystitis infective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeria sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ear infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L,MIKUSKOVA E,ORAVCOVA I,CINGELOVA S,DRGONA L,MLADOSIEVICOVA B. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA 2017?64(3):474-481.", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20190208", "receivedate": "20190208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15937086, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "SK-ASPEN-GLO2018SK005736", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OBINUTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OBINUTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBRUTINIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBRUTINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IDELALISIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDELALISIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": "3", "drugadministrationroute": 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection bacterial", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia fungal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cholecystitis infective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeria sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Ear infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterocolitis infectious", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L, MIKUSKOVA E, ORAVCOVA L, CINGELOVA S, DRGONA L AND MLADOSIEVICOVA B.. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA. 2017?64(3):474-481", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20180615", "receivedate": "20180615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15016180, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180711" } ]
{ "abstract": "In December 2019, the World Health Organization (WHO) announced a series of pneumonia cases caused by an unknown origin, discovered in Wuhan, China. A dangerous virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a disease named acute respiratory syndrome, which was later popularly called coronavirus infection (COVID-19). Patients with acute COVID-19 are at high risk of thrombosis in various blood vessels due to hypercoagulability, blood stasis, and endothelial damage. In this study, we present a case report of a patient with COVID-19, who was hospitalized in one of the hospitals in Sanandaj, Iran. There were symptoms of fever, chills, muscle aches, cough, and tachycardia. Laboratory tests showed high levels of CRP, ESR, Ferritin CLIA, LDH and D-Dimer in this patient. Doppler ultrasound of the patient also revealed an abnormal finding, thrombosis in the right greater saphenous vein. This suggests that COVID-19 may lead to other negative effects through damage to blood vessels.", "affiliations": "School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.;Department of Radiology, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. [email protected].", "authors": "Hesam-Shariati\|Negin\|N\|;Fatehi\|Poya\|P\|;Fathi\|Fardin\|F\|;Abouzaripour\|Morteza\|M\|;Hesam Shariati\|Mohammad Bakhtiar\|MB\|http://orcid.org/0000-0002-2000-5197", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s40794-021-00131-9", "fulltext": "\n==== Front\nTrop Dis Travel Med Vaccines\nTrop Dis Travel Med Vaccines\nTropical Diseases, Travel Medicine and Vaccines\n2055-0936\nBioMed Central London\n\n131\n10.1186/s40794-021-00131-9\nCase Report\nA case report of greater saphenous vein thrombosis in a patient with coronavirus (COVID-19) infection\nHesam-Shariati Negin 1\nFatehi Poya 2\nFathi Fardin 3\nAbouzaripour Morteza 4\nhttp://orcid.org/0000-0002-2000-5197\nHesam Shariati Mohammad Bakhtiar [email protected]\[email protected]\n\n4\n1 grid.1005.4 0000 0004 4902 0432 School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia\n2 grid.484406.a 0000 0004 0417 6812 Department of Radiology, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran\n3 grid.484406.a 0000 0004 0417 6812 Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran\n4 grid.484406.a 0000 0004 0417 6812 Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran\n3 3 2021\n3 3 2021\n2021\n7 630 9 2020\n21 2 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nIn December 2019, the World Health Organization (WHO) announced a series of pneumonia cases caused by an unknown origin, discovered in Wuhan, China. A dangerous virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a disease named acute respiratory syndrome, which was later popularly called coronavirus infection (COVID-19). Patients with acute COVID-19 are at high risk of thrombosis in various blood vessels due to hypercoagulability, blood stasis, and endothelial damage. In this study, we present a case report of a patient with COVID-19, who was hospitalized in one of the hospitals in Sanandaj, Iran. There were symptoms of fever, chills, muscle aches, cough, and tachycardia. Laboratory tests showed high levels of CRP, ESR, Ferritin CLIA, LDH and D-Dimer in this patient. Doppler ultrasound of the patient also revealed an abnormal finding, thrombosis in the right greater saphenous vein. This suggests that COVID-19 may lead to other negative effects through damage to blood vessels.\n\nKeywords\n\nSuperficial vein thrombosis\nCoronavirus\nCOVID-19\nUltrasonography\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nCoronavirus has been widespread around the world since early 2020. The disease is highly contagious and, in severe cases, can lead to acute respiratory syndrome or organ failure [1, 2]. In January 2020, the World Health Organization (WHO) announced the outbreak of the disease as a “public health emergency of international concern” [3]. To date, the virus has led to an unprecedented global health crisis that has resulted in over 2 million death worldwide [4].\n\nSeveral studies have shown that superficial vein thrombosis (SVT) is a common venous disease that appears to be medically benign but can cause serious complications and may be associated with complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE) [5, 6]. The prevalence of SVT is estimated to be about 3 to 11%, while the incidence of thrombosis in the greater saphenous vein (GSV) is about 60 to 80% of the time [7, 8]. The proximity of the greater saphenous vein to the saphenofemoral junction (SFJ) increases the possibility of displacement of blood clots and their entry into the deep venous system and as a result makes SVT a serious concern [9].\n\nThere is a risk for venous and arterial thrombosis in patients with SARS-Cov2 due to excessive coagulation status, blood stasis, and damage to vascular endothelial cells in this condition [10]. As the clinical signs of venous and arterial thrombosis are ambiguous, it is very important to use imaging techniques such as Doppler ultrasound and computed tomography (CT) angiography to prevent catastrophic complications such as pulmonary embolism and mortality [11]. In this case report, the course of a patient with coronavirus is described.\n\nCase presentation\n\nA 40-year-old man with one-week symptoms of cough, fever, fatigue, muscle aches, diarrhea, palpitations, and shortness of breath but no chest pain was admitted to Tohid Hospital, Sanandaj, Iran. Before admission, the patient was diagnosed with COVID-19 by an infectious disease specialist based on the initial symptoms. Both CT scans (Fig. 1) and the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed the infection. The patient had no history of underlying diseases such as diabetes, heart disease, hypertension, or cancer. At the hospital’s emergency department, the physical examinations showed that the patient had an irregular heart rate of 145 beats/min, blood pressure of 82/75 mmHg, temperature of 38.4 °C, respiratory rate of 26 breaths/min, and oxygen saturation of 89%. Paraclinical and laboratory results showed that routine blood tests, renal function, and electrolytes were completely normal. The influenza A and B antigen tests were also negative. However, the other laboratory findings were all abnormal, which are briefly listed in Table 1. In CT scans of the lungs (Fig. 1), bronchovascular marking is evident. Additionally, multiple foci of parenchymal turbidity and ground-glass opacity were observed with greater density at the margins and at the base of the lungs. Therefore, the patient was started on medical treatment with Naproxen, Hydroxychloroquine, Famotidine, Zinc, Neurobion, and anticoagulants by injecting heparin and taking acetylsalicylic acid tablets. Fig. 1 Axial without contrast-enhanced chest computed tomography (CT) image showing a coronavirus disease (COVID-19) infection\n\nTable 1 The results of laboratory findings\n\n\tTest Name\tUnit\tReference range\tResults\tFlag\t\n1\tBUN\tmg/dl\t6–20\t32\tHi\t\n2\tCPK\tIU/L\tmale: 0–171\t55\t\t\n3\tLDH\tU/L\t235–470\t510\tHi\t\n4\tNa(ser)\tmEq/L\t138–145\t134\tLOW\t\n5\tK(ser)\tmEq/L\t3.6–5.9\t3.8\t\t\n6\tCr\tmg/dl\tmale:0.8–1.3 mg/dl\t0.7\tLOW\t\n7\tCRP\tmg/l\t0–6\t30\tHi\t\n8\tESR\tmm\t5–12\t18\tHi\t\n9\tFerritin CLIA\tng/mL\t50–434\t511\tHi\t\n10\tD-Dimer(CLIA-Siemens)\tng/mL\t< 885\t> 7500\tHi\t\n\nThree days after hospitalization, Doppler ultrasound was performed on the lower limb due to numbness and tingling (paresthesia) in the right leg, in addition to swelling, redness, pain, and sensitivity to touch. Examination of the main veins of both lower limbs showed no evidence of occlusion in the external iliac, common femoral, popliteal, anterior and posterior tibialis, and peroneal. However, more detailed examination revealed that thrombosis was evident at the beginning of the greater saphenous vein of the right leg from distal to proximal (Fig. 2). The patient was discharged after 12 days of hospitalization with complete recovery from COVID-19. The anticoagulation treatment for the GSV thrombosis was continued for the patient, and no negative side effect caused by SVT was reported after the treatment. Fig. 2 Doppler ultrasound images of the lower right limb showing a superficial vein thrombosis (SVT). Anterior accessory saphenous vein (AASV), great saphenous vein (GSV), common femoral vein (CFV), and common femoral artery (CFA) in the Doppler ultrasound images of the lower right limb\n\nDiscussion\n\nIn this case report, we presented a patient with COVID-19 who was hospitalized in Tohid Hospital, Sanandaj, Iran and later was diagnosed with a thrombosis in his right GSV. This patient had common COVID-19 symptoms such as fever, dry cough, shortness of breath, and muscle pain [12] but no risk factor for SVT. Paraclinical tests and CT scans of the chest confirmed the COVID-19 diagnosis, and although there was no obvious evidence of SVT, detailed examination by Doppler ultrasound revealed a thrombosis in the patient’s GSV.\n\nStudies have shown that the most important and stable hemostatic disorders associated with COVID-19 include mild thrombocytopenia [13] and an increase in D-dimer amount [14]. There is evidence showing thrombotic abnormalities, in addition to abnormalities in the function of various organs in patients with COVID-19 [15], which lead to higher mortality. However, as far as we can ascertain there are few reports of SVT and its side effects in patients with COVID-19.\n\nPathophysiologically, patients with COVID-19 may have a higher risk for developing venous thrombosis, usually due to diarrhea, hypotension, recurrent long-term infections, and dehydration [16]. Therefore, in patients with coronavirus, assessing the risk of DVT and SVT are essential to reduce complications and mortality risk. Studies have shown that patients prone to DVT usually have one of the following criteria: age over 75, respiratory and heart failure, history of previous thrombosis, acute onset of chronic pulmonary obstruction, acute cerebral infarction, malignant tumor, limb varicose veins, obesity, chronic kidney disease, inflammatory bowel disease, and more than 3 days of bed rest [17].\n\nIn one study on a patient with COVID-19, CT images of angiography showed signs of acute cerebral infarction and DVT in both lower limbs [18]. In our case report, the patient was suspected of having thromboembolism due to having similar lesions on his leg, however after a CT scan of his chest, his diagnosis with COVID-19 was confirmed, while there was no evidence of pulmonary thromboembolism. The physicians at the hospital also suspected SVT and DVT due to numbness, swelling, and pain in the right leg, which were examined by Doppler ultrasound of all blood vessels, including the common iliac, small saphenous, and greater saphenous. Since many studies have reported respiratory distress along with other clinical evidence of venous thrombosis, pulmonary embolism should be suspected [19, 20].\n\nA recent study on the intensive care unit (ICU) patients with COVID-19 found that the rate of thrombotic disorders in these patients is 31% [21]. Further, medical images have shown that 27% of such thrombotic disorders are due to venous thromboembolism, 3.7% to arterial thrombosis, and 81% to pulmonary embolism, which is the most common complication of thrombosis in ICU patients [21]. The possible reasons for venous thrombosis may include the fact that COVID-19 attacks the human body via the 2-angiotensin converting enzyme, which is found in various blood vessels and organs of the body [22]. Ultimately, coronaviruses cause cytokine waterfalls, including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα in the body, which can increase the risk of complications such as blood clots. This cytokine storm can be associated with the severity of the disease and its negative consequences [23, 24]. Blood clots formed in DVT may also have a variety of causes, including vascular damage, surgery, special medications, and limited mobility [25], but the exact cause of COVID-19-induced DVT is still unknown [26].\n\nConclusion\n\nCOVID-19 is an emerging source of venous thrombosis due to factors such as excessive coagulation, blood stasis, and endothelial damage. The main mechanism of SVT and DVT formation due to COVID-19 is unknown and has not yet been examined. Although COVID-19 cases presented with SVT and DVT are rare, recognizing SVT and DVT as potential complications of COVID 19 infection will be of great value. Imaging techniques such as CT, MRI, and ultrasound can confirm the diagnosis of SVT and DVT. Due to the possibility of COVID-19 infection in patients presenting with venous thrombosis or other thromboembolic diseases, it seems important to consider the presence of COVID-19 in their diagnosis.\n\nAcknowledgements\n\nThe authors thank all the teaching and medical staff of Kurdistan University of Medical Sciences for their effort in eradicating the virus around the clock.\n\nAuthors’ contributions\n\nMBHS supervised the study and wrote the manuscript; PF collected the clinical data; MA and FF analyzed the data and images; and NHS reviewed the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\n\nNo source of funding.\n\nAvailability of data and materials\n\nI have presented the data of the patient in the manuscript as a Table. I have submitted the figures separately as figures.\n\nDeclarations\n\nEthical approval and consent to participate\n\nThis research has been confirmed by the Research Center of Kurdistan University of Medical Sciences and Ethics Committee with the file number IR.MUK.REC.1399.087.\n\nConsent for publication\n\nWritten informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article which was approved by the Research Center of Kurdistan University of Medical Sciences.\n\nCompeting interests\n\nAll authors declare that there is no conflict of interest that prejudices the impartiality of this scientific work.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Holshue ML, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929–36.\n2. Wang D Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China JAMA 2020 323 11 1061 1069 10.1001/jama.2020.1585 32031570\n3. Li L, et al. Using Artificial Intelligence to Detect COVID-19 and Community-acquired Pneumonia Based on Pulmonary CT: Evaluation of the Diagnostic Accuracy. Radiology. 2020;296(2):E65–71.\n4. Lodigiani C, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9–14.\n5. Sobreira ML Prevalence of deep vein thrombosis and pulmonary embolism in superficial thrombophlebitis of the lower limbs: prospective study of 60 cases Int Angiol 2009 28 5 400 19935595\n6. Subramaniam P Van Doornum S Superficial thrombophlebitis: underlying hypercoagulable states Aust N Z J Surg 1999 69 6 461 463 10.1046/j.1440-1622.1999.01599.x 10392894\n7. Decousus H Leizorovicz A Superficial thrombophlebitis of the legs: still a lot to learn J Thromb Haemost 2005 3 6 1149 1151 10.1111/j.1538-7836.2005.01445.x 15946201\n8. Leon L Clinical significance of superficial vein thrombosis Eur J Vasc Endovasc Surg 2005 29 1 10 17 10.1016/j.ejvs.2004.09.021 15570265\n9. Sover ER Brammer HM Rowedder AM Thrombosis of the proximal greater saphenous vein: ultrasonographic diagnosis and clinical significance J Ultrasound Med 1997 16 2 113 116 10.7863/jum.1997.16.2.113 9166803\n10. NHCotPsRo, C New coronavirus pneumonia prevention and control program (seventh trial edition) 2020\n11. Dunnihoo DR Postpartum ovarian vein thrombophlebitis: a review Obstet Gynecol Surv 1991 46 7 415 427 10.1097/00006254-199107000-00002 1876354\n12. Li Y Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China 2020\n13. Lippi G, et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020;506:145–8.\n14. Terpos E, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834–47.\n15. Vickers NJ Animal communication: when i’m calling you, will you answer too? Curr Biol 2017 27 14 R713 R715 10.1016/j.cub.2017.05.064 28743020\n16. Zhou B, et al. Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report. J Thromb Thrombolysis. 2020;50(1):229–32.\n17. Wells PS Forgie MA Rodger MA Treatment of venous thromboembolism JAMA 2014 311 7 717 728 10.1001/jama.2014.65 24549552\n18. Zhou B, et al. A case of coronavirus disease 2019 with concomitant acute cerebral infarction and deep vein thrombosis. Front Neurol. 2020;11:296.\n19. Xie Y COVID-19 complicated by acute pulmonary embolism Radiol Cardiothorac Imaging 2020 2 2 e200067 10.1148/ryct.2020200067\n20. Danzi GB Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020 41 19 1858 10.1093/eurheartj/ehaa254 32227120\n21. Klok FA, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145–7.\n22. Zhang H Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target Intensive Care Med 2020 46 4 586 590 10.1007/s00134-020-05985-9 32125455\n23. Zheng Y-Y COVID-19 and the cardiovascular system Nat Rev Cardiol 2020 17 5 259 260 10.1038/s41569-020-0360-5 32139904\n24. Huang C Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 10223 497 506 10.1016/S0140-6736(20)30183-5 31986264\n25. Tarannum N Azam MS Premchand RK May-Thurner syndrome and recurrent DVT: a case report Indian J Clin Cardiol 2020 1 1 13 16 10.1177/2632463619898010\n26. Davoodi L COVID-19 presented with deep vein thrombosis: an unusual presenting J Investig Med High Impact Case Rep 2020 8 2324709620931239 32493073\n\n", "fulltext_license": "CC BY", "issn_linking": "2055-0936", "issue": "7(1)", "journal": "Tropical diseases, travel medicine and vaccines", "keywords": "COVID-19; Case report; Coronavirus; Superficial vein thrombosis; Ultrasonography", "medline_ta": "Trop Dis Travel Med Vaccines", "mesh_terms": null, "nlm_unique_id": "101674442", "other_id": null, "pages": "6", "pmc": null, "pmid": "33658082", "pubdate": "2021-03-03", "publication_types": "D016428:Journal Article", "references": "24549552;10392894;19935595;32178975;32031570;32282949;32125455;32004427;32353746;32291094;28743020;15570265;1876354;32139904;32306290;32390931;32227120;9166803;32191588;15946201;31986264;32134381;32493073", "title": "A case report of greater saphenous vein thrombosis in a patient with coronavirus (COVID-19) infection.", "title_normalized": "a case report of 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{ "abstract": "Solitary cysticercus localized to the head and neck musculature is an unusual form of presentation of cysticercosis. Since it is rare and has non-specific manifestations, it can present a diagnostic challenge to the clinician. Our patient was a 16-year-old female who presented with a gradually increasing, painful swelling over right temple region of 6-month duration. Ultrasound and computed tomography scan revealed the presence of a solitary cysticercus in the right temporalis muscle. Surgical excision of the lesion was combined with a 4-week course of the anti-helminthic drug, Albendazole. Patient had a satisfactory resolution of symptoms and there was no recurrence in a follow-up period of 3 years. We suggest that cysticercosis should be considered as one of the possibilities in the differential diagnosis of swellings in the maxillofacial region, especially in the endemic areas. Imaging studies play an important role in confirmation of the diagnosis.", "affiliations": "Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India.;Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India.", "authors": "Cheruvu\|Ved Prakash R\|VPR\|;Khan\|Manal M\|MM\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/jscr/rjab223", "fulltext": "\n==== Front\nJ Surg Case Rep\nJ Surg Case Rep\njscr\nJournal of Surgical Case Reports\n2042-8812\nOxford University Press\n\n10.1093/jscr/rjab223\nrjab223\nCase Report\nAcademicSubjects/MED00910\njscrep/090\nSolitary cysticercus in the right temporalis muscle: case report of a rare form of presentation of cysticercosis\nCheruvu Ved Prakash R Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India\n\nKhan Manal M Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India\n\nCorrespondence address. R. No. 1017, 1st Floor, Academic Block, Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Saketnagar, Bhopal, Madhya Pradesh 462020, India. Tel: +91-8872209777; E-mail: [email protected]\n6 2021\n04 6 2021\n04 6 2021\n2021 6 rjab22322 4 2021\n11 5 2021\nPublished by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2021.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]\n\nAbstract\n\nSolitary cysticercus localized to the head and neck musculature is an unusual form of presentation of cysticercosis. Since it is rare and has non-specific manifestations, it can present a diagnostic challenge to the clinician. Our patient was a 16-year-old female who presented with a gradually increasing, painful swelling over right temple region of 6-month duration. Ultrasound and computed tomography scan revealed the presence of a solitary cysticercus in the right temporalis muscle. Surgical excision of the lesion was combined with a 4-week course of the anti-helminthic drug, Albendazole. Patient had a satisfactory resolution of symptoms and there was no recurrence in a follow-up period of 3 years. We suggest that cysticercosis should be considered as one of the possibilities in the differential diagnosis of swellings in the maxillofacial region, especially in the endemic areas. Imaging studies play an important role in confirmation of the diagnosis.\n==== Body\nINTRODUCTION\n\nCysticercosis is a parasitic affliction of the tissues caused by Cysticercus cellulosae, which is the larval stage of pork tape worm Taenia solium. It was described for the first time by Johannes Udalric Rumler in 1555 [1]. It commonly occurs in the areas where there is a combination of uncontrolled pig breeding, poor sanitation and close interaction between humans and animals. This condition is endemic in the developing countries of Asia, Africa and Latin America. In 2010, cysticercosis was designated as one of the 17 ‘neglected tropical diseases (NTDs)’ of worldwide public health importance by the World Health Organization (WHO). In the year 2015, the WHO’s Foodborne Disease Burden Epidemiology Reference Group established that T. solium was a leading cause of mortality from food-borne illnesses, resulting in 2.8 million disability-adjusted life-years [2].\n\nCysticercus cellulosae is found in muscles and other tissues of pigs that usually serve as intermediate hosts, whereas humans are the definitive hosts and harbor the adult worm. Pigs acquire the infection when they ingest contaminated food or water that contains proglottids or eggs from human feces. The eggs develop into cysticerci in pig muscles.\n\nFigure 1 Picture at initial presentation, frontal view, arrow indicates the swelling.\n\nFigure 2 Picture at initial presentation, oblique view.\n\nFigure 3 No restriction of mouth opening at initial presentation.\n\nFigure 4 Intraoperative picture, arrow indicates the cysticercus cyst.\n\nHuman infection occurs when these are ingested through the consumption of raw or undercooked pork. Humans can also acquire infection through T. solium eggs due to poor hygiene (via fecal–oral route) or ingestion of contaminated water or food [2]. In this case, humans become the accidental intermediate hosts. These ova are digested in the stomach and oncospheres are released, which penetrate the intestinal wall and reach the circulation [3]. This may lead to cysticercosis that commonly involves the brain, meninges and eyes, which together constitute 86% of the cases. Less commonly they are located in the muscles, subcutaneous tissues, liver, heart, lungs and peritoneum [4]. Rarely, they are localized to the oral and perioral tissues like the muscles of mastication, muscles of facial expression, suprahyoid muscles, post-cervical musculature, tongue, buccal mucosa and lips [5–7]. Isolated head and neck muscular cysticercosis without the involvement of central nervous system is rare and only few cases are reported in the literature [8]. These cases have non-specific clinical manifestations and present a diagnostic challenge to the clinician [9].\n\nFigure 5 Three months post-surgery, frontal view.\n\nFigure 6 Three months post-surgery, oblique view.\n\nFigure 7 Three months post-surgery, lateral view.\n\nFigure 8 Three-year follow-up, frontal view.\n\nCASE REPORT\n\nA 16-year-old female patient had presented to us with the complaint of a gradually increasing painful swelling over the right temple region of 6 months duration. She had a history of minor trauma to the site due to a fall 6 months back. There was no restriction in mouth opening or difficulty in chewing. There were no symptoms suggestive of neurological involvement.\n\nOn examination, there was a solitary swelling in the right temporal region with ill-defined margins. It had a soft to firm consistency and was mildly tender on palpation. Mouth opening was adequate (Figs 1–3). There were no other significant findings on examination.\n\nUltrasound revealed a hypoechoic cystic lesion in the right temporalis muscle with an eccentric hyperechoic nodule. Computed tomography (CT) scan confirmed the presence of a well-defined cystic lesion with an eccentric hypointense nidus in the right temporalis muscle. There were no other similar lesions in the head and neck region. These features suggested a diagnosis of a solitary cysticercosis involving the right temporalis muscle.\n\nPatient was initially kept on conservative treatment with Albendazole 15 mg/kg body weight/day in two divided doses for 2 weeks. As there was no relief in the pain or swelling, we decided to go for surgical exploration. The lesion was approached through a vertical incision in the right temporal region. Intraoperatively, ~5 ml of pus and a white opalescent cystic lesion, within a cavity were found (Fig. 4). The cavity and surgical field were thoroughly irrigated with Povidone-Iodine before closing the incision over a suction drain. Culture of the pus did not yield growth of any microbes. The suture line healed well and the swelling resolved (Figs 5–7). Histopathological examination confirmed the lesion to be a cysticercus cyst.\n\nAlbendazole was continued for 2 more weeks. Patient was followed-up regularly and there was no recurrence during a 3-year follow-up period (Figs 8–10).\n\nFigure 9 Three-year follow-up, oblique view.\n\nFigure 10 Three-year follow-up, lateral view.\n\nDISCUSSION\n\nThe clinical course of cysticercosis depends on the number of lesions, the tissues affected and the reaction of the tissues to these organisms [6]. Commonly, patients present with multiple lesions such as cysts of different sizes or multiple nodular calcifications and these may be associated with varying degrees of host response [10]. Cysticercosis may remain asymptomatic for a variable period or present with severe local symptoms. Various types of clinical presentations such as myalgic, myopathic, nodular or mass like and the rare pseudohypertrophy have been reported [9]. The cysts are of ovoid or round shape, white or opalescent color, up to 1.5-cm size and contain an invaginated scolex with hooklets [9].\n\nIsolated head and neck muscle cysticercosis is unusual and solitary cysticercosis localized to temporalis muscle is rarer [11]. Since it is rare and has non-specific manifestations, it can present a diagnostic challenge to the clinician [9].\n\nImaging studies (ultrasonography, CT or magnetic resonance imaging) play an important role in the diagnosis of cysticercosis. Vijayaraghavan described four kinds of sonographic appearances of muscular cysticercosis [12].\n\nTreatment of cysticercosis should be based on the clinical manifestations and the tissues affected. Praziquantel and Albendazole are the recommended anti-helminthic medications [13]. Surgical excision is the treatment of choice for ventricular, ocular, spinal and symptomatic subcutaneous cysticerci [14].\n\nIn the maxillofacial region, prognosis is favorable in contrast to the seriousness of the disease in the cerebral, ocular and cardiac sites [15]. There are no reported recurrences after treatment.\n\nWe suggest that cysticercosis should be considered as one of the possibilities in the differential diagnosis of swellings in the maxillofacial region, especially in the endemic areas. Imaging studies play an important role in confirming the diagnosis and should be sought out in cases with non-specific clinical manifestations.\n\nACKNOWLEDGMENTS\n\nWe acknowledge the contributions of our residents and staff in helping with the patient care and follow-up.\n==== Refs\nReferences\n\n1. Chand S, Mishra M, Singh G, Singh A, Tandon S. Orofacial cysticercosis: report of a rare case with review of literature. Natl J Maxillofac Surg 2016;7 :209–12.28356697\n2. World Health Organisation. Taeniasis/Cysticercosis [Internet]. [12 April 2021, date last accessed]. Available from: https://www.who.int/news-room/fact-sheets/detail/taeniasis-cysticercosis.\n3. Singh S, Sreenivasan V, Garg K, Wazir ND, Rajput JS, Sandhu Virk P. Cysticercosis involving muscle of mastication: a review and report of two cases. Case Rep Dent 2013; 2013 :814126.\n4. Rao SC, Sharma H, Vinay KN, Vidya KC. Oral Cysticercosis - A Case Report. Int. Journal of Clinical Dental Science 2011;2 :36–9.\n5. Timoşca G, Gavriliţă L. Cysticercosis of the maxillofacial region. A clinicopathologic study of five cases. Oral Surg Oral Med Oral Pathol 1974;37 :390–400.4521458\n6. Kinnman J, Chi CH, Park JH. Cysticercosis in otolaryngology. Arch Otolaryngol 1976;102 :144–7.1267689\n7. Tschen EH, Tschen EA, Smith EB. Cutaneous cysticercosis treated with metrifonate. Arch Dermatol 1981;117 :507–9.7259247\n8. Abdelwahab IF, Klein MJ, Hermann G, Abdul-Quader M. Solitary cysticercosis of the biceps brachii in a vegetarian: a rare and unusual pseudotumor. Skeletal Radiol 2003;32 :424–8.12730733\n9. Sharma P, Neupane S, Shrestha M, Dwivedi R, Paudel K. An ultrasonographic evaluation of solitary muscular and soft tissue cysticercosis. Kathmandu Univ Med J 2010;8 :257–60.\n10. Nash TE. Human case management and treatment of cysticercosis. Acta Trop 2003;87 :61–9.12781379\n11. Rastogi S, Arora P, Devi P, Wazir SS, Kapoor S. Importance of ultrasonography and magnetic resonance imaging in diagnosis of cysticercosis of temporalis muscle mimicking temporal space infection. Contemp Clin Dent 2013;4 :504.24403797\n12. Vijayaraghavan SB. Sonographic appearances in cysticercosis. Ultrasound Med 2004;23 :423–7.\n13. Kumar V, Abbas A, Faustro N. Pathological Basis of Diseases, 7th edn. New York: W B Saunders, 2004, 406–7.\n14. Kumar BD, Dave B, Meghana SM. Cysticercosis of masseter. Indian J Dent Res 2011;22 :617.22124076\n15. Deshmukh A, Avadhani A, Tupkari JV, Sardar M. Cysticercosis of the upper lip. J Oral Maxillofac Pathol 2011;15 :219.22529585\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2042-8812", "issue": "2021(6)", "journal": "Journal of surgical case reports", "keywords": null, "medline_ta": "J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101560169", "other_id": null, "pages": "rjab223", "pmc": null, "pmid": "34104406", "pubdate": "2021-06", "publication_types": "D002363:Case Reports", "references": "24396612;12781379;22124076;12730733;15055791;4521458;22529585;1267689;24403797;28356697;7259247;21209548", "title": "Solitary cysticercus in the right temporalis muscle: case report of a rare form of presentation of cysticercosis.", "title_normalized": "solitary cysticercus in the right temporalis muscle case report of a rare form of presentation of cysticercosis" }	[ { "companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2022-06654", "fulfillexpeditecriteria": "2", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALBENDAZOLE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "211636", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MILLIGRAM/KILOGRAM, QD (IN TWO DIVIDED DOSES FOR 2 WEEK. LATER, ALBENDAZOLE WAS CONTINUED FOR 2 M", "drugenddate": null, "drugenddateformat": null, "drugindication": "Taeniasis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALBENDAZOLE" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Cheruvu VPR, Khan MM. Solitary cysticercus in the right temporalis muscle: Case report of a rare form of presentation of cysticercosis. Journal of Surgical Case Reports. 2021;2021(6):1-4", "literaturereference_normalized": "solitary cysticercus in the right temporalis muscle case report of a rare form of presentation of cysticercosis", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20220509", "receivedate": "20220509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20804157, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently demonstrated cardiovascular (CV) safety versus placebo in Asians with advanced type 2 diabetes mellitus (T2DM) in the CARMELINA® trial. We assessed its CV safety compared with the sulfonylurea glimepiride in Asians with relatively early T2DM in the CAROLINA® trial.\nBased on prespecified and post hoc subgroup analyses of the multinational CAROLINA® trial in which adults with relatively early T2DM and elevated CV risk were randomized to linagliptin or glimepiride added to usual care, we analyzed data for participants from Asian countries. This included the primary outcome defined as time to first CV death, non-fatal myocardial infarction, or non-fatal stroke [three-point major adverse cardiovascular events (3P-MACE)].\nOf the 6033 participants, 933 (15.5%) were from Asia. During a median follow-up of 6.2 years, 3P-MACE occurred in 9.5% and 11.1% of the linagliptin and glimepiride groups, respectively (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.57-1.26]), consistent with the overall population (HR 0.98; 95% CI 0.84-1.13; P = 0.17 for treatment by region interaction). Similarly, there were no significant differences between groups for other outcomes, including CV death (HR 0.73; 95% CI 0.38-1.38), non-CV mortality (HR 0.76; 95% CI 0.37-1.57) and hospitalization for heart failure (HR 0.89; 95% CI 0.36-2.19). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; 95% CI 0.19-0.33; P < 0.0001) despite similar glycemic control. Body weight was slightly lower with linagliptin relative to glimepiride: weighted average mean difference over 256 weeks of - 1.82 kg (95% CI - 2.28 to - 1.35).\nIn Asian patients, linagliptin demonstrated similar CV safety to glimepiride with a markedly lower rate of hypoglycemia and modestly lower weight.", "affiliations": "Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470 Japan.;Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.;Dallas Diabetes Research Center at Medical City and University of Texas Southwestern Medical Center, Dallas, TX USA.;Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Internal Medicine 1, Faculty of Medicine, Shimane University, Shimane, Japan.;Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.;Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.;Boehringer Ingelheim Norway KS, Asker, Norway.;Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.", "authors": "Kadowaki\|Takashi\|T\|;Wang\|Guang\|G\|;Rosenstock\|Julio\|J\|;Yabe\|Daisuke\|D\|;Peng\|Yongde\|Y\|;Kanasaki\|Keizo\|K\|;Mu\|Yiming\|Y\|;Mattheus\|Michaela\|M\|;Keller\|Annett\|A\|;Okamura\|Tomoo\|T\|;Johansen\|Odd Erik\|OE\|;Marx\|Nikolaus\|N\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1007/s13340-020-00447-5", "fulltext": null, "fulltext_license": null, "issn_linking": "2190-1678", "issue": "12(1)", "journal": "Diabetology international", "keywords": "Cardiovascular; Diabetes mellitus, type 2", "medline_ta": "Diabetol Int", "mesh_terms": null, "nlm_unique_id": "101553224", "other_id": null, "pages": "87-100", "pmc": null, "pmid": "33479584", "pubdate": "2021-01", "publication_types": "D016428:Journal Article", "references": "30291106;28025462;30690856;4926376;30418475;31271669;19470990;1091761;24300015;17070446;32444457;8842603;31497854;23842096;29974673;29582574;6985989;30983138;27464265;32206483;30926258;23803294;16239637;17517853;23589542;26908931;30497881;29527102;23449634;31748210;27133171;31857443;25287289;31536101;31002328;25780262;28428321;23637538;23551121;18539916;31504427;31239281", "title": "Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial.", "title_normalized": "effect of linagliptin a dipeptidyl peptidase 4 inhibitor compared with the sulfonylurea glimepiride on cardiovascular outcomes in asians with type 2 diabetes subgroup analysis of the randomized carolina trial" }	[ { "companynumb": "US-PFIZER INC-2012197505", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, 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"drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LASIX" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "69", "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20120529" } }, "primarysource": { "literaturereference": "KADOWAKI, T.. EFFECT OF LINAGLIPTIN, A DIPEPTIDYL PEPTIDASE?4 INHIBITOR, COMPARED WITH THE SULFONYLUREA GLIMEPIRIDE ON CARDIOVASCULAR OUTCOMES IN ASIANS WITH TYPE 2 DIABETES: SUBGROUP ANALYSIS OF THE RANDOMIZED CAROLINA TRIAL. DIABETOLOGY INTERNATIONAL. 2021?12 (1):87?100", "literaturereference_normalized": "effect of linagliptin a dipeptidyl peptidase 4 inhibitor compared with the sulfonylurea glimepiride on cardiovascular outcomes in asians with type 2 diabetes subgroup analysis of the randomized carolina trial", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "US", "receiptdate": "20210127", "receivedate": "20120820", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 8732903, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210420" } ]
{ "abstract": "The avoidance of any form of anticoagulation is advised in cases of cholesterol embolization syndrome (CES). We herein describe a case of CES in a man with a history of unprovoked pulmonary embolism for which warfarinization was performed. Despite anecdotal reports of successful anticoagulation in CES patients with certain indications, irreversible renal failure, which was sufficiently severe to require chronic hemodialysis, eventually developed in our patient. Our results emphasize the pitfalls of this procedure, which imply its limited feasibility and safety. Several therapeutic concerns associated with this case are also discussed.", "affiliations": "Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.", "authors": "Igarashi\|Yusuke\|Y\|;Akimoto\|Tetsu\|T\|;Kobayashi\|Takahisa\|T\|;Iwazu\|Yoshitaka\|Y\|;Miki\|Takuya\|T\|;Otani-Takei\|Naoko\|N\|;Imai\|Toshimi\|T\|;Sugase\|Taro\|T\|;Masuda\|Takahiro\|T\|;Takeda\|Shin-Ichi\|SI\|;Muto\|Shigeaki\|S\|;Nagata\|Daisuke\|D\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/1179547616684649", "fulltext": "\n==== Front\nClin Med Insights Case RepClin Med Insights Case RepICRspicrClinical Medicine Insights. Case Reports1179-5476SAGE Publications Sage UK: London, England 2846949710.1177/117954761668464910.1177_1179547616684649ICR-41061Case ReportPerforming Anticoagulation: A Puzzling Case of Cholesterol Embolization Syndrome Igarashi Yusuke Akimoto Tetsu Kobayashi Takahisa Iwazu Yoshitaka Miki Takuya Otani-Takei Naoko Imai Toshimi Sugase Taro Masuda Takahiro Takeda Shin-ichi Muto Shigeaki Nagata Daisuke Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, JapanTetsu Akimoto, Division of Nephrology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan. Email: [email protected] 2 2017 2017 10 11795476166846495 10 2016 21 11 2016 © The Author(s) 20172017SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).The avoidance of any form of anticoagulation is advised in cases of cholesterol embolization syndrome (CES). We herein describe a case of CES in a man with a history of unprovoked pulmonary embolism for which warfarinization was performed. Despite anecdotal reports of successful anticoagulation in CES patients with certain indications, irreversible renal failure, which was sufficiently severe to require chronic hemodialysis, eventually developed in our patient. Our results emphasize the pitfalls of this procedure, which imply its limited feasibility and safety. Several therapeutic concerns associated with this case are also discussed.\n\nCholesterol crystal embolizationpulmonary embolismwarfarinend-stage kidney diseasehemodialysiscover-dateJanuary-December 2017\n==== Body\nIntroduction\nCholesterol embolization syndrome (CES) is a multisystem ischemic damage characterized by the occlusion of small vessels with cholesterol crystals that originate from ruptured atherosclerotic plaques lining the walls of major arteries.1 Plaque rupture may be spontaneous, iatrogenic after arterial manipulations, and/or related to thrombolytic therapy and anticoagulation.1,2 Although any organ may be affected, the brain, kidneys, gastrointestinal tract, skin, and skeletal muscles of the lower extremities are the most frequently involved.2 No specific treatment has been established for CES, and therapeutic modalities for this disease are still symptomatic and preventive.1–3 The avoidance of any form of anticoagulation is an alternative therapeutic option1–3; however, this strategy may not necessarily be appropriate for some subsets of CES patients with separate indications, such as mechanical prosthetic valves, atrial fibrillation, and deep vein thrombosis.1,2,4 In the current report, we describe our experience with one such case of CES in a man who had a history of unprovoked pulmonary embolism (PE), which obliged us to pursue anticoagulation with warfarin during the observation period. Several therapeutic concerns that emerged in this case are also discussed.\n\nCase Report\nA 76-year-old man was admitted in June 2014 due to progressive deterioration of renal function, loss of appetite, and asthenia. Nine months prior to his admission (September 2013), he was diagnosed with effort angina and infrarenal abdominal aortic aneurysm. At the beginning of October 2013, he was found to have unprovoked PE for which he had received oral warfarin, delivering a prothrombin time-international normalized ratio (PT-INR) of 1.7 to 2.1 (reference range: 0.9-1.2) with a favorable clinical course. He had no history of renal disease, and steady serum creatinine (sCr) levels ranging between 0.96 and 1.12 mg/dL (reference range: 0.63-1.03 mg/dL) were noted until mid-December 2013. His sCr level was 1.89 mg/dL in mid-March 2014 and increased to 7.33 mg/dL in early June 2014. Therefore, he was referred and admitted to our hospital for further examination. His medical history included a diagnosis of acute myocardial infarction at 58 years of age. He had been a smoker for more than 40 years but denied the use of any drugs.\n\nAt the time of admission, the patient was alert and had a temperature of 36.4°C, a heart rate of 89 beats/min, and a blood pressure of 176/94 mm Hg. His physical examination revealed livedo reticularis on the soles of his toes and a blue-purple discoloration of all toes bilaterally (Figure 1A), whereas his feet were warm to the touch and the peripheral pulse remained intact. Laboratory examinations revealed the following: blood urea nitrogen (BUN), 64 mg/dL (reference range: 8-20 mg/dL); sCr, 7.23 mg/dL; white blood cell count, 9800/µL (reference range: 3900-9800/µL); eosinophils, 1092/µL (reference range: 0-400/µL); platelet count, 166 × 103/µL (reference range: 130-369 × 103/µL); erythrocyte sedimentation rate (ESR), 59 mm/h (reference range: 0-10 mm/h); serum albumin, 3.5 g/dL (reference range: 6.9-8.4 g/dL); triglycerides, 203 mg/dL (reference range: 40-185 mg/dL); low-density lipoprotein (LDL) cholesterol, 129 mg/dL (reference range: <139 mg/dL), fibrinogen, 410 mg/dL (reference range: 129-271 mg/dL); fibrin/fibrinogen degradation products, 13.5 µg/mL (reference range: 0-5 µg/mL); D-dimer, 5900 µg/L (reference range: 0-1500 µg/L); PT-INR, 1.76; C3, 104 mg/dL (reference range: 86-160 mg/dL); C4, 45 mg/dL (reference range: 17-45 mg/dL); and C-reactive protein, 0.49 mg/dL (reference range: 0-0.14 mg/dL). Tests for anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane antibodies, hepatitis B virus surface antigen (HBsAg), anti-HBsAg antibodies, and antibodies to the hepatitis C virus were all negative. His urine was trace positive for protein, 2+ for occult blood, and contained 0.09 g of protein in a 24-hour specimen, whereas his creatinine clearance was 3.9 mL/min. The urinary excretion of β2-microglobulin and N-acetyl-beta-d-glucosaminidase was 22 856 µg/L (reference range: <200 µg/L) and 5.4 U/g·Cr (reference range: 0.9-2.4 U/g·Cr), respectively. A computed tomographic scan revealed a calcified thoracic aorta without a dimensional disorder and an infrarenal aortic aneurysm with a maximum diameter of approximately 4.4 cm. Diagnostic noncontrast-enhanced T2-weighted half-fourier-acquired single-shot turbo spin ecocho (HASTE) magnetic resonance imaging subsequently revealed hypointense areas and bright signals, which were suggestive of an atheromatous plaque consisting of lipids and fibrous tissues, respectively,5 in the abdominal aorta (Figure 1B). Oral warfarin was discontinued on admission, and the patient was subjected to empirical treatment with pravastatin at a dose of 10 mg/day combined with limaprost alfadex at a dose of 30 µg/day. A 5-mm-deep punch biopsy was performed on clinical day 7 within the territory of livedo reticularis on the lateral aspect of the left first toe. Typical biconvex needle-shaped empty spaces, suggestive of cholesterol clefts,1,3 were observed within the lumen of the arteriole in the subcutis (Figure 1C). A diagnosis of CES was made based on pathological and imaging findings as well as clinical manifestations.\n\nFigure 1. Physical, magnetic resonance imaging (MRI), and pathological findings. Bluish reticulated patches were noted on the soles and tips of the toes (A), whereas T2-weighted HASTE diagnostic MRI (B) at a slightly more cephalic position from the renal arteries revealed an atherosclerotic plaque consisting of lipids (arrow) and fibrous (arrowhead) tissues in the abdominal aorta. Abnormal fluid-filled lesions (*), which may be ascribed to bilateral simple renal cysts, were also noted. Light microscopy of cutaneous biopsy sections revealed characteristic cholesterol clefts occluding the lumen of the arteriole (C, hematoxylin-eosin stain; the scale bar is indicated).\n\nDue to the elevated D-dimer level of 10 600 µg/L confirmed on clinical day 8, the decision was made to resume anticoagulation therapy despite our failure to detect deep venous thrombotic lesions using ultrasonography. The patient was treated with intravenous heparin and then switched to warfarin 2.5 mg/day on clinical day 30. Oral prednisolone (PSL) at a dose of 20 mg/day was also initiated on clinical day 22, resulting in the amelioration of eosinophilia and cutaneous manifestations within a few days and the subsequent stabilization of sCr levels at approximately 4.3 mg/dL. His elevated blood pressure was also controlled at approximately 120-130/70-80 mm Hg with irbesartan (100 mg/day) and amlodipine besilate (5 mg/day). However, sCr levels started to increase when PSL was tapered to 5 mg/day. The patient developed general fatigue, appetite loss, decline in urine output, and progressive swelling in both legs without any calf pain at the end of September 2014, with an elevated sCr level of 8.07 mg/dL, and was readmitted for further examinations. Similar to his initial admission, a laboratory analysis at this point revealed mild hypoalbuminemia (3.6 g/dL), whereas echocardiography and chest radiograph findings did not support the concurrent presence of heart failure. The relationship between deteriorated cutaneous manifestations and recurrent eosinophilia of 1365/µL resulted in the diagnosis of relapsed CES. The patient received hemodialysis (HD). After the resumption of an increased dose of PSL (15 mg/day) and the addition of a transient session of LDL apheresis (LDL-A) to the therapeutic regimen, his cutaneous manifestations improved and eosinophilia disappeared; however, severely deteriorated renal function did not recover, and he was finally started on a periodic HD program with favorable volume control (Figure 2).\n\nFigure 2. Changes in renal parameter values, PT-INR, and percentage of eosinophils. The number “0” was designated as the point of the initial admission, and the patient was discharged on clinical day 51. There was a transient improvement in sCr levels, whereas the irreversible nature of severe renal failure eventually resulted in the initiation of chronic HD despite an increase in the dose of PSL (15 mg/day) combined with 9 sessions of LDL-A. Note that the amounts of urinary excreted proteins, β2MG, and NAG were almost completely constant during the observation period. The conversion of BUN (mg/dL) to urea (mmol/L) is accomplished by multiplying BUN by 0.357. To convert milligram per deciliter to micromole per liter for sCr, multiply by 88.4.\n\nDiscussion\nThe clinical presentation of CES often consists of various signs specific to end-organ damage and systemic inflammatory responses.1 Patients with CES are more likely to be older men with a high prevalence of traditional cardiovascular risk factors and cardiovascular diseases6 and may present with a wide spectrum of clinical symptoms, including fever, weight loss, fatigue, anorexia, and myalgia with an elevated leukocyte count, rapid ESR, elevated C-reactive protein levels, high eosinophil blood counts, and, much more rarely, hypocomplementemia.1–3 The diagnostic hallmark of this disease is the histological confirmation of intravascular cholesterol crystals in biopsy specimens, whereas any organ system may be regarded as a candidate target for the procedure in theory.1,2 Although skin and muscle biopsies have a high diagnostic yield because of their favorable accessibility, it is important to note that tissues affected by CES are at risk of poor wound healing.1,2 Consequently, the clinical features of our patient are not surprising; however, the significance of our results needs to be evaluated carefully in terms of renal outcome after the resumption of anticoagulation.\n\nAlthough a causal link between anticoagulation and CES has yet to be proven or denied,1–3 anticoagulation may lead to plaque hemorrhaging, plaque rupture, and subsequent cholesterol crystal embolization.1,7–10 Thus, therapeutic options for CES ordinarily include a withdrawal from or the avoidance of any form of anticoagulation unless there is a separate indication, such as mechanical prosthetic valves, atrial fibrillation, and deep vein thrombosis.1,2 In the present case, we did not identify any associated triggers nor did we identify risk factors for PE, including recent major surgery, prolonged immobilization, and obesity.11–13 Previous anecdotal case reports demonstrating the successful use of warfarin and/or heparin for specific indications in patients with CES4,14–16 as well as the unprovoked nature of the disease, which may require indefinite long-term anticoagulation,11,17-19 and elevations in D-dimer levels after the suspension of anticoagulation prompted us to resume warfarinization to prevent the recurrence of PE in the present case. The dose of warfarin was controlled according to the recommended target PT-INR for venous thromboembolism based on the Japanese therapeutic guidance.11\n\nOur failure to perform a renal histological analysis may preclude us from precisely evaluating the impact of CES on renal pathology in the present patient. A number of conditions including small-vessel vasculitis and acute interstitial nephritis may simulate renal CES.20,21 However, the results of serological tests, as well as longitudinal data regarding urinary parameters, were unremarkable for these specific types of renal damage. The presence of a triad characterized by precipitating events such as anticoagulation, subacute renal failure, and pathologically confirmed peripheral cholesterol embolization prompted us to diagnose our patient with atheroembolic renal disease, as practiced in ordinary clinical settings.3,6 Fluctuations in estimated glomerular filtration rates may occasionally be observed during the given period of time before the commencement of renal replacement therapy, particularly in patients with cardiovascular disease22; thus, the transient improvement in renal function in our patient may mirror, at least in part, the natural course of end-stage kidney disease. Nevertheless, the tapering of PSL may be expected to attenuate corticosteroid-dependent lipid scavenging,23 thereby precipitating irreversible end-stage kidney disease through the exacerbation of latent inflammatory tissue injury due to warfarinization-mediated cholesterol embolism. We consider our results to emphasize the pitfalls of continuing or resuming anticoagulation even in CES patients who have separate indications, implying the limited feasibility and safety of this procedure.\n\nThe clinical course of the present patient did not allow us to precisely evaluate the therapeutic significance of statins and LDL-A, which have been attempted anecdotally as a therapeutic option for CES with limited success.1,2,24 Otherwise, our case may have emphasized the necessity of an extensive evaluation of the potential benefits of corticosteroids among patients with CES. Although the maintenance dose, duration, and tapering schedule of oral PSL in the present patient may not necessarily be adequate in terms of the overall renal outcome, the immediate decrease observed in sCr levels after the commencement of the treatment implies the therapeutic benefit of immunomodulation with steroids. The discrepancy between the results obtained for sCr and BUN levels after the resumption of the increased dose, as well as the initial dosing of oral PSL, was not unexpected because BUN levels are often elevated by excessive tissue catabolism resulting from the administration of corticosteroids.25,26\n\nRapid improvements in deteriorated renal function caused by CES have been demonstrated in patients treated with various therapeutic regimens using corticosteroids,3,27–29 implying that a number of these decisions are potentially empirical. We need to focus on previous findings showing that the tapering of corticosteroids coincides with the recurrence of CES, as in the present patient. In some subsets of CES patients, it may be necessary to either increase the dose or resume agents with careful monitoring for signs of exacerbation.28,30–33 There are currently no clear recommendations regarding how to administer corticosteroids to CES patients. No reliable indicators that may allow us to assess the optimal timing for the tapering of such agents have been reported. It also remains unclear which CES patients will benefit the most from corticosteroid treatments. Further encounters with similar cases to our patient will contribute to elucidating the therapeutic significance, as well as optimal duration and dosing of corticosteroids for this disease, thereby leading to the development of appropriate strategies for the treatment of CES patients.\n\nPeer Review:Seven peer reviewers contributed to the peer review report. Reviewers’ reports totaled 790 words, excluding any confidential comments to the academic editor.\n\nAuthor Contributions: YIgarashi and TA drafted the manuscript. TK, YIwazu, TMiki, NOT, TI, TS, and TMasuda helped with the acquisition of clinical data. ST, SM, and DN provided a detailed review of the contents and structure of the manuscript, resulting in significant changes to the original document. All the authors have read and approved the final manuscript.\n\nDisclosures and Ethics: As a requirement for publication, the authors have provided the publisher with signed confirmation of compliance with legal and ethical obligations, including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality, and (where applicable) the protection of human and animal research subjects. The authors have read and confirmed their agreement with the International Committee of Medical Journal Editors (ICMJE) authorship and conflict of interest criteria. The authors have also confirmed that this manuscript is unique and not under consideration for publication or published in any other publications and that they have permission from the rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by a Grant-in-Aid for Research on Advanced Chronic Kidney Disease, Practical Research Project for Renal Diseases, from the Japan Agency for Medical Research and Development, AMED.\n==== Refs\nReferences\n1 \nKronzon I Saric M. \nCholesterol embolization syndrome . Circulation . 2010 ;122 :631 –641 .20697039 \n2 \nQuinones A Saric M. \nThe cholesterol emboli syndrome in atherosclerosis . Curr Atheroscler Rep . 2013 ;15 :315 .23423524 \n3 \nMeyrier A. \nCholesterol crystal embolism: diagnosis and treatment . Kidney Int . 2006 ;69 :1308 –1312 .16614719 \n4 \nKim H Zhen DB Lieske JC \nTreatment of cholesterol embolization syndrome in the setting of an acute indication for anticoagulation therapy . J Med Cases . 2014 ;5 :376 –379 .25197328 \n5 \nFrank H. \nCharacterization of atherosclerotic plaques by magnetic resonance imaging . Am Heart J . 2001 ;141 :S45 –S48 .11174358 \n6 \nScolari F Ravani P Gaggi R \nThe challenge of diagnosing atheroembolic renal disease: clinical features and prognostic factors . Circulation . 2007 ;116 :298 –304 .17606842 \n7 \nBruns FJ Segel DP Adler S. \nControl of cholesterol embolization by discontinuation of anticoagulant therapy . Am J Med Sci . 1978 ;275 :105 –108 .665707 \n8 \nHyman BT Landas SK Ashman RF Schelper RL Robinson RA. \nWarfarin-related purple toes syndrome and cholesterol microembolization . Am J Med . 1987 ;82 :1233 –1237 .3605140 \n9 \nTalmadge DB Spyropoulos AC. \nPurple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome . Pharmacotherapy . 2003 ;23 :674 –677 .12741443 \n10 \nCortez AF Sakuma TH Lima RB \nCholesterol crystal embolization caused by anticoagulant therapy . Int J Dermatol . 2009 ;48 :989 –990 .19702986 \n11 \nNakamura M Yamada N Ito M. \nCurrent management of venous thromboembolism in Japan: current epidemiology and advances in anticoagulant therapy . J Cardiol . 2015 ;66 :451 –\n459 .25896176 \n12 \nNakamura M Fujioka H Yamada N \nClinical characteristics of acute pulmonary thromboembolism in Japan: results of a multicenter registry in the Japanese Society of Pulmonary Embolism Research . Clin Cardiol . 2001 ;24 :132 –138 .11214743 \n13 \nGoldhaber SZ. \nPulmonary embolism . N Engl J Med . 1998 ;339 :93 –104 .9654541 \n14 \nWakabayashi T Yoshizawa Y Kawana S. \nSuccessful use of heparin and warfarin in the treatment of cholesterol crystal embolization . J Dermatol . 2008 ;35 :111 –114 .18271808 \n15 \nAcker CG. \nCholesterol microembolization and stable renal function with continued anticoagulation . South Med J . 1992 ;85 :210 –212 .1738893 \n16 \nMoll S Huffman J. \nCholesterol emboli associated with warfarin treatment . Am J Hematol . 2004 ;77 :194 –195 .15389900 \n17 \nKearon C Gent M Hirsh J \nA comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism . N Engl J Med . 1999 ;340 :901 –907 .10089183 \n18 \nGoldhaber SZ Elliott CG. \nAcute pulmonary embolism: part II: risk stratification, treatment, and prevention . Circulation . 2003 ;108 :2834 –2838 .14662690 \n19 \nJaff MR McMurtry MS Archer SL ; and American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology . Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association . Circulation . 2011 ;123 :1788 –1830 .21422387 \n20 \nVidt DG. \nCholesterol emboli: a common cause of renal failure . Annu Rev Med . 1997 ;48 :375 –385 .9046969 \n21 \nScolari F Tardanico R Zani R \nCholesterol crystal embolism: a recognizable cause of renal disease . Am J Kidney Dis . 2000 ;36 :1089 –1109 .11096032 \n22 \nAmbrogi V Thilly N Boini S \nPatterns and predictors of kidney function decline in the last year prior to dialysis . Nephron Clin Pract . 2009 ;111 :c95 –\nc101 .19142021 \n23 \nCheng C Tsuneyama K Zheng H \nEnhanced scavenging of lipid substances is a possible effect of corticosteroids in the treatment of cholesterol crystal embolism . Pathol Res Pract . 2006 ;202 :591 –598 .16814943 \n24 \nHasegawa M Sugiyama S. \nApheresis in the treatment of cholesterol embolic disease . Ther Apher Dial . 2003 ;7 :435 –438 .12887728 \n25 \nDossetor JB. \nCreatininemia versus uremia: the relative significance of blood urea nitrogen and serum creatinine concentrations in azotemia . Ann Intern Med . 1966 ;65 :1287 –1299 .5928490 \n26 \nCauthen CA Lipinski MJ Abbate A \nRelation of blood urea nitrogen to long-term mortality in patients with heart failure . Am J Cardiol . 2008 ;101 :1643 –1647 .18489944 \n27 \nMann SJ Sos TA. \nTreatment of atheroembolization with corticosteroids . Am J Hypertens . 2001 ;14 :831 –834 .11497203 \n28 \nKoga J Ohno M Okamoto K \nCholesterol embolization treated with corticosteroids: two case reports . Angiology . 2005 ;56 :497 –501 .16079936 \n29 \nNakayama M Izumaru K Nagata M \nThe effect of low-dose corticosteroids on short- and long-term renal outcome in patients with cholesterol crystal embolism . Ren Fail . 2011 ;33 :298 –306 .21401354 \n30 \nFabbian F Catalano C Lambertini D Bordin V Di Landro D. \nA possible role of corticosteroids in cholesterol crystal embolization . Nephron . 1999 ;83 :189 –190 .10516511 \n31 \nHasegawa M Kawashima S Shikano M \nThe evaluation of corticosteroid therapy in conjunction with plasma exchange in the treatment of renal cholesterol embolic disease. A report of 5 cases . Am J Nephrol . 2000 ;20 :263 –267 .10970977 \n32 \nStabellini N Rizzioli E Trapassi MR Fabbian F Catalano C Gilli P. \nRenal cholesterol microembolism: is steroid therapy effective? \nNephron . 2000 ;86 :239 –\n240 .11015020 \n33 \nGraziani G Santostasi S Angelini C Badalamenti S. \nCorticosteroids in cholesterol emboli syndrome . Nephron . 2001 ;87 :371 –373 .11287784\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-5476", "issue": "10()", "journal": "Clinical medicine insights. Case reports", "keywords": "Cholesterol crystal embolization; end-stage kidney disease; hemodialysis; pulmonary embolism; warfarin", "medline_ta": "Clin Med Insights Case Rep", "mesh_terms": null, "nlm_unique_id": "101531893", "other_id": null, "pages": "1179547616684649", "pmc": null, "pmid": "28469497", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "16614719;11214743;12887728;17606842;18489944;5928490;3605140;19142021;9046969;11174358;10970977;16814943;665707;11497203;20697039;1738893;19702986;16079936;21401354;12741443;11096032;18271808;21422387;15389900;11287784;25197328;14662690;10516511;23423524;25896176;11015020;10089183;9654541", "title": "Performing Anticoagulation: A Puzzling Case of Cholesterol Embolization Syndrome.", "title_normalized": "performing anticoagulation a puzzling case of cholesterol embolization syndrome" }	[ { "companynumb": "JP-TEVA-2017-JP-836028", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "40145", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Chronic kidney disease" }, { "drugrecuraction": "Livedo reticularis" }, { "drugrecuraction": "Atheroembolism" } ], "drugseparatedosagenumb": null, "drugstartdate": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atheroembolism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Livedo reticularis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201312" } }, "primarysource": { "literaturereference": "IGARASHI Y, AKIMOTO T, KOBAYASHI T, IWAZU Y, MIKI T, OTANI-TAKEI N, ET AL. 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{ "abstract": "A 49-year-old woman who had previously received treatment with cytotoxic drugs for metastatic gestational trophoblastic disease (GTD) presented with a witnessed tonic-clonic seizure, headache, confusion and blindness, 6 days after the uneventful administration of a general anaesthetic and 2 months after cessation of chemotherapy. Magnetic resonance imaging showed relatively symmetrical, subcortical, white matter abnormalities, predominantly affecting the occipital, posterior temporal and parietal lobes and the cerebellum. T2-dependent abnormalities and elevated regional apparent diffusion coefficient were present in a pattern typical for posterior reversible encephalopathy syndrome (PRES). The clinical and radiological manifestations were resolved completely with supportive therapy. This case of PRES may be a late complication of gemcitabine or cisplatin therapy precipitated by a general anaesthetic, or associated electrolyte or blood pressure disturbance.", "affiliations": "Department of Imaging, Charing Cross Hospital, Fulham Palace Road, London, UK.", "authors": "Rangi\|P S\|PS\|;Partridge\|W J\|WJ\|;Newlands\|E S\|ES\|;Waldman\|A D\|AD\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine", "country": "Germany", "delete": false, "doi": "10.1007/s00234-005-1376-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3940", "issue": "47(8)", "journal": "Neuroradiology", "keywords": null, "medline_ta": "Neuroradiology", "mesh_terms": "D000768:Anesthesia, General; D000964:Antimetabolites, Antineoplastic; D001794:Blood Pressure; D001921:Brain; D001927:Brain Diseases; D003841:Deoxycytidine; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D031901:Gestational Trophoblastic Disease; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D013577:Syndrome; D014882:Water-Electrolyte Balance", "nlm_unique_id": "1302751", "other_id": null, "pages": "586-90", "pmc": null, "pmid": "15997391", "pubdate": "2005-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10954269;6150182;9158653;8587375;12063238;7856903;7581123;3178528;184880;1632361;8884627;9541291;7595753;1569451;9536483;9818862;11295355;8559202;9613500;9010526;3531716;11559490;12888158;7282395", "title": "Posterior reversible encephalopathy syndrome: a possible late interaction between cytotoxic agents and general anaesthesia.", "title_normalized": "posterior reversible encephalopathy syndrome a possible late interaction between cytotoxic agents and general anaesthesia" }	[ { "companynumb": "GB-PFIZER INC-2009157023", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT HYDATIDIFORM MOLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT HYDATIDIFORM MOLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAXOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT HYDATIDIFORM MOLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAXOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "160 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "160", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPANOLOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT HYDATIDIFORM MOLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT HYDATIDIFORM MOLE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WALDMAN A.D., NEWLANDS E.S., RANGI P.S., PARTRIDGE W.J.. POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME: A POSSIBLE LATE INTERACTION BETWEEN CYTOTOXIC AGENTS AND GENERAL ANAESTHESIA.. NEURORADIOLOGY. 2005;47 (8):586-590", "literaturereference_normalized": "posterior reversible encephalopathy syndrome a possible late interaction between cytotoxic agents and general anaesthesia", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20171005", "receivedate": "20171005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14047747, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "GB-DRREDDYS-GER/UKI/17/0095153", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "091365", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED,FREQ:NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAXOL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FREQ:NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED, FREQ:NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED, FREQ: NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WALDMAN A, NEWLANDS E, RANGI P, PARTRIDGE W. POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME: A POSSIBLE LATE INTERACTION BETWEEN CYTOTOXIC AGENTS AND GENERAL ANAESTHESIA. NEURORADIOLOGY. 2005?47(8):586-90.", "literaturereference_normalized": "posterior reversible encephalopathy syndrome a possible late interaction between cytotoxic agents and general anaesthesia", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180216", "receivedate": "20171219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14303107, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "The risk of de novo hepatitis B virus infection is lower after liver transplant using hepatitis B core antibody-negative donors into negative recipients versus hepatitis B core antibody-positive donors but can occur. Here, we present a 34-year-old male patient with acute de novo hepatitis B virus that developed 7 months after successful liver transplant. The case we report here is the first in the literature with regard to both switch from tenofovir to entecavir treatment and the presentation of de novo acute hepatitis B virus after liver transplant. The switch in treatment protocol resulted in significant improvements in serologic and biochemical levels, and the patient was discharged from the hospital on day 35 after admittance.", "affiliations": "From the Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey.", "authors": "Akbulut\|Sami\|S\|;Harputluoglu\|Murat\|M\|;Yilmaz\|Sezai\|S\|", "chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir", "country": "Turkey", "delete": false, "doi": "10.6002/ect.2018.0072", "fulltext": null, "fulltext_license": null, "issn_linking": "1304-0855", "issue": "16(5)", "journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation", "keywords": null, "medline_ta": "Exp Clin Transplant", "mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D057915:Drug Substitution; D006147:Guanine; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D000068698:Tenofovir; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "101207333", "other_id": null, "pages": "635-637", "pmc": null, "pmid": "29790455", "pubdate": "2018-10", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Successful Management of De Novo Acute Hepatitis B Virus Infection With Entecavir in a Living-Donor Liver Transplant Patient.", "title_normalized": "successful management of de novo acute hepatitis b virus infection with entecavir in a living donor liver transplant patient" }	[ { "companynumb": "PHHY2018TR116135", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AKBULUT S, HARPUTLUOGLU M, YILMAZ S. SUCCESSFUL MANAGEMENT OF DE NOVO ACUTE HEPATITIS B VIRUS INFECTION WITH ENTECAVIR IN A LIVING-DONOR LIVER TRANSPLANT PATIENT. EXPERIMENTAL AND CLINICAL TRANSPLANTATION. 2018?5:635-7", "literaturereference_normalized": "successful management of de novo acute hepatitis b virus infection with entecavir in a living donor liver transplant patient", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20181010", "receivedate": "20181010", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15485498, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "OBJECTIVE\nThis observational study was based on a series of clinical cases in which failure of sinus augmentations occurred in patients who received prophylactic clindamycin therapy.\n\n\nMETHODS\nBetween the years 2006 and 2010, a retrospective observational study was performed. The study consisted of 1,874 patients (723 males and 1,151 females) in whom sinus augmentations were performed prior to placement of dental implants.\n\n\nRESULTS\nIn nine (0.48%) patients (four males and five females), infection of the graft material inside the sinus floor occurred, and six patients developed an abscess in the site of surgery, 4 to 6 weeks postoperatively. In three patients, a buccal fistula with pus draining was observed 5 to 8 weeks postoperatively. In all patients, the source of infection was from the grafted material within the sinus. A common manifestation in all nine patients was that they had self-reported penicillin allergy and had been prescribed clindamycin (300 mg every 6 hours for 10 days).\n\n\nCONCLUSIONS\nProphylactic clindamycin therapy following sinus augmentation procedures seems to be a risk factor for infections and loss of grafting material following these surgical techniques.", "affiliations": null, "authors": "Khoury\|Fouad\|F\|;Javed\|Fawad\|F\|;Romanos\|Georgios E\|GE\|", "chemical_list": "D000900:Anti-Bacterial Agents; D015921:Dental Implants; D002981:Clindamycin", "country": "United States", "delete": false, "doi": "10.11607/jomi.6517", "fulltext": null, "fulltext_license": null, "issn_linking": "0882-2786", "issue": "33(5)", "journal": "The International journal of oral & maxillofacial implants", "keywords": null, "medline_ta": "Int J Oral Maxillofac Implants", "mesh_terms": "D000038:Abscess; D000900:Anti-Bacterial Agents; D016866:Bacteroidaceae Infections; D002981:Clindamycin; D003758:Dental Implantation, Endosseous; D015921:Dental Implants; D005260:Female; D006801:Humans; D008297:Male; D008443:Maxillary Sinus; D015523:Maxillary Sinusitis; D008875:Middle Aged; D011183:Postoperative Complications; D018720:Prevotella; D012189:Retrospective Studies; D012307:Risk Factors; D059546:Sinus Floor Augmentation", "nlm_unique_id": "8611905", "other_id": null, "pages": "1136-1139", "pmc": null, "pmid": "30231102", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": null, "title": "Sinus Augmentation Failure and Postoperative Infections Associated with Prophylactic Clindamycin Therapy: An Observational Case Series.", "title_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series" }	[ { "companynumb": "US-TEVA-2018-US-988159", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719957, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089513", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706208, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988160", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191203", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719958, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-TEVA-2018-US-987954", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719948, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089510", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706986, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089522", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705426, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988163", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15720019, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988162", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719989, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089511", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705889, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055935", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H,DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-9", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055909", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES.. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445629, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055872", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H (DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055933", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. SEP/OCT. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445762, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-TEVA-2018-US-988166", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719992, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055923", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fistula", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. SEP/OCT?. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445680, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-TEVA-2018-US-988158", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719950, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719990, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089515", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706185, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055924", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fistula", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. SEP/OCT?. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445685, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055873", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H (DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2018M1089529", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705421, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089517", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988165", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719991, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055875", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H 9DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445443, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2018M1089528", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705423, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055905", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES.. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-9", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2018M1089519", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706583, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "Absolute immature platelet counts (A-IPC) aid in diagnosis and treatment follow-up in thrombotic thrombocytopenic purpura (TTP). A-IPC was used to follow a patient on mycophenolate mofetil (MMF) maintenance therapy treated with a prolonged therapeutic plasma exchange (TPE) regimen for relapsing TTP. On admission, the platelet (PLT) count was 95 × 109/L declining to 14 × 109/L in 5 days. Daily TPE was initiated for suspected TTP, and MMF was discontinued. A-IPC and PLT count were 1 × 109/L and 14 × 109/L, respectively, prior to first TPE. A-IPC improved to 3.2 × 109/L with 1 TPE, and on day 5, A-IPC and PLT count were 7.5 × 109/L and 218 × 109/L, respectively. On day 6, A-IPC and PLT count decreased to 4.8 × 109/L and 132 × 109/L further worsening to 0.4 × 109/L and 13 × 109/L, respectively. ADAMTS13 activity remained <5% with an inhibitor; counts did not recover. Initial improvement followed by rapidly declining A-IPC despite therapy suggested production suppression. In TTP, A-IPC may aid in establishing early therapy effects over PLT production.", "affiliations": "Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.;Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.;Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA, [email protected].", "authors": "Kundrapu\|Sirisha\|S\|;Reeves\|Hollie M\|HM\|;Maitta\|Robert W\|RW\|", "chemical_list": "D000903:Antibiotics, Antineoplastic; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D009173:Mycophenolic Acid", "country": "Switzerland", "delete": false, "doi": "10.1159/000510913", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5792", "issue": "144(4)", "journal": "Acta haematologica", "keywords": "Absolute immature platelet count; Immature platelets; Thrombotic thrombocytopenic purpura", "medline_ta": "Acta Haematol", "mesh_terms": "D000071120:ADAMTS13 Protein; D000903:Antibiotics, Antineoplastic; D001792:Blood Platelets; D006801:Humans; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D010951:Plasma Exchange; D010976:Platelet Count; D011697:Purpura, Thrombotic Thrombocytopenic; D012008:Recurrence", "nlm_unique_id": "0141053", "other_id": null, "pages": "465-469", "pmc": null, "pmid": "33238282", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": null, "title": "Absolute Immature Platelet Counts Suggest Platelet Production Suppression during Complicated Relapsing Thrombotic Thrombocytopenic Purpura.", "title_normalized": "absolute immature platelet counts suggest platelet production suppression during complicated relapsing thrombotic thrombocytopenic purpura" }	[ { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2020-08786", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "THROMBOTIC THROMBOCYTOPENIC PURPURA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FAMOTIDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FAMOTIDINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NOREPINEPHRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOREPINEPHRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombotic thrombocytopenic purpura", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Urinary tract infection pseudomonal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "KUNDRAPU S, REEVES H, MAITTA R.. ABSOLUTE IMMATURE PLATELET COUNTS SUGGEST PLATELET PRODUCTION SUPPRESSION DURING COMPLICATED RELAPSING THROMBOTIC THROMBOCYTOPENIC PURPURA. ACTA HAEMATOL. 2020?25:1?5", "literaturereference_normalized": "absolute immature platelet counts suggest platelet production suppression during complicated relapsing thrombotic thrombocytopenic purpura", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210129", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615340, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210419" } ]
{ "abstract": "OBJECTIVE\nPulmonary thromboembolism (PTE) may be one of the causes of sudden death in hospitalized psychiatric patients. The aim of our study was to investigate whether fatal PTE in these patients may be the result of their prolonged physical immobilization, particularly when there were associated risk factors, and to emphasize the importance of this problem.\n\n\nMETHODS\nA retrospective analysis of medical records of psychiatric patients died suddenly at the Department of Intensive Care of the Clinic of Psychiatry \"Dr Laza Lazarevic\", Belgrade, in the period January 1, 2010 - December 31, 2011, was performed. Data of those for which the autopsy showed PTE as the immediate cause of death were extracted, and the presence of risk factors for the development of deep vein thrombosis analyzed.\n\n\nRESULTS\nIn the observed period, out of 4,001 hospitalized psychiatric patients 53 died, and for 18 of them autopsy was required due to sudden death. In five patients, autopsy revealed PTE as a direct and sole cause of death. All the five patients were males, mean age 45.2 years, and during hospitalization all received strong antipsychotics and diazepam. Of the total duration of their hospital stay (mean 8.2 days), they were temporarily immobilized during an average 4.2 days. Four of them had acute infection, three were active smokers, and the two had a body mass index > 30 kg/m2.\n\n\nCONCLUSIONS\nOur results suggest a possible link between prolonged physical immobilization of psychiatric patients who also receive antipsychotic therapy, and total PTE.", "affiliations": "Clinic for Psychiatric Disorders \"Dr Laza Lazarević\", Belgrade, Serbia. [email protected]", "authors": "Stefanović\|Vesna\|V\|;Kuzmanović\|Ana\|A\|;Stefanović\|Slavisa\|S\|", "chemical_list": "D014150:Antipsychotic Agents", "country": "Serbia", "delete": false, "doi": "10.2298/vsp1310903s", "fulltext": null, "fulltext_license": null, "issn_linking": "0042-8450", "issue": "70(10)", "journal": "Vojnosanitetski pregled", "keywords": null, "medline_ta": "Vojnosanit Pregl", "mesh_terms": "D014150:Antipsychotic Agents; D002423:Cause of Death; D003645:Death, Sudden; D006760:Hospitalization; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D011655:Pulmonary Embolism; D012149:Restraint, Physical; D012189:Retrospective Studies; D012307:Risk Factors; D055771:Serbia; D013997:Time Factors; D020246:Venous Thrombosis", "nlm_unique_id": "21530700R", "other_id": null, "pages": "903-7", "pmc": null, "pmid": "24313170", "pubdate": "2013-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients.", "title_normalized": "fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients" }	[ { "companynumb": "RS-FRESENIUS KABI-FK201503891", "fulfillexpeditecriteria": "1", "occurcountry": "RS", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIOLYTIC THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HALOPERIDOL LACTATE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "075689", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOTHERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL INJECTION (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STEFANOVIC V,KUZMANOVIC A,STEFANOVIC S. FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. 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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. 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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. MILITARY MEDICAL AND PHARMACEUTICAL REVIEW 2013 OCT;10:903-907.", "literaturereference_normalized": "fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients", "qualification": "3", "reportercountry": "RS" }, "primarysourcecountry": "RS", "receiptdate": "20150818", "receivedate": "20150818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11392312, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "RS-MYLANLABS-2013SP007393", "fulfillexpeditecriteria": "1", "occurcountry": "RS", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "RISPERIDONE" 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"drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPTOPRIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HALOPERIDOL" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "075440", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOTIC DISORDER", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", 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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. 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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. MILITARY MEDICAL AND PHARMACEUTICAL REVIEW 2013 OCT;10:903-907.", "literaturereference_normalized": "fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients", "qualification": "3", "reportercountry": "RS" }, "primarysourcecountry": "RS", "receiptdate": "20150818", "receivedate": "20150818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11392311, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" }, { "companynumb": "RS-FRESENIUS KABI-FK201503866", "fulfillexpeditecriteria": "1", "occurcountry": "RS", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HALOPERIDOL LACTATE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "075689", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PSYCHOTHERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HALOPERIDOL INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIAZEPAM" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANXIOLYTIC THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEMOPRES" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "STEFANOVIC V,KUZMANOVIC A,STEFANOVIC S. FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. VOJNOSANITETSKI PREGLED 2013 OCT;10:903-907.", "literaturereference_normalized": "fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients", "qualification": "3", "reportercountry": "RS" }, "primarysourcecountry": "RS", "receiptdate": "20150818", "receivedate": "20150818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11392323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" } ]
{ "abstract": "BACKGROUND\nThis study aimed to determine the efficacy and complications of intravitreal chemotherapy-assisted endoresection for refractory International Classification of Retinoblastoma (ICRB) group D retinoblastoma in monocular patients.\n\n\nMETHODS\nIn this retrospective case series, intravitreal chemotherapy-assisted endoresection by pars plana vitrectomy was performed in 11 eyes with refractory ICRB group D retinoblastoma unresponsive to standard therapies in monocular patients.\n\n\nRESULTS\nAcross a mean follow-up period of 42.7 months, globe salvage was attained in all 11 eyes (100%). There were no cases of extra-ocular tumour seeding or remote metastasis. In 9 eyes (81.8%), tumour control was achieved with one pars plana vitrectomy; in 2 cases (18.2%), repeated treatment, such as laser therapy, intravitreal chemotherapy or a second pars plana vitrectomy, was needed. Retinal reattachment was achieved in all 4 eyes (100%) with previous retinal detachment. Four eyes (36.4%) required subsequent cataract surgery due to secondary cataract. Ten eyes (90.9%) had improvement in best-corrected visual acuity at the last follow-up.\n\n\nCONCLUSIONS\nIntravitreal chemotherapy-assisted endoresection appears to be a safe and effective globe-salvaging method for refractory group D retinoblastoma. It is a promising alternative to enucleation and a supplementary therapeutic strategy for those unresponsive to standard therapies, especially for the monocular retinoblastoma patients.", "affiliations": "Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China. [email protected].", "authors": "Yu\|Xiling\|X\|;Li\|Xueke\|X\|;Xing\|Yue\|Y\|;Lu\|Siduo\|S\|;Tanumiharjo\|Silvia\|S\|;Ma\|Jin\|J\|http://orcid.org/0000-0003-3072-9065", "chemical_list": "D019772:Topotecan", "country": "England", "delete": false, "doi": "10.1186/s12885-020-07314-1", "fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407 BioMed Central London \n\n7314\n10.1186/s12885-020-07314-1\nResearch Article\nEffectiveness of intravitreal chemotherapy-assisted endoresection in monocular patients with group D retinoblastoma\nYu Xiling Li Xueke Xing Yue Lu Siduo Tanumiharjo Silvia http://orcid.org/0000-0003-3072-9065Ma Jin [email protected] grid.12981.330000 0001 2360 039XZhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China \n26 8 2020 \n26 8 2020 \n2020 \n20 80814 6 2020 18 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThis study aimed to determine the efficacy and complications of intravitreal chemotherapy-assisted endoresection for refractory International Classification of Retinoblastoma (ICRB) group D retinoblastoma in monocular patients.\n\nMethods\nIn this retrospective case series, intravitreal chemotherapy-assisted endoresection by pars plana vitrectomy was performed in 11 eyes with refractory ICRB group D retinoblastoma unresponsive to standard therapies in monocular patients.\n\nResults\nAcross a mean follow-up period of 42.7 months, globe salvage was attained in all 11 eyes (100%). There were no cases of extra-ocular tumour seeding or remote metastasis. In 9 eyes (81.8%), tumour control was achieved with one pars plana vitrectomy; in 2 cases (18.2%), repeated treatment, such as laser therapy, intravitreal chemotherapy or a second pars plana vitrectomy, was needed. Retinal reattachment was achieved in all 4 eyes (100%) with previous retinal detachment. Four eyes (36.4%) required subsequent cataract surgery due to secondary cataract. Ten eyes (90.9%) had improvement in best-corrected visual acuity at the last follow-up.\n\nConclusion\nIntravitreal chemotherapy-assisted endoresection appears to be a safe and effective globe-salvaging method for refractory group D retinoblastoma. It is a promising alternative to enucleation and a supplementary therapeutic strategy for those unresponsive to standard therapies, especially for the monocular retinoblastoma patients.\n\nKeywords\nRefractory retinoblastomaIntravitreal chemotherapyEndoresectionPars plana vitrectomy Science and Technology Program of Guangzhou201607010070Ma Jin National Natural Science Foundation of Guangdong2016A0303133642018A0303130293Yu Xiling Ma Jin issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nOver the past two decades, the management of retinoblastoma has dramatically changed from eye-sacrificing methods to eye-preserving alternatives [1]. Eye preservation can be achieved in as much as 90–100% of eyes classified as group A, B or C retinoblastoma, but it is still challenging in group D and E retinoblastoma classified according to the International Classification of Retinoblastoma (ICRB) criteria [2]. Recent research has suggested that it is safe to attempt eye-preserving methods for group D cases, while enucleation is still recommended for group E cases [3]. Recent studies have shown some progress in the globe salvage of group D retinoblastoma with the single or combined use of intravenous chemotherapy (IVC), intra-arterial chemotherapy (IAC) and intravitreal chemotherapy (IViC), but persistent or recurrent vitreous and subretinal seeding can still occur in some refractory cases [4]. Eye preservation is especially important for monocular patients for whom the other affected eye has been previously enucleated for unmanageable progressive retinoblastoma and who require the remaining eye to retain visual function.\n\nIViC was first introduced in 2003 [5], and it has become one of the most effective treatments against the vitreous seeding of retinoblastoma [6]. Several studies have proven that IViC has increased the eye-preserving rate in group D retinoblastoma [3, 4, 7]. However, the recurrent refractory vitreous and subretinal seeding of the tumour remains a major challenge of this method [6]. The efficiency of IViC is reduced when there is a high burden of vitreous seeding, as tumour growth cannot be controlled even with repeated IViC. Furthermore, sight-threatening tumour-related complications, such as persistent retinal detachment or vitreous haemorrhage, cannot be solved through IViC.\n\nTheoretically, endoresection by pars plana vitrectomy (PPV) is the ideal way to eradicate a tumour and solve vitreoretinal complications, but its use in the treatment of retinoblastoma has been controversial due to the high risk of metastasis, orbital seeding and extraocular extension [8]. However, the recent success of IViC has raised the possibility of surgical intervention again [9, 10]. In this study, we attempted IViC-assisted endoresection in refractory monocular ICRB group D retinoblastoma patients. Intraocular surgery was carefully executed and combined with effective local chemotherapy and a series of safety measures. We evaluated the therapeutic effect and complications with a mean follow-up of 42.7 months.\n\nMethods\nStudy subjects\nThis retrospective cohort study was conducted between May 2013 and March 2019. The children were referred for this study when refractory retinoblastoma was unresponsive with uncontrolled intravitreal seeding or tumour recurrence after receiving six cycles of systemic chemotherapy with a standard vincristine/etoposide/carboplatin (VEC) regimen in all cases and different strategies of local chemotherapy (IAC and/or IViC, Table 1). The children consecutively included were diagnosed with group D retinoblastoma, classified according to International Classification of Retinoblastoma (ICRB) criteria, with the other affected eye previously enucleated due to progressive retinoblastoma. All the included patients had no tumour involvement of the anterior segment or a suggestion of extraocular metastasis on neuroimaging. All of the cases are classified as cT2bN0M0H1 according to the 8th edition American Joint Committee on Cancer/Union for International Cancer Control Clinical Staging System (8th ed. cTNMH).\nTable 1 Characteristics of patients with ICRB group D retinoblastoma underwent intravitreal chemotherapy-assisted endoresection\n\nNo.\tAge (months)\tVitreous seeds Classificationa\tSubretinal seeds\tRetinal detachment\tTMN Classificationb\tTreatment history\t\n01\t36\tDust\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\n02\t48\tDust\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\n03\t8\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n04\t30\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n05\t24\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n06\t78\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n07\t71\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n08\t65\tCloud\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n09\t88\tCloud\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\n10\t31\tSpheres\tY\tN\tcT2bN0M0H1\tIVC + IAC + IViC\t\n11\t29\tSpheres\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\nIVC Intravenous chemotherapy, IViC Intravitreal chemotherapy, IAC Intra-arterial chemotherapy\n\naVitreous seeding was classified by the criteria of Francis, J. H. et al. [11]\n\nbAccording to the 8th edition American Joint Committee on Cancer/Union for International Cancer Control Clinical Staging System (8th ed. cTNMH)\n\n\n\nTreatment protocol\nIViC using topotecan (20μg/0.1 ml) was performed once, 1 week before surgery. While performing 25-gauge PPV, intraoperative IViC of 5 μg/ml topotecan in irrigation fluid (balanced salt solution) was applied. The visible intravitreal tumour cells were removed through vitrectomy; the subretinal tumour lesions were removed with extended resection accompanied by electrocoagulation at least 3 mm from the margin of the mass. To avoid retinal detachment, laser coagulation was applied to the boundaries after resection (Fig. 1). Cryotherapy was used when required. Calcified lesions were only removed if they were directly involved with the active tumour, or were located subretinally (Fig. 2). Silicone oil tamponade was applied in all cases. Intravitreal injection of topotecan (20 μg/0.1 ml) was applied at the end of the PPV. In all the cases, the lens was preserved during PPV.\nFig. 1 Chemotherapy-assisted endoresection of subretinal tumour in group D retinoblastoma in case 7. a and b The subretinal tumour was removed with extended resection by electrocoagulation (white arrows show the edge of electrocoagulation, black triangle shows the removed tumour and white asterisks show the scar of the regressed tumour after previous IViC). c One day after the endoresection, white arrows show the laser scarring around the resected lesion. d Sixteen months after endoresection and 1 month after silicone oil removal, no tumour recurrence was found (white asterisks show the scar of the regressed tumour)\n\nFig. 2 Reservation of calcified lesions during chemotherapy-assisted endoresection in group D retinoblastoma in case 11. a Refractory vitreous and subretinal seeds with massive calcification lesion in the only eye of a patient with bilateral retinoblastoma after IVC and IViC. b The resection of the tumour and the reservation of some calcified lesions, 1 month after surgery\n\n\n\nSafety measures were undertaken to prevent orbital/extraocular extension of the tumour from the surgical incisions. All three incisions were sutured with absorbable 8–0 sutures to remain strictly watertight. Cryotherapy and sub-conjunctival injections of topotecan (20 μg/0.1 ml) were applied to all three of the sutured incision sites.\n\nAfter surgery, all patients underwent routine eye examinations as well as neuroimaging (CT and MRI) to evaluate if there was any tumour recurrence, metastasis or orbital/extraocular extension. IViC and laser treatment were applied when there was any sign of recurrence. Additional PPV was performed when recurrence could not be controlled by IViC and/or laser treatment. Cataract surgery was performed for secondary cataract at least 6 months after the first PPV if there was no sign of recurrence or involvement of the anterior segment. Silicon oil removal was considered when any oil-related complications occurred in the eye, such as oil emulsification, oil migration, secondary glaucoma, etc.\n\nThis study was performed after obtaining informed consent from the patients and their family, and it was approved by the Board of Ethics at Sun Yat-Sen University Zhongshan Ophthalmological Center.\n\nResults\nA total of 11 eyes were included in this retrospective cohort study conducted between May 2013 and February 2019. The basic information, ocular features and treatment history of the patients are presented in Table 1. The age of the patients ranged from 8 to 88 months, with an average age of 3.9 years. All of the patients were monocular, in which the other affected eye had been previously enucleated due to progressive retinoblastoma; the eyes included for combined therapy were classified as group D according to ICRB criteria. Subretinal seeding and vitreous seeding were observed in all the included cases. Vitreous seeding was classified according to the criteria by Francis et al [11]. No anterior segment or extraocular metastasis was found in any of the patients. Retinal detachment was observed in 4 patients (cases 1, 2, 9 and 11). Before referral to our hospital, all of the patients had previously received IVC and IViC; 1 patient (case 10) had also received IAC.\n\nThe follow-up time, tumour recurrence and metastasis, post-operative complications and subsequent treatments are presented in Table 2. Until March 2020, the follow-up time from PPV ranged from 12 months to 83 months, with a mean of 42.7 months. There was no case of anterior segment or extraocular tumour extension during follow-up period. Eye preservation was achieved in all 11 cases (100%). Vitreous and subretinal seeding control required PPV, once, in 9 cases (9/11, 81.8%), and no tumour recurrence was observed during follow-up.\nTable 2 Treatment outcomes of patients who underwent chemotherapy-assisted endoresection\n\nNo.\tFollow-up\n(months)\tRecurrence\tMetastasis\tComplicated\ncataract\tRetreatment\tPre-op\nBCVA\tLast BCVA\t\n01\t83\tNo\tNo\tNo\tNo\tHM\tFC\t\n02\t81\tNo\tNo\tNo\tNo\tHM\t20/400\t\n03\t79\tNo\tNo\tNo\tNo\tLP\t20/200\t\n04\t65\tNo\tNo\tNo\tNo\tLP\t20/800\t\n05\t33\tNo\tNo\tNo\tNo\tLP\t20/100\t\n06\t30\tNo\tNo\tNo\tCataract surgery\tLP\t20/125\t\n07\t23\tNo\tNo\tYes\tNo\tHM\t20/400\t\n08\t23\tYes\tNo\tYes\tPPV, IViC, cataract surgery\tLP\t20/200\t\n09\t23\tYes\tNo\tYes\tLaser, IViC, PPV, Cataract surgery\tHM\tFC\t\n10\t18\tNo\tNo\tYes\tCataract surgery\tLP\tHM\t\n11\t12\tNo\tNo\tNo\tNo\tLP\tLP\t\nPPV Pars plana vitrectomy, IViC Intravitreal chemotherapy\n\n\n\nTwo cases (8 and 9) showed tumour recurrence after primary PPV without intravitreal seeding or anterior chamber involvement. In case 9, tumour recurrence was found 2 months after PPV, and it was observed as a focal solid tumour at the edge of previous endoresection. After repeated IViC (topotecan 20 μg/0.1 ml, every 2 weeks for 5 times) and retinal laser photocoagulation, the tumour regressed and no recurrence was observed during the follow-up period (Fig. 3). In case 8, tumour recurrence happened 12 months after PPV; it presented as multi-focal subretinal seeding with pre-retinal haemorrhage, without any vitreous seeding. After repeated IViC (topotecan 20 μg/0.1 ml, every 2 weeks for 3 times) and retinal laser photocoagulation, tumour growth could not be effectively controlled, so PPV with endoresection was performed again and no recurrence was observed by the end of the last follow-up.\nFig. 3 The management and result of focal tumour recurrence and retinal redetachment after chemotherapy-assisted endoresection in case 9. a Refractory vitreous and subretinal seeds with retinal detachment before chemotherapy-assisted endoresection. b White arrows show the edge of the resection of the tumour, 1 week after endoresection. c and d Focal tumour recurrence (white asterisk) with silicon oil tamponade. e and f Regression of the tumour (white asterisk) after 5 sessions of IViC and laser coagulation\n\n\n\nThree of the 4 cases with pre-surgical retinal detachment achieved anatomical restoration of the retina after undergoing PPV once. One case (case 9) had recurrent retinal detachment 12 months after the first surgery, and retinal reattachment was achieved after a second PPV with no recurrent retinal detachment during subsequent follow-up. Secondary cataract was observed in 4 cases (cases 6, 8, 9 and 10) and cataract surgery (phacoemulsification and intraocular lens implantation) was performed. Silicone oil removal was performed in 2 cases (cases 6, 7) when silicone oil emulsification was seen. Silicon oil was not removed when focal recurrence was found (case 9); in this situation, further IViC and laser treatment were done in the silicon oil-filled eye.\n\nThe changes in best corrected visual acuity (BCVA) are shown in Table 2. Up to the last follow-up examination, 10 of the11 patients showed improvement in BCVA; in 4 cases the patient’s vision improved to ≥20/200. One patient (case 11) had no change in BCVA after PPV.\n\nDiscussion\nFor many years, the risk of dissemination, seeding and extraocular spread has been the biggest obstacle for surgical intervention in patients with retinoblastoma. Honavar et al. reported an unfavourable outcome in 75% of patients with retinoblastoma who underwent PPV in 2001 [12]. With the rapid development of local chemotherapy treatments in recent years, this situation may come to an end. Several studies have reported on the combined use of IViC and PPV for advanced retinoblastoma in small sample cases [9, 10, 13]. Recently, Zhao et al. reported on planned PPV with IViC in 21 cases of refractory retinoblastoma, with eye preservation achieved in 85.7% (18/21) of the cases with a median of 5.1 years of follow-up [9]. In our study, eye preservation was achieved in 100% of the cases during an average follow-up of 42.7 months, without any seeding through the surgical tracts or metastasis. These encouraging results revealed that the combined use of IViC (both preoperatively and intraoperatively) significantly improved the safety of a surgical intervention for retinoblastoma. Moreover, to reduce the risk of surgical incision seeding, some safety measures should be taken, such as using a minimally invasive incision and applying strictly water-tight sutures, cryotherapy and subconjunctival injections of anti-tumour drugs at the incision sites. In general, we believe that IViC-assisted endoresection by PPV can be carefully considered as a supplementary therapy in the refractory cases when standard therapies have failed prior to second eye enucleation.\n\nIViC-assisted endoresection should be performed with strict control of the indications and contraindications. We suggest that only previously treated (IVC/IAC/IViC) refractory ICRB group D cases with obvious vitreous and/or subretinal seeding should be considered for this form of treatment. The direct and definite removal of tumour is the significant advantage of endoresection, so it is especially helpful for cases with a high burden of vitreous and/or subretinal seeding. The IViC-assisted endoresection by PPV can reduce the tumour size and its resulting burden while facilitating extensive and uniformed distribution of the chemotherapeutic drug in the vitreous cavity, which further enhances the efficiency of the drug and reduces the amount of treatment required and the retinal toxicity of repeated IViC [6].\n\nThe contraindication of endoresection for retinoblastoma is any sign of tumour metastasis in the anterior segment or extraocular metastasis, which suggests that ICRB group E cases should be excluded. In the study by Zhao et al., the retinoblastoma was not controlled by one-time use of PPV in 4 patients, all of whom demonstrated tumour metastases in the anterior chamber of the eyes, and only one eye was preserved [9]. This result is consistent with the findings reported in many previous studies that anterior chamber tumour metastasis is a danger sign that implies poor prognosis and a high risk of recurrence and extraocular metastasis [14, 15]. Moreover, in these eyes, PPV may greatly increase the risk of iatrogenic seeding because the incision is very close to the anterior segment of the eye. Consequently, we also suggest lens-preserving PPV even when there is partial opacity of the lens, in order to minimise disturbance to the anterior segment during surgery and lower the risk of iatrogenic seeding to the anterior segment. It should be noted that secondary cataract might develop due to silicone tamponade or chemotherapeutic drug toxicity after PPV. In our opinion, cataract surgery should be cautiously considered at least 6 months after PPV when there is no sign of tumour recurrence or metastasis.\n\nAlthough many preventive measures have been used, the tumour can still recur. In our study, two cases had single or multiple focal subretinal tumour recurrence. Fortunately, the recurrent tumours could be eradicated by repeated IViC, laser coagulation or a second PPV. The relatively good prognosis was mostly attributed to the absence of recurrent vitreous seeding. We assumed the silicone oil tamponade helped confine the tumour as a focal lesion of the retina, thus limiting intravitreal tumour seeding. Therefore, intravitreal silicone oil tamponade is recommended during PPV to prevent tumour dissemination, especially vitreous seeding. Since the tumour may recur a long time after surgery (e.g. in case 8, tumour recurrence was observed 12 months after PPV), we suggest that the silicone oil tamponade time should be prolonged appropriately, unless any oil-related complications occur.\n\nIn addition to eradicating intraocular tumours, IViC-assisted PPV can also help address the sight-threatening vitreoretinal complications of retinoblastoma, such as vitreous haemorrhage and persistent retinal detachment. In our study, 4 of the11 eyes had pre-surgical retinal detachment, and all of them achieved successful anatomical retinal reattachment after PPV. This is especially crucial for monocular patients who have no other alternative for retaining visual function and who require eye preservation. In our study,10 of the 11 monocular patient had improved vision after PPV; in 4 cases, the patient’s vision had improved to ≥20/200. The favourable visual function outcomes also proved the value and good prospect of this treatment strategy.\n\nHowever, this study has some limitations. Like any new technique, it is difficult to conduct a randomised controlled trial for treating retinoblastoma, as it is a relatively rare disease. The follow-up period in this study was also relatively short, with a mean of 42.7 months (ranging from 12 months to 83 months). Since retinoblastoma could recur years later, further follow-up is required to evaluate the long-term effects of this treatment method. We also used topotecan instead of melphalan because topotecan was the only chemotherapy drug currently approved in mainland China for the treatment of retinoblastoma.\n\nConclusions\nThis study showed encouraging results for using IViC-assisted endoresection to control ICRB group D retinoblastoma. This suggests that it might be considered to be a supplementary therapeutic strategy for some refractory cases that are unresponsive to standard therapies, especially for monocular patients for whom the other affected eye has been previously enucleated.\n\nAbbreviations\nICRBInternational Classification of Retinoblastoma\n\nIVCIntravenous chemotherapy\n\nIACIntra-arterial chemotherapy\n\nIViCIntravitreal chemotherapy\n\nPPVPars plana vitrectomy\n\nVECVincristine/etoposide/carboplatin.\n\nBCVABest corrected visual acuity\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nXY and JM contributed to the conception and design of the study; XL, YX and SL organised the database; XY performed the statistical analysis; XY wrote the first draft of the manuscript; ST and JM wrote sections of the manuscript. All the authors contributed to the manuscript revision, and to reading and approving the submitted version.\n\nFunding\nThis study was supported by the Science and Technology Program of Guangzhou (201607010070) and the National Natural Science Foundation of Guangdong (2016A030313364, 2020A1515010190 and 2018A0303130293). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAvailability of data and materials\nThe datasets used during and/or analysed in this study are available from the corresponding author upon request.\n\nEthics approval and consent to participate\nThis study was performed after obtaining written informed consent from the parents/guardians of the minors included in this study (minors are considered anyone under the age of 16). It was approved by the Board of Ethics at Sun Yat-Sen University Zhongshan Ophthalmological Center.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Al-Nawaiseh I Jammal HM Khader YS Jaradat I Barham R Retinoblastoma in Jordan, 2003–2013: ocular survival and associated factors Ophthal Epidemiol 2014 21 6 406 411 10.3109/09286586.2014.967781 \n2. Shields CL Mashayekhi A Au AK Czyz C Leahey A Meadows AT The international classification of retinoblastoma predicts chemoreduction success Ophthalmology 2006 13 12 2276 2280 10.1016/j.ophtha.2006.06.018 \n3. Shields CL Manjandavida FP Arepalli S Kaliki S Lally SE Shields JA Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results JAMA Ophthalmol 2014 132 3 319 325 10.1001/jamaophthalmol.2013.7666 24407202 \n4. Ghassemi F Shields CL Ghadimi H Khodabandeh A Roohipoor R Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma JAMA Ophthalmol. 2014 132 8 936 941 10.1001/jamaophthalmol.2014.414 24789622 \n5. Kaneko A Suzuki S Eye-preservation treatment of retinoblastoma with vitreous seeding Jpn J Clin Oncol 2003 33 12 601 607 10.1093/jjco/hyg113 14769836 \n6. Francis JH Brodie SE Marr B Zabor EC Mondesire-Crump I Abramson DH Efficacy and toxicity of intravitreous chemotherapy for retinoblastoma: four-year experience Ophthalmology 2017 124 4 488 495 10.1016/j.ophtha.2016.12.015 28089679 \n7. Munier FL Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013 Ophthalmic Genet 2014 35 4 193207 10.3109/13816810.2014.973045 \n8. Warden SM Mukai S Pars plana vitrectomy in eyes treated for retinoblastoma Retina (Philadelphia, PA) 2006 26 Suppl 7 S53 S56 10.1097/01.iae.0000244289.01875.78 \n9. Zhao J Li Q Wu S Jin L Ma X Jin M Pars plana vitrectomy and endoresection of refractory intraocular retinoblastoma Ophthalmology 2018 125 2 320 322 10.1016/j.ophtha.2017.10.015 29153457 \n10. Yarovoy AA Ushakova TL Gorshkov IM Polyakov VG Golubeva OV Gorovtsova OV Intraocular surgery with melphalan irrigation for vitreous hemorrhage in an only eye with retinoblastoma Eur J Ophtalmol 2015 26 1 e17 e19 10.5301/ejo.5000683 \n11. Francis JH Abramson DH Gaillard MC Marr BP Beck-Popovic M Munier FL The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan Ophthalmology 2015 122 6 1173 1179 10.1016/j.ophtha.2015.01.017 25795478 \n12. Honavar SG Shields CL Shields JA Demirci H Naduvilath TJ Intraocular surgery after treatment of retinoblastoma Arch Ophthalmol. (Chicago, IL : 1960) 2001 119 11 1613 1621 10.1001/archopht.119.11.1613 \n13. Lee JH Han JW Hahn SM Lyu CJ Kim DJ Lee SC Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy for retinoblastoma with vitreous seeds Graefes Arch Clin Exp Ophthalmol [Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie] 2016 254 2 391 394 10.1007/s00417-015-3202-0 \n14. Abramson DH Shields CL Munier FL Chantada GL Treatment of retinoblastoma in 2015: agreement and disagreement JAMA Ophthalmol 2015 133 11 1341 1347 10.1001/jamaophthalmol.2015.3108 26378747 \n15. Shields CL Lally SE Leahey AM Jabbour PM Caywood EH Schwendeman R Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy Curr Opin Ophthalmol 2014 25 5 374 385 10.1097/icu.0000000000000091 25014750\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "20(1)", "journal": "BMC cancer", "keywords": "Endoresection; Intravitreal chemotherapy; Pars plana vitrectomy; Refractory retinoblastoma", "medline_ta": "BMC Cancer", "mesh_terms": "D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D009366:Neoplasm Seeding; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D016879:Salvage Therapy; D019772:Topotecan; D016896:Treatment Outcome; D014792:Visual Acuity; D014821:Vitrectomy; D014822:Vitreous Body", "nlm_unique_id": "100967800", "other_id": null, "pages": "808", "pmc": null, "pmid": "32847550", "pubdate": "2020-08-26", "publication_types": "D016428:Journal Article", "references": "26511530;16996605;28089679;11709011;26428220;16946680;26378747;24407202;29153457;24789622;25795478;25014750;25321846;25317653;14769836", "title": "Effectiveness of intravitreal chemotherapy-assisted endoresection in monocular patients with group D retinoblastoma.", "title_normalized": "effectiveness of intravitreal chemotherapy assisted endoresection in monocular patients with group d retinoblastoma" }	[ { "companynumb": "CN-ACCORD-223284", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPOTECAN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202351", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INTRAVITREAL 20 UG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPOTECAN" } ], "patientagegroup": "3", "patientonsetage": "88", "patientonsetageunit": "802", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cataract", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YU X, LI X, XING Y, LU S, TANUMIHARJO S, MA J. EFFECTIVENESS OF INTRAVITREAL CHEMOTHERAPY?ASSISTED ENDORESECTION IN MONOCULAR PATIENTS WITH GROUP D RETINOBLASTOMA. BMC CANCER. 2020 AUG 26?20(1):808.", "literaturereference_normalized": "effectiveness of intravitreal chemotherapy assisted endoresection in monocular patients with group d retinoblastoma", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20210422", "receivedate": "20210422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19167584, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "CN-ACCORD-223285", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPOTECAN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202351", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INTRAVITREAL 20 UG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPOTECAN" } ], "patientagegroup": "3", "patientonsetage": "31", "patientonsetageunit": "802", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cataract", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YU X, LI X, XING Y, LU S, TANUMIHARJO S, MA J. EFFECTIVENESS OF INTRAVITREAL CHEMOTHERAPY?ASSISTED ENDORESECTION IN MONOCULAR PATIENTS WITH GROUP D RETINOBLASTOMA. BMC CANCER. 2020 AUG 26?20(1):808.", "literaturereference_normalized": "effectiveness of intravitreal chemotherapy assisted endoresection in monocular patients with group d retinoblastoma", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20210422", "receivedate": "20210422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19167582, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "CN-ACCORD-223283", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPOTECAN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202351", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INTRAVITREAL 20 UG/0.1 ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPOTECAN" } ], "patientagegroup": "3", "patientonsetage": "65", "patientonsetageunit": "802", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cataract", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YU X, LI X, XING Y, LU S, TANUMIHARJO S, MA J. EFFECTIVENESS OF INTRAVITREAL CHEMOTHERAPY?ASSISTED ENDORESECTION IN MONOCULAR PATIENTS WITH GROUP D RETINOBLASTOMA. BMC CANCER. 2020 AUG 26?20(1):808.", "literaturereference_normalized": "effectiveness of intravitreal chemotherapy assisted endoresection in monocular patients with group d retinoblastoma", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20210422", "receivedate": "20210422", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19167583, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "A previously healthy 48-year-old active duty man, who had been treated for an elbow abscess 3 weeks earlier, presented to an emergency department in Bahrain with tachycardia, pericardial friction rub and jugular venous distention. Cardiac tamponade was confirmed on transthoracic echocardiogram and he was taken for emergent pericardiocentesis. Pericardial fluid cultures grew community-acquired methicillin-resistant Staphylococcus aureus Despite ongoing treatment with intravenous vancomycin, he developed a recurrent fibrinous pericardial effusion and constrictive pericarditis requiring pericardiectomy. Though he initially did well postoperatively, he developed drug reaction with eosinophilia and systemic symptoms syndrome in response to vancomycin. He was transitioned to ceftaroline and started on high-dose steroids. He recovered during a week-long admission and was discharged home. Several weeks later at follow-up he was doing well and had resumed moderate intensity exercise.", "affiliations": "Department of Aviation Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.;Department of Emergency Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.;Department of Cardiology, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.", "authors": "DeYoung\|Henry\|H\|;Bloom\|Adam\|A\|;Tamayo\|Sally\|S\|", "chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D013256:Steroids; C490727:T 91825; D014640:Vancomycin", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-221931", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "cardiovascular system; infections", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D063926:Drug Hypersensitivity Syndrome; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009205:Myocarditis; D010490:Pericardial Effusion; D010492:Pericardiectomy; D010493:Pericarditis; D011183:Postoperative Complications; D013203:Staphylococcal Infections; D013256:Steroids; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "29018016", "pubdate": "2017-10-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16933824;24550331;22627263;25855795;8227835;25635199;26320112;28360036;22311935;21115457;20622739;25282211;12923044;24343828;22797874;21575282;19352300;23903515", "title": "Successful treatment of community-acquired methicillin-resistant Staphylococcus aureus purulent myopericarditis.", "title_normalized": "successful treatment of community acquired methicillin resistant staphylococcus aureus purulent myopericarditis" }	[ { "companynumb": "US-009507513-1711USA001547", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DAPTOMYCIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "021572", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CUBICIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEYOUNG H, BLOOM A, TAMAYO S. SUCCESSFUL TREATMENT OF COMMUNITY-ACQUIRED METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PURULENT MYOPERICARDITIS. BMJ CASE REPORTS. 2017", "literaturereference_normalized": "successful treatment of community acquired methicillin resistant staphylococcus aureus purulent myopericarditis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171110", "receivedate": "20171110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14176599, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "US-AXELLIA-001189", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "091377", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEYOUNG H, BLOOM A, TAMAYO S. SUCCESSFUL TREATMENT OF COMMUNITY-ACQUIRED METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS PURULENT MYOPERICARDITIS. BMJ CASE REP. 2017 OCT 10;2017.", "literaturereference_normalized": "successful treatment of community acquired methicillin resistant staphylococcus aureus purulent myopericarditis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171113", "receivedate": "20171113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14182061, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" } ]
{ "abstract": "Staphylococcus lugdunensis (S. lugdunensis) is a coagulase negative staphylococcus (CoNS) that can cause destructive infective endocarditis. S. lugdunensis, unlike other CoNS, should be considered to be a pathogen. We report the first case of S. lugdunensis endocarditis causing ventricular septal defect and destruction of the aortic and mitral valves. A 53-year-old male with morbid obesity and COPD presented with intermittent fever and progressive shortness of breath for 2 weeks. Chest examination showed bilateral basal crepitations, and a grade 2 systolic murmur along the right sternal border. The leukocyte count was 26,000 cells/μl with 89% neutrophils. He was treated with intravenous vancomycin and ceftriaxone. Blood cultures grew Staphylococcus lugdunensis. Transthoracic echocardiogram, which was limited by body habitus, showed no definite valvular vegetations. Repeat transthoracic echocardiogram performed one week later revealed a large aortic valve vegetation Vancomycin was switched to daptomycin on day 4 because of difficulty achieving therapeutic levels of vancomycin and the development of renal insufficiency. Open heart surgery on day 10 revealed aortic valve and mitral valve vegetations with destruction, left ventricular outflow tract (LVOT) septal abscess and ventricular septal defect (VSD). Bio-prosthetic aortic and mitral valve replacement, LVOT and VSD repair were done. Intraoperative cultures grew Staphylococcus lugdunensis. The patient was discharged home with daptomycin to complete 6 weeks of treatment. S. lugdunensis can cause rapidly progressive endocarditis with valve and septal destruction. Early diagnosis and therapy are essential, with consideration of valve replacement.", "affiliations": "Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.", "authors": "Ishiekwene\|Celestine\|C\|;Ghitan\|Monica\|M\|;Kuhn-Basti\|Margaret\|M\|;Chapnick\|Edward\|E\|;Lin\|Yu Shia\|YS\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2016.10.011", "fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(16)30118-410.1016/j.idcr.2016.10.011Case ReportStaphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves Ishiekwene Celestine [email protected]⁎Ghitan Monica Kuhn-Basti Margaret Chapnick Edward Lin Yu Shia Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA⁎ Corresponding author at: 2775 Shore Parkway, Apt. 1D, Brooklyn, NY, 11223, USA. [email protected] 11 2016 2017 22 11 2016 7 14 15 17 10 2016 28 10 2016 28 10 2016 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Staphylococcus lugdunensis (S. lugdunensis) is a coagulase negative staphylococcus (CoNS) that can cause destructive infective endocarditis. S. lugdunensis, unlike other CoNS, should be considered to be a pathogen. We report the first case of S. lugdunensis endocarditis causing ventricular septal defect and destruction of the aortic and mitral valves.\n\nA 53-year-old male with morbid obesity and COPD presented with intermittent fever and progressive shortness of breath for 2 weeks.\n\nChest examination showed bilateral basal crepitations, and a grade 2 systolic murmur along the right sternal border. The leukocyte count was 26,000 cells/μl with 89% neutrophils. He was treated with intravenous vancomycin and ceftriaxone. Blood cultures grew Staphylococcus lugdunensis. Transthoracic echocardiogram, which was limited by body habitus, showed no definite valvular vegetations. Repeat transthoracic echocardiogram performed one week later revealed a large aortic valve vegetation Vancomycin was switched to daptomycin on day 4 because of difficulty achieving therapeutic levels of vancomycin and the development of renal insufficiency.\n\nOpen heart surgery on day 10 revealed aortic valve and mitral valve vegetations with destruction, left ventricular outflow tract (LVOT) septal abscess and ventricular septal defect (VSD). Bio-prosthetic aortic and mitral valve replacement, LVOT and VSD repair were done. Intraoperative cultures grew Staphylococcus lugdunensis. The patient was discharged home with daptomycin to complete 6 weeks of treatment.\n\nS. lugdunensis can cause rapidly progressive endocarditis with valve and septal destruction. Early diagnosis and therapy are essential, with consideration of valve replacement.\n\nKeywords\nStaphylococcus aureusS. aureusStaphylococcus lugdunensisS. lugdunensisLugdunensisInfective endocarditis\n==== Body\nIntroduction\nStaphylococcus lugdunensis (S. lugdunensis) is a coagulase negative staphylococcus (CoNS) that can cause destructive infective endocarditis as well as broad range of other clinical manifestations. S. lugdunensis, unlike other CoNS, should be taken as a pathogen when reported by microbiology laboratory. We are reporting a rare case of S. lugdunensis endocarditis causing ventricular septal defect; and aortic and mitral valves destruction.\n\nCase presentation\nA 53-year-old Caucasian male presented with intermittent fever, progressive shortness of breath and recurrent left big toe pain for 2 weeks. He had presented twice to the Emergency Department (ED) in the previous month, 2 weeks apart, with intermittent fever and left great toe pain. The leukocyte count was 16,000/μl with 85% neutrophils and fever of 101°F but the other vital signs were normal. He was discharged on a week’s course of oral antibiotics after both visits (clindamycin and prednisone then cefpodoxime and doxycycline on the 1st and 2nd visits respectively) for presumptive gouty arthritis of the left great toe with cellulitis. Symptoms were somewhat improved while on antibiotics but recurred and progressively got worse with associated shortness of breath.\n\nPast medical history was significant for morbid obesity and COPD, obstructive sleep apnea treated with nighttime CPAP (continuous positive airway pressure), abdominal aortic aneurysm, and pericarditis complicated by pericardial effusion requiring a pericardial window 3 years previously. Previous echocardiography done 3 years previously did not show VSD (ventricular septal defect).\n\nOn examination, the temperature was 99.3°F, heart rate 107/min and regular, respiratory rate 34/minute, blood pressure 86/54 mmHg, oxygen saturation 89% on room air. Chest examination showed bilateral basal crepitations, and cardiovascular examination revealed a grade 2 systolic murmur along the right sternal border. Skin around the left great toe was erythematous and mildly tender.\n\nTwo sets of blood cultures were drawn. The leukocyte count was 26,000 cells/μl (reference range 4.8–10.8) with 89% neutrophils (reference range 37.9–70.5), creatinine2.2 mg/dl (reference range 0.7–1.3), blood urea nitrogen 72 mg/dl (reference range 7–21), AST 890 (reference range 8–26), ALT 1173 IU/L (reference range 6–51), total bilirubin1.4 mg/dl (reference range 0.4–1.1) and alkaline phosphatase 200 IU/L (reference range 37–109).\n\nTransthoracic echocardiogram (TTE) showed an ejection fraction of 50%; thickened aortic valve leaflets, mildly increased LVOT/AV velocities; no definite valvular vegetation, and a moderately dilated aortic root (4.8 cm). The study was limited by body habitus. Chest computerize tomography ruled out pulmonary embolism.\n\nThe patient refused a transesophageal echocardiogram, and a repeat transthoracic echocardiogram performed one week later revealed an aortic valve vegetation of 1.9 × 1.2 cm, with partial destruction of the leaflet and baseline thickening of the valve.\n\nHe was treated with intravenous vancomycin and ceftriaxone. Two sets of blood cultures grew Staphylococcus lugdunensis. Vancomycin was switched to daptomycin on day 4 because of difficulty achieving therapeutic levels of vancomycin and the development of renal insufficiency.\n\nThe patient underwent open heart surgery on day 10. Aortic valve vegetation with destruction, a vegetation on the mitral valve with regurgitation, left ventricular outflow tract (LVOT) septal abscess and ventricular septal defect (VSD) were seen. Bio-prosthetic aortic and mitral valve replacement, LVOT and VSD repair were done. Intraoperative cultures grew Staphylococcus lugdunensis. The post-operative course was complicated by complete heart block requiring permanent pacemaker placement, IV line-related infection and pneumonia with respiratory failure.\n\nThe patient was discharged home on hospital day 39 to complete 6 weeks of treatment with daptomycin.\n\nDiscussion\nWe report the first case of S. lugdunensis endocarditis causing VSD. S. lugdunensis is a CoNS first isolated in France in 1988 [1]. It is a commensal of the human skin, especially below the waist, and can be as virulent as Staphylococcus aureus. S. lugdunensis, like other CoNS, has the ability to adhere and produce biofilm, which enables growth on bioprosthetic materials and native tissues [2]. Adhesion to vessel walls and cardiac valves is facilitated by its binding to von Willibrand factor [3], [4]. Fbl is a fibrinogen-binding protein peculiar to S. lugdunensis. Fbl is similar to clumping factor A, which is a fibrinogen-binding protein of S. aureus that plays an important role in its virulence [5]. Though CoNS can be considered a contaminant, S. lugdunensis should be regarded as a pathogen.\n\nS. lugdunensis causes a spectrum of disease including skin and soft tissue infection, bacteremia, infective endocarditis, osteomyelitis, arthritis and catheter related infection [6], [7], [8], [9]. It has been reported as a cause of destructive infective endocarditis with large vegetations visualized on echocardiography and the destruction of the native valves as can occur with S. aureus\n[10]. It mostly cause left sided infective endocarditis [11], although tricuspid valve involvement has been reported [11], [12].\n\nMost S. lugdunensis isolates are susceptible to oxacillin, and the presence of the mecA gene is rare [13]. Our patient was initially treated with intravenous vancomycin and ceftriaxone subsequently switched to daptomycin. Surgical treatment is needed for most patients with S. lugdunensis infective endocarditis [14], [15].\n\nS. lugdunensis can cause rapidly progressive endocarditis with valve and septal destruction. Early diagnosis and therapy are essential, with consideration of valve replacement.\n\nConflict of interest\nNo conflict of interest.\n==== Refs\nReferences\n1 Etienne J. Brun Y. Fleurette J. Staphylococcus lugdunensis endocarditis J Clin Pathol 42 August (8) 1989 892 893 PMID: 2768531 2768531 \n2 Hussain M. Steinbacher T. Peters G. Heilmann C. Becker K. The adhesive properties of the Staphylococcus lugdunensis multifunctional autolysin AtlL and its role in biofilm formation and internalization Int J Med Microbiol 305 January (1) 2015 129 139 PMID: 25515664 25515664 \n3 Speziale P. Pietrocola G. Foster T.J. Geoghegan J.A. Protein-based biofilm matrices in Staphylococci Front Cell Infect Microbiol 10 December (4) 2014 171 PMID: 25540773 \n4 Liesenborghs L. Peetermans M. Claes J. Veloso T.R. Vandenbriele C. Criel M. Shear-resistant binding to von willebrand factor allows Staphylococcus lugdunensis to adhere to the cardiac valves and initiate endocarditis J Infect Dis January (6) 2016 PMID: 26743845 \n5 Mitchell J. Tristan A. Foster T.J. Characterization of the fibrinogen binding surface protein Fbl of Staphylococcus lugdunensis Microbiology 150 11 2004 3831 3841 PMID: 15528668 15528668 \n6 Lin J.F. Cheng C.W. Kuo A.J. Liu T.P. Yang C.C. Huang C.T. Clinical experience and microbiologic characteristics of invasive Staphylococcus lugdunensis infection in a tertiary center in northern Taiwan J Microbiol Immunol Infect 48 August (4) 2015 406 412 PMID: 24529852 24529852 \n7 Matas A. Veiga A. Gabriel J.P. Brain Abscess due to Staphylococcus lugdunensis in the absence of Endocarditis or Bacteremia Case Rep Neurol 7 January (1) 2015 1 5 PMID: 25759658 25759658 \n8 Kear S. Smith C. Mirmiran R. Hofinger D. Staphylococcus lugdunensis : a rare pathogen for osteomyelitis of the foot J Foot Ankle Surg August (21) 2014 PMID: 25154651 \n9 Patel S. Lloyd J.R. Subungual abscess caused by Staphylococcus lugdunensis Cutis 92 September (3) 2013 125 126 PMID: 24153139. 24153139 \n10 Sabe M.A. Shrestha N.K. Gordon S. Menon V. Staphylococcus lugdunensis : a rare but destructive cause of coagulase-negative Staphylococcus infective endocarditis Eur Heart J Acute Cardiovasc Care 3 September (3) 2014 275 280 PMID: 24523355 24523355 \n11 Patil R. Patil T. Hussain K.M. Staphylococcus lugdunensis native tricuspid valve endocarditis: a case report and review of literature J Gen Intern Med 26 October (10) 2011 1209 1211 PMID: 21538169 21538169 \n12 Chung K.P. Chang H.T. Liao C.H. Chu F.Y. Hsueh P.R. Staphylococcus lugdunensis endocarditis with isolated tricuspid valve involvement J Microbiol Immunol Infect 45 June (3) 2012 248 250 PMID: 22041168 22041168 \n13 Becker K. Pagnier I. Schuhen B. Wenzelburger F. Friedrich A.W. Kipp F. Does nasal colonization by methicillin-resistant coagulase-negative staphylococci and methicillin-susceptible Staphylococcus aureus strains occur frequently enough to represent a risk of false-positive methicillin-resistant S. aureus determinations by molecular methods? J Clin Microbiol 44 1 2006 229 PMID: 16390977 16390977 \n14 Anguera I. Río A. Miró J.M. Matínez-Lacasa X. Marco F. Gumá J.R. Hospital clinic endocarditis study group Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles Heart 91 2 2005 PMID: 15657200 \n15 Naji D.I. Pak A. Lawless J. Main M.L. Rapid progression of Staphylococcus lugdunensis mechanical prosthetic valve endocarditis Echo Res Pract 2 September (3) 2015 I11 I12 PMID: 26693342 26693342\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-2509", "issue": "7()", "journal": "IDCases", "keywords": "Infective endocarditis; Lugdunensis; S. aureus; S. lugdunensis; Staphylococcus aureus; Staphylococcus lugdunensis", "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "14-15", "pmc": null, "pmid": "27920984", "pubdate": "2017", "publication_types": "D016428:Journal Article; D002363:Case Reports", "references": "16390977;24523355;15657200;25540773;15528668;26743845;24153139;2768531;25515664;21538169;25154651;24529852;26693342;25759658;22041168", "title": "Staphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves.", "title_normalized": "staphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves" }	[ { "companynumb": "US-AXELLIA-001019", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "091377", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Antibiotic level below therapeutic", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ISHIEKWENE C, GHITAN M, KUHN-BASTI M, CHAPNICK E, LIN YS. STAPHYLOCOCCUS LUGDUNENSIS ENDOCARDITIS WITH DESTRUCTION OF THE VENTRICULAR SEPTUM AND MULTIPLE NATIVE VALVES. IDCASES. 2016 NOV 22;7:14-15.", "literaturereference_normalized": "staphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161223", "receivedate": "20161223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13057609, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]
{ "abstract": "We report a case of an elderly woman on polypharmacy who developed appetite loss, general fatigue and muscle weakness mainly from secondary adrenal insufficiency caused by quitting one semiregular single-dose medicine. Because the degree of insufficiency was mild, her symptoms were eliminated after some time without additional treatment. The present case includes important lessons related to medication management in elderly patients. Additionally, the present case also warns us to be cautious while diagnosing geriatric syndromes as a part of the physiological aging process or additional disease symptoms. Drug-induced geriatric syndrome from quitting semiregular-use drugs should be investigated in future studies.", "affiliations": "Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Division of Community Medicine, School of Medicine, Tohoku Medical and Pharmaceutical University, 1-12-1 Fukumuro, Miyaginoku, Sendai, Japan.;Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.", "authors": "Tomita\|Naoki\|N\|;Ishiki\|Aiko\|A\|;Okinaga\|Shoji\|S\|;Furukawa\|Katsutoshi\|K\|;Arai\|Hiroyuki\|H\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/omcr/omz047", "fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omz047omz047Case ReportDevelopment of geriatric syndromes after taking countermeasures for polypharmacy: an overlooked issue of quitting semiregular single-dose medicine Tomita Naoki 1Ishiki Aiko 1Okinaga Shoji 1Furukawa Katsutoshi 2Arai Hiroyuki 11 Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan2 Division of Community Medicine, School of Medicine, Tohoku Medical and Pharmaceutical University, 1-12-1 Fukumuro, Miyaginoku, Sendai, JapanCorrespondence address. Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Tel: +81-22-717-7182; Fax: +81-22-717-8498; E-mail: [email protected] 2019 14 6 2019 14 6 2019 2019 6 omz04720 1 2019 29 3 2019 22 4 2019 © The Author(s) 2019. Published by Oxford University Press.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]\nWe report a case of an elderly woman on polypharmacy who developed appetite loss, general fatigue and muscle weakness mainly from secondary adrenal insufficiency caused by quitting one semiregular single-dose medicine. Because the degree of insufficiency was mild, her symptoms were eliminated after some time without additional treatment. The present case includes important lessons related to medication management in elderly patients. Additionally, the present case also warns us to be cautious while diagnosing geriatric syndromes as a part of the physiological aging process or additional disease symptoms. Drug-induced geriatric syndrome from quitting semiregular-use drugs should be investigated in future studies.\n==== Body\nINTRODUCTION\nAdverse drug reactions (ADRs) in elderly patients can be mistaken as part of physiological aging or an additional disease symptom (1). The differentiation of ADRs from physiological aging or disease symptoms requires utmost care, particularly when the ADRs are caused by reducing the number of drugs (2). This becomes difficult if a patient is taking semiregular-use drugs.\n\nCASE REPORT\nAt the end of July 2015, a 78-year-old woman visited a general hospital for appetite loss, general fatigue and muscle weakness. Because she was taking several drugs, her doctor stopped some medications, including antidiabetics (metformin 500 mg/day and vildagliptin 100 mg/day), antihypertensive agents (amlodipine 5 mg/day, candesartan 8 mg/day and doxazocine 1 mg/day) and statins (pitavastatin calcium 1 mg/day), as these could cause ADRs. She was also directed to stop all over-the-counter and semiregular-use drugs. However, her symptoms did not improve. Over 2 months, her weight reduced by ~2.0–50.7 kg (body mass index: 23.2 kg/m2). By the end of September, she developed mild fever and was admitted to our hospital, accompanied by her granddaughter. Her children took turns with her hospital visits, except when she was temporarily admitted to a nearby clinic.\n\nShe had some concomitant disease, including hypertension, type II diabetes mellitus, osteoporosis, osteoarthritis, insomnia, bronchial asthma and skin rash, resulting in regular hospital visits. She regularly took more than 10 oral medications (including diabetic drugs, antihypertensive drugs, benzodiazepine and proton pump inhibitors). Besides hearing difficulties, she was diagnosed with mild cognitive impairment 1 year before admission. Her daughter-in-law helped her manage regular drugs. She had good adherence to regular medicines.\n\nAlthough she had right knee osteoarthritis, she could walk independently. Pretibial and pedal edema was observed in both legs. She had a rash, a mild headache with no neck stiffness and a body temperature of ~ 37.5°C. She had no diarrhea, vomiting or abdominal pain, and she defecated every other day without laxatives. There were no signs of upper respiratory tract infections. Her muscle strength was not sufficient to open a bottle cap. Pyramidal/extra-pyramidal signs and ataxia was not observed. She had no significant family history of disease.\n\nIn blood tests, inflammation was negative (white blood cell count: 6.3 × 103/μL; C-reactive protein: 0.2 mg/dL). Eosinophilia (16.6% [1046/μL]) and hypokalemia (2.8 mmol/L) with normal serum sodium level (144 mmol/L) were observed with indications of malnutrition (albumin: 3.0 g/dL; total cholesterol: 139 mg/dL; total lymphocyte count: 29.0% [1827/μL]). Procalcitonin level was 0.08 ng/mL. Total serum calcium corrected for albumin level was 11.0 mg/dL. Zinc deficiency was not observed. Thyroid hormones were within normal range (FT3: 4.72 pg/mL; FT4: 1.63 ng/dL; human thyroid-stimulating hormone: 0.646 μIU/mL). Hemoglobin A1c, fasting blood glucose, blood urea nitrogen and creatinine levels were 6.4%, 105 mg/dL, 5.0 mg/dL and 0.60 mg/dL, respectively, with normal transaminase and biliary enzyme activity. Autoantibodies were negative, and urine was clear. Occult blood was not detected in her stool.\n\nChest x-ray was normal. Electrocardiogram showed sinus arrhythmia (75 bpm). Abdominal ultrasonography, computed tomography and upper gastrointestinal tract endoscopy showed no significant abnormalities.\n\nHer mini mental state examination score was 24/30, and immediate recall failure was observed. Her geriatric depression scale score was 6/15. Magnetic resonance imaging of brain showed only bilateral hippocampal atrophy.\n\nImmediately after admission, we stopped donepezil 5 mg/day as it was found to be prescribed for 2 months. However, improvement was negligible to alleviate malnutrition. There were no other potentially inappropriate medications (PIMs) or risky combinations in her regular drugs (3–5).\n\nAs fever was sustained at ~ 37.5°C, and we performed lumbar puncture; cerebrospinal fluid and laboratory tests were normal. One month after the patient’s admission, her granddaughter informed that the patient sometime visited a clinic and obtained ointments and medicines to relieve itching, which she managed herself. Based on doctor’s instruction, in July 2015, the family had taken these drugs away. Shortly afterwards, she developed mild fever. We asked the concerned doctor what types of medicines he had prescribed. We found she had been taking an antihistamine (d-crolefeniraminmarein acid) containing a steroid (betametazone 0.25 mg/tablet) almost every other week for 10 years, without anybody’s knowledge. There seemed to be no non-adherence to the drug.\n\nBased on the information provided, we speculated that her symptoms were related to adrenal insufficiency, derived from quitting semiregular use of this steroid-containing agent. One month after admission, we performed the adrenocorticotropic hormone (ACTH) loading test. Peak cortisol level was 16.0 μg/dL after 90 min, which was slightly lower than standard, indicating mild adrenal insufficiency. Fortunately, her appetite and pyrexia began to recover when the test was performed. Two months after admission, fever lysis was achieved without the initiation of steroid medications. Eosinophilia and hypokalemia gradually improved toward the date of discharge. On her visit to our outpatient clinic after discharge, we found that muscle strength and cognition had recovered, even though we did not restart cholinesterase inhibitors. Likewise, it was unnecessary to restart medications for diabetes mellitus and dyslipidemia. We restarted olmesartan 10 mg/day a few days after admission, during the hospital stay and after discharge. No additional anti-hypertensive drugs were required.\n\nBased on her symptoms, clinical course and recovery without additional treatment, infectious, malignant and autoimmune diseases were unlikely. The ACTH test results indicated that secondary adrenal insufficiency occurred from quitting semiregular use of a steroid-containing antihistamine agent. We conclude that appetite loss, which was caused by multiple factors (i.e. hot climate, initiation of cholinesterase inhibitor), and subsequent cessation of steroid-containing agent has triggered mild secondary adrenal insufficiency. We asked her family to fix a person in charge of her health and warned them to consult a specialist when symptomatic treatment is not effective.\n\nDISCUSSION\nWe described an elderly woman on polypharmacy who developed appetite loss, muscle weakness and general fatigue from multiple factors, mainly secondary adrenal insufficiency caused by quitting one semiregular single-dose medicine. Reducing polypharmacy, even semiregular-use drugs, should be performed carefully (6, 7), especially when multiple prescribers are present.\n\nThe detection of ADRs becomes difficult if symptoms are like those of geriatric syndrome (1). Distinction becomes even more difficult if the symptoms are derived from semiregular-use medicines and if stopping the prescription is the cause. Adrenal insufficiency manifests symptoms that can be confused with geriatric syndrome or multimorbidity (8). Several reports of secondary adrenal insufficiency from the steroid-containing antihistamine exist in Japan. The present case report adds an important lesson for the management of PIMs.\n\nConflict of interest statement\nNone declared.\n\nFunding\nThis study did not receive any external funding.\n\nEthical approval\nAs this is a case report, we did not obtain any ethical approval. Written informed consent was obtained.\n\nConsent\nWritten permission was granted by the patient and the primary caregiver of the patient.\n\nGuarantor\nNaoki Tomita.\n\nAuthor contributions\n.T. is responsible for patient diagnosis and care and manuscript preparation; A.I., S.O. and K.F. also helped with patient diagnosis and gave advice on the manuscript; and H.A. contributed with intellectual inputs, patient diagnosis and gave advice on the manuscript. All authors read the final version of the manuscript.\n==== Refs\nReferences\n1. \nShah BM , Hajjar ER \nPolypharmacy, adverse drug reactions, and geriatric syndromes . Clin Geriatr Med 2012 ;28 :173 –86 .22500537 \n2. \nMishima E , Nishimiya K , Fujiwara Y , Nishizawa M , Kiyomoto H , Ito S \nSerious hypocalcemia after withdrawal of vitamin D analog in bedridden nonagenarians with previous thyroidectomy: a report of two cases . J Am Geriatr Soc 2016 ;64 :1374 –6 .27321630 \n3. \nAmerican Geriatric Society 2015 Beers Criteria Update Expert Panel \nAmerican Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults . J Am Geriatr Soc 2015 ;63 :2227 –46 .26446832 \n4. \nO'Mahony D , O'Sullivan D , Byrne S , O'Connor MN , Ryan C , Gallagher P \nSTOPP/START criteria for potentially inappropriate prescribing in older people: version 2 . Age Aging 2015 ;44 :213 –8 .\n5. \nKojima T , Mizukami K , Tomita N , Arai H , Ohrui T , Eto M, et al. \nScreening tool for older persons’ appropriate prescriptions for Japanese: report of the Japan Geriatrics Society Working Group on “guidelines for medical treatment and its safety in the elderly” . Geriatr Gerontol Int 2017 ;17 :363 .28240452 \n6. \nScott IA , Hilmer SN , Reeve E , Potter K , Le Couteur D , Rigby D, et al. \nReducing inappropriate polypharmacy: the process of deprescribing . JAMA Intern Med 2015 ;175 :827 –34 .25798731 \n7. \nSergi G , De Rui M , Sarti S , Manzato E \nPolypharmacy in the elderly: can comprehensive geriatric assessment reduce inappropriate medication use? Drugs Aging 2011 ;28 :509 –18 .21721596 \n8. \nKojima G , Laurel P , Inaba M , Tanabe M \nUnveiling adrenal insufficiency can make a difference in elderly adults . J Am Geriatr Soc 2014 ;62 :2456 –7 .25516051\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2053-8855", "issue": "2019(6)", "journal": "Oxford medical case reports", "keywords": null, "medline_ta": "Oxf Med Case Reports", "mesh_terms": null, "nlm_unique_id": "101642070", "other_id": null, "pages": "omz047", "pmc": null, "pmid": "31214359", "pubdate": "2019-06", "publication_types": "D002363:Case Reports", "references": "21721596;22500537;25324330;25516051;25798731;26446832;27321630;27594406", "title": "Development of geriatric syndromes after taking countermeasures for polypharmacy: an overlooked issue of quitting semiregular single-dose medicine.", "title_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine" }	[ { "companynumb": "JP-TEVA-2019-JP-1087160", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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"drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PITAVASTATIN CALCIUM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Secondary adrenocortical insufficiency", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Steroid withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Oedema peripheral", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sinus arrhythmia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201507" } }, "primarysource": { "literaturereference": "TOMITA N, ISHIKI A, OKINAGA S, FURUKAWA K, ARAI H. DEVELOPMENT OF GERIATRIC SYNDROMES AFTER TAKING COUNTERMEASURES FOR POLYPHARMACY: AN OVERLOOKED ISSUE OF QUITTING SEMIREGULAR SINGLE-DOSE MEDICINE. OXF-MED-CASE-REPORTS 2019?2019(6):259-261.", "literaturereference_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190802", "receivedate": "20190802", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16660254, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "PHHY2019JP173295", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "91198", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Secondary adrenocortical insufficiency", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TOMITA N, ISHIKI A, OKINAGA S, FURUKAWA K, ARAI H. DEVELOPMENT OF GERIATRIC SYNDROMES AFTER TAKING COUNTERMEASURES FOR POLYPHARMACY: AN OVERLOOKED ISSUE OF QUITTING SEMIREGULAR SINGLE-DOSE MEDICINE.. OXFORD MEDICAL CASE REPORTS. 2019?1-3", "literaturereference_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190802", "receivedate": "20190802", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16661785, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "JP-ACCORD-150262", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201335", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201505", "drugstartdateformat": "610", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL/DONEPEZIL HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANDESARTAN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANDESARTAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PITAVASTATIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITAVASTATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXAZOSIN MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXAZOSIN" }, { "actiondrug": "1", "activesubstance": null, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN/OLMESARTAN MEDOXOMIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE\\DEXCHLORPHENIRAMINE MALEATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "EVERY OTHER WEEK, STRENGTH 0.25 MG", "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "PRURITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELESTAMINE" } ], "patientagegroup": "6", "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Secondary adrenocortical insufficiency", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2015" } }, "primarysource": { "literaturereference": "TOMITA N, ISHIKI A, OKINAGA S, FURUKAWA K, ARAI H. DEVELOPMENT OF GERIATRIC SYNDROMES AFTER TAKING COUNTERMEASURES FOR POLYPHARMACY: AN OVERLOOKED ISSUE OF QUITTING SEMIREGULAR SINGLE-DOSE MEDICINE. OXFORD MEDICAL CASE REPORTS. 2019?6:ARTICLE NUMBER OMZ047 (259 - 261).", "literaturereference_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190805", "receivedate": "20190805", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16667121, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy. Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily. The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.\n\n\n\nThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.\n\n\n\nThis was a phase I study with a 3+3 design in patients with treatment-naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.\n\n\n\nA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose-limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment-related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression-free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated-ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated-ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.\n\n\n\nTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.", "affiliations": "Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Moffitt Cancer Center, Tampa, Florida, USA.;Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Internal Medicine, Advent Health, Orlando, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.", "authors": "Kim\|Richard\|R\|https://orcid.org/0000-0002-8448-844X;Tan\|Elaine\|E\|;Wang\|Emily\|E\|;Mahipal\|Amit\|A\|;Chen\|Dung-Tsa\|DT\|;Cao\|Biwei\|B\|;Masawi\|Fadzai\|F\|;Machado\|Cindy\|C\|;Yu\|James\|J\|;Kim\|Dae Won\|DW\|", "chemical_list": "D010671:Phenylurea Compounds; D011728:Pyridones; D011744:Pyrimidinones; D009536:Niacinamide; C560077:trametinib; D000077157:Sorafenib", "country": "United States", "delete": false, "doi": "10.1634/theoncologist.2020-0759", "fulltext": null, "fulltext_license": null, "issn_linking": "1083-7159", "issue": "25(12)", "journal": "The oncologist", "keywords": null, "medline_ta": "Oncologist", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D006801:Humans; D007963:Leukocytes, Mononuclear; D008113:Liver Neoplasms; D009536:Niacinamide; D010671:Phenylurea Compounds; D011728:Pyridones; D011744:Pyrimidinones; D000077157:Sorafenib", "nlm_unique_id": "9607837", "other_id": null, "pages": "e1893-e1899", "pmc": null, "pmid": "32776632", "pubdate": "2020-12", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "18650514;25294897;29030911;29950351;26644411;19910069;19698189;30030148;28276530;9223425;22663011;19095497;22805291;24204195;27681866", "title": "A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer.", "title_normalized": "a phase i trial of trametinib in combination with sorafenib in patients with advanced hepatocellular cancer" }	[ { "companynumb": "NVSC2020US232622", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TRAMETINIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "204114", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG, QD (1 AND 1.5 MILLIGRAMS (MG) FLAT DOSE, DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMETINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, QD (200 AND 400 MILLIGRAMS (MG) FLAT DOSE, DAILY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HEPATOCELLULAR CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KIM R, TAN E, WANG E, MAHIPAL A, CHEN DT, CAO B ET AL.. A PHASE I TRIAL OF TRAMETINIB IN COMBINATION WITH SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CANCER. THE ONCOLOGIST. 2020?9999:1?9", "literaturereference_normalized": "a phase i trial of trametinib in combination with sorafenib in patients with advanced hepatocellular cancer", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200824", "receivedate": "20200824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18188898, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "We report the case of a young patient treated with rituximab-containing chemotherapy who was infected with measles despite previous vaccination. Treatment with vitamin A, ribavirin, and immunoglobulins was started; nevertheless he developed severe pneumonitis and deceased. Broad vaccination coverage is crucial in protecting vulnerable subjects.", "affiliations": "Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.", "authors": "Jent\|Philipp\|P\|0000-0002-1838-9208;Trippel\|Mafalda\|M\|;Frey\|Manuel\|M\|;Pöllinger\|Alexander\|A\|;Berezowska\|Sabina\|S\|;Langer\|Rupert\|R\|;Furrer\|Hansjakob\|H\|;Béguelin\|Charles\|C\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1093/ofid/ofy244", "fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidOpen Forum Infectious Diseases2328-8957Oxford University Press US 10.1093/ofid/ofy244ofy244Brief ReportsFatal Measles Virus Infection After Rituximab-Containing Chemotherapy in a Previously Vaccinated Patient http://orcid.org/0000-0002-1838-9208Jent Philipp 1Trippel Mafalda 2Frey Manuel 3Pöllinger Alexander 4Berezowska Sabina 2Langer Rupert 2Furrer Hansjakob 1Béguelin Charles 11 Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland2 Institute of Pathology, University of Bern, Bern, Switzerland3 Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland4 Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandCorrespondence: P. Jent, MD, Department of Infectious Diseases, Inselspital, Bern University Hospital, Freiburgstrasse 16p, CH-3010 Bern, Switzerland ([email protected]).11 2018 01 11 2018 01 11 2018 5 11 ofy24419 7 2018 20 9 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected]\nWe report the case of a young patient treated with rituximab-containing chemotherapy who was infected with measles despite previous vaccination. Treatment with vitamin A, ribavirin, and immunoglobulins was started; nevertheless he developed severe pneumonitis and deceased. Broad vaccination coverage is crucial in protecting vulnerable subjects.\n\nimmunocompromisedmeaslesrituximabvaccination\n==== Body\nCASE PRESENTATION\nWe present the case of a 26-year-old man who was hospitalized with fever and neutropenia. He was known to have chronic lymphocytic leukemia (CLL; small lymphocytic lymphoma, low risk, Binet stade B, Rai II; 11q deletion, no TP53 mutation), diagnosed 7 months before admission, and had been treated with 7 cycles of chemotherapy with fludarabine, cyclophosphamide, and rituximab until 1 month before admission. He had been receiving Pneumocystis pneumonia prophylaxis with trimethoprim/sulfamethoxazole and herpes simplex virus prophylaxis with valaciclovir. There was no recent travel history, no known animal contact, no recent sexual risk exposure, and no known infectious disease in close contacts. Vaccinations had been completed according to Swiss national recommendations, including 2 documented measles, mumps, and rubella (MMR) vaccine doses in 1993 and 1999.\n\nAt hospital entry, the patient reported sore throat, unproductive cough, and fever without chills since 1 day before admission. The clinical exam was only remarkable for pharyngitis and the previously known cervical lymphadenopathy. C-reactive protein was moderately elevated (53 mg/L). The patient was thrombocytopenic (73 G/L) and had a leukocytopenia (1.08 G/L; 0.67 G/L neutrophile granulocytes). A chest x-ray showed no infiltrates, and a rapid-antigen detection test for group A streptococci from a throat swab was negative.\n\nEmpirical treatment with cefepime was started. Blood cultures and multiplex polymerase chain reaction (PCR) for respiratory viruses using a nasopharyngeal swab remained negative. Four days after symptom onset, the patient developed a confluent maculopapular rash of the face and upper trunk. Skin biopsy showed a perivascular lymphohistiocytic infiltrate and necrotic keratinocytes—changes compatible with an exanthematous drug eruption. For this reason, trimethoprim/sulfamethoxazole was stopped, and cefepime was switched to meropenem.\n\nBesides a progressive craniocaudal evolution of the maculopapular rash (Figure 1B), the patient developed ulcerative stomatitis compatible with Koplik spots (Figure 1A) and bilateral conjunctivitis on day 7 after symptom onset. These findings raised the suspicion of a measles virus infection, although the patient had been vaccinated as a child, as previously described. Positive measles real-time PCR from a throat swab confirmed the suspected diagnosis. In the month before, there had been no measles outbreaks in the patient’s region of residence, and he was not aware of any contact with a measles-infected individual. Measles IgG and IgM (Serion ELISA classic, Virion/Serion GmbH, Würzburg, Germany) and rubella virus IgG were negative on day 6 after symptom onset, and mumps virus IgG was borderline positive (93 U/mL; cutoff, 70 U/mL), despite documented prior vaccination with 2 doses. Total IgG was in the lower normal range (8.6 G/L; normal range, 7–16 G/L).\n\nFigure 1. A, Enanthema, no scale available. B, Maculopapular rash (back of the patient), no scale available. C, Computed tomography lung scan with nodular peribronchial infiltrates. D, Histology of the lung section (hematoxylin and eosin stain, 80× magnification) of the patient. Giant cell pneumonitis: numerous syncytial multinuclear giant cells with intracytoplasmic and intranuclear inclusions lining the alveolar walls, with a background of diffuse alveolar damage.\n\nTreatment with intravenous ribavirin, intravenous immunoglobulins, and vitamin A was started. On day 8 after symptom onset, the patient developed progressive dyspnea and hypoxia in addition to the unproductive cough, while the fever persisted. A chest computed tomography scan showed bilateral, in part nodular pulmonary consolidations with adjacent ground glass infiltrations, compatible with pneumonitis (Figure 1C). Elevated transaminases up to 2 to 3 times the upper norm were observed as well. On day 15, he fulfilled the definition of acute respiratory distress syndrome (ARDS) and required invasive ventilation, and on the following day veno-venous extracorporeal membrane oxygenation (VV-ECMO). On day 17 after the onset of symptoms, the patient developed venous bleeding at the puncture site of the VV-ECMO and succumbed to mixed shock and severe pneumonitis.\n\nPostmortem examination showed macroscopically severe diffuse micronodular parenchymal consolidations of the lungs. Apart from the aspect of a diffuse alveolar damage, correlating with the clinical picture of ARDS, histology revealed numerous syncytial multinuclear giant cells with intracytoplasmic and intranuclear inclusions lining the alveolar walls, consistent with measles pneumonitis (Figure 1D).\n\nDISCUSSION\nThe presented case demonstrates the severity of measles infections in immunocompromised patients and highlights the importance of herd immunity, as rituximab can compromise previously acquired humoral immunity.\n\nMeasles in immunocompromised patients bears serious complications in about 80% of cases. Pneumonitis is the principal complication, accounting for most measles-associated deaths [1]. Clinical presentation in immunocompromised patients frequently is atypical, with 27%–40% of patients presenting without a rash [1].\n\nHumoral immunity plays the main role in preventing measles virus infection, with neutralizing antibody titers at the time of exposure correlating with protection from disease [2]. In our patient, a serum sample from before the start of rituximab was not available, but he had received 2 documented MMR vaccine doses before his infection, which induces long-lasting protection in 97% of vaccinated subjects [3]. However, at the time of diagnosis, he had no measurable antibodies to measles or rubella, and he had borderline mumps IgG. We assume this is due to his rituximab-containing chemotherapy. Additionally, the patient’s underlying disease may have played a role in his vulnerability, although pretreatment hypogammaglobulinemia in CLL is far less commonly seen than after treatment with rituximab [4]. Rituximab, a monoclonal CD-20 antibody, is known to induce transient hypogammaglobulinemia in 39% of patients [5]. After application of rituximab, the immune response to recall antigens is reduced [6]. Additionally, fludarabine, in addition to its effect on T-lymphocytes, also leads to prominent B-cell depletion [7]; the combination of fludarabine with rituximab has been independently associated with higher infection rates [8]. A primary vaccine failure cannot be ruled out as an explanation for the missing immunity against measles; however, it is a far less probable explanation given the vaccine’s high 2-dose effectiveness and the multiple reasons for humoral immunodeficiency depicted above.\n\nImmune control of measles infection is primarily dependent on T-lymphocyte cytolytic response, whereas humoral immunity seems to play only a minor role in disease control. B-lymphocyte-depleted rhesus monkeys have a clinical and virological course of measles infection that is indistinguishable from that of healthy monkeys [9]. Children with hypogammaglobinemia have a normal disease course, in contrast to children with cellular immune defects [1, 10], in whom measles infection is associated with a high risk of complications. Mainly the T-lymphocyte cytolytic response is associated with clearance of infection [11]. In our patient, the T-lymphocyte cytolytic response was heavily compromised due to chemotherapy with fludarabine and cyclophosphamide.\n\nEvidence on treatment options in severe measles infection is limited. Management consists primarily of supportive therapy and treatment of secondary bacterial infections.\n\nRibavirin, a ribosyl purine analogue, shows in vitro activity against measles virus [12]. One nonblinded randomized trial with ribavirin vs supportive therapy in 100 nonimmunocompromised patients found a reduced time to resolution of fever with ribavirin (mean, 7.3 vs 3.2 days). Furthermore, in the ribavirin group, there were no complications vs 11% with respiratory symptoms, 2% with encephalitis, and 2% with a fatal outcome in the control group [13]. The use of intravenous or aerosolized ribavirin in severe measles infection in immunocompromised patients has also been reported in a few case reports and series, but a significant survival benefit could not be proven in these series [1]. One case series [14] found significantly higher mortality in pediatric oncologic patients with measles infection if ribavirin application was delayed, but the observation was based on only 2 patients with a fatal outcome.\n\nReduced mortality and major complications after oral application of vitamin A in children with measles infection have been demonstrated in several randomized controlled trials in third world or developing countries [15]. It is unclear if this effect is transferable to immunocompromised patients in populations with a lower prevalence of vitamin A deficiency. Nevertheless, in most case series of severe measles infection, the patients have received oral vitamin A.\n\nThe use of intravenous immunoglobulins in severe measles infection in immunocompromised patients is common, but there is no evidence of its ability to improve the disease course. On the other side, its effect as postexposure prophylaxis is well established. Given the limited role of humoral immunity in disease control (see further up), a relevant benefit of intravenous immunoglobulin administration for a therapeutic indication in measles is improbable.\n\nGiven the fact that therapeutic options in severe measles infection are limited, as described above, the role of herd immunity to protect vulnerable (eg, immunocompromised, children younger than age 1 year) subjects is crucial. A recent drop in vaccination coverage in Europe, with 2-vaccine-dose coverage below the World Health Organization (WHO) herd immunity threshold of 95% in 20 of 27 reporting countries, led to an epidemic of more than 14 000 cases, including 30 fatal ones in 2017. MMR 1-dose coverage in the United States is still below the WHO herd immunity threshold, with local variation. In this epidemiologic situation of limited herd immunity, a cocooning vaccination strategy should be envisaged, namely to vaccinate people with close contact to patients whose immunosuppressive therapy is hampering their vaccination protection.\n\nCONCLUSIONS\nMeasles virus infections in immunocompromised patients often have an atypical presentation and can even occur in previously vaccinated individuals (eg, after rituximab), as shown in this case presentation. Given the limited therapeutic options, herd immunity, namely high immunization coverage and a cocooning strategy, is crucial to the protection of vulnerable subjects. Ongoing efforts to raise confidence in vaccines and increase population immunity should be intensified.\n\nAcknowledgments\nWe thank the family of the patient for giving us the opportunity to publish this case.\n\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nKaplan LJ , Daum RS , Smaron M , McCarthy CA \nSevere measles in immunocompromised patients . JAMA 1992 ; 267 :1237 –41 .1538561 \n2. \nChen RT , Markowitz LE , Albrecht P , et al \nMeasles antibody: reevaluation of protective titers . J Infect Dis 1990 ; 162 :1036 –42 .2230231 \n3. \nMarkowitz LE , Preblud SR , Fine PE , Orenstein WA \nDuration of live measles vaccine-induced immunity . Pediatr Infect Dis J 1990 ; 9 :101 –10 .2179836 \n4. \nBaliakas P , Xochelli A , Minga E , et al \nRevisiting hypogammaglobulinemia in chronic lymphocytic leukemia: a combined clinicobiological approach . Blood 2014 ; 124 :5633 .\n5. \nCasulo C , Maragulia J , Zelenetz AD \nIncidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections . Clin Lymphoma Myeloma Leuk 2013 ; 13 :106 –11 .23276889 \n6. \nvan der Kolk LE , Baars JW , Prins MH , van Oers MH \nRituximab treatment results in impaired secondary humoral immune responsiveness . Blood 2002 ; 100 :2257 –9 .12200395 \n7. \nTakada K , Danning CL , Kuroiwa T , et al \nLymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects . Ann Rheum Dis 2003 ; 62 :1112 –5 .14583577 \n8. \nCabanillas F , Liboy I , Pavia O , Rivera E \nHigh incidence of non-neutropenic infections induced by rituximab plus fludarabine and associated with hypogammaglobulinemia: a frequently unrecognized and easily treatable complication . Ann Oncol 2006 ; 17 :1424 –7 .16966368 \n9. \nPermar SR , Klumpp SA , Mansfield KG , et al \nLimited contribution of humoral immunity to the clearance of measles viremia in rhesus monkeys . J Infect Dis 2004 ; 190 :998 –1005 .15295708 \n10. \nPermar SR , Griffin DE , Letvin NL \nImmune containment and consequences of measles virus infection in healthy and immunocompromised individuals . Clin Vaccine Immunol 2006 ; 13 :437 –43 .16603610 \n11. \nPermar SR , Klumpp SA , Mansfield KG , et al \nRole of CD8(+) lymphocytes in control and clearance of measles virus infection of rhesus monkeys . J Virol 2003 ; 77 :4396 –400 .12634396 \n12. \nShigeta S , Mori S , Baba M , et al \nAntiviral activities of ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, and 6’-®-6’-C-methylneplanocin A against several ortho- and paramyxoviruses . Antimicrob Agents Chemother 1992 ; 36 :435 –9 .1605607 \n13. \nPal G \nEffects of ribavirin on measles . J Indian Med Assoc 2011 ; 109 :666 –7 .22480102 \n14. \nRoy Moulik N , Kumar A , Jain A , Jain P \nMeasles outbreak in a pediatric oncology unit and the role of ribavirin in prevention of complications and containment of the outbreak . Pediatr Blood Cancer 2013 ; 60 :E122 –4 .23629813 \n15. \nHussey GD , Klein M \nA randomized, controlled trial of vitamin A in children with severe measles . N Engl J Med 1990 ; 323 :160 –4 .2194128\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2328-8957", "issue": "5(11)", "journal": "Open forum infectious diseases", "keywords": "immunocompromised; measles; rituximab; vaccination", "medline_ta": "Open Forum Infect Dis", "mesh_terms": null, "nlm_unique_id": "101637045", "other_id": null, "pages": "ofy244", "pmc": null, "pmid": "30397623", "pubdate": "2018-11", "publication_types": "D016428:Journal Article", "references": "12200395;16966368;22480102;12634396;14583577;23276889;15295708;2179836;1605607;1538561;2194128;2230231;23629813;16603610", "title": "Fatal Measles Virus Infection After Rituximab-Containing Chemotherapy in a Previously Vaccinated Patient.", "title_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient" }	[ { "companynumb": "CH-TEVA-2018-CH-991662", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", 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"patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia measles", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Vaccination failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "JENT P, TRIPPEL M, FREY M, POLLINGER A, BEREZOWSKA S, LANGER R, ET AL. FATAL MEASLES VIRUS INFECTION AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY IN A PREVIOUSLY VACCINATED PATIENT. OPEN-FORUM-INFECT-DIS 2018?5:NO. 11.", "literaturereference_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20181224", "receivedate": "20181224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15756209, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "CH-MYLANLABS-2018M1091992", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, 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}, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACICLOVIR" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia measles", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "JENT P, TRIPPEL M, FREY M, POLLINGER A, BEREZOWSKA S, LANGER R, ET AL. FATAL MEASLES VIRUS INFECTION AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY IN A PREVIOUSLY VACCINATED PATIENT. OPEN-FORUM-INFECT-DIS 2018?5:NO. 11.", "literaturereference_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20181220", "receivedate": "20181220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15746832, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "CH-ROCHE-2215172", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": 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null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACICLOVIR" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Measles", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "JENT P, TRIPPEL M, FREY M, POLLINGER A, BEREZOWSKA S, LANGER R, FURRER H AND BEGUELIN C. FATAL MEASLES VIRUS INFECTION AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY IN A PREVIOUSLY VACCINATED PATIENT. OPEN FORUM INFECTIOUS DISEASES 2018 NOV 01?5(11):1-3.", "literaturereference_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20181116", "receivedate": "20181116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15624751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]
{ "abstract": "To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.\n\n\n\nProspective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.\n\n\n\nTwo hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.\n\n\n\nGH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.", "affiliations": "Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain", "authors": "Martín-Begué\|Nieves\|N\|0000-0003-0365-1266;Mogas\|Eduard\|E\|0000-0001-8501-5364;Wolley Dod\|Charlotte\|C\|0000-0001-9442-3802;Alarcón\|Silvia\|S\|0000-0003-1467-4797;Clemente\|María\|M\|0000-0002-3721-5043;Campos-Martorell\|Ariadna\|A\|0000-0002-8134-4934;Fábregas\|Ana\|A\|0000-0001-8137-6189;Yeste\|Diego\|D\|0000-0002-6620-6525", "chemical_list": null, "country": "Turkey", "delete": false, "doi": "10.4274/jcrpe.galenos.2020.2020.0007", "fulltext": "\n==== Front\nJ Clin Res Pediatr Endocrinol\nJ Clin Res Pediatr Endocrinol\nJCRPE\nJournal of Clinical Research in Pediatric Endocrinology\n1308-5727\n1308-5735\nGalenos Publishing\n\n33006547\n10.4274/jcrpe.galenos.2020.2020.0007\n40516\nOriginal Article\nGrowth Hormone Treatment and Papilledema: A Prospective Pilot Study\nMartín-Begué Nieves 1https://orcid.org/0000-0003-0365-1266\n\nMogas Eduard 2https://orcid.org/0000-0001-8501-5364\n\nDod Charlotte Wolley 1https://orcid.org/0000-0001-9442-3802\n\nAlarcón Silvia 1https://orcid.org/0000-0003-1467-4797\n\nClemente María 234https://orcid.org/0000-0002-3721-5043\n\nCampos-Martorell Ariadna 23https://orcid.org/0000-0002-8134-4934\n\nFábregas Ana 2https://orcid.org/0000-0001-8137-6189\n\nYeste Diego 234https://orcid.org/0000-0002-6620-6525\n\n1 Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain\n2 Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain\n3 Universitat Autònoma de Barcelona (UAB), Barcelona, Spain\n4 Centro de Investigación Biomédica en Red: Enfermedades Raras (CIBERER), Madrid, Spain\n Address for Correspondence: Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain Phone: +034934893166 E-mail:[email protected]\n6 2021\n2 6 2021\n13 2 146151\n16 1 2020\n16 9 2020\n©Copyright 2021 by Turkish Pediatric Endocrinology and Diabetes Society \| The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective:\n\nTo investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.\n\nMethods:\n\nProspective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.\n\nResults:\n\nTwo hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.\n\nConclusion:\n\nGH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.\n\nGrowth hormone treatment\npseudotumor cerebri syndrome\nidiopathic intracranial hypertension\npapilledema\nrisk factors\n==== Body\nWhat is already known on this topic?\n\nGrowth hormone (GH) replacement therapy is a risk factor for secondary pseudotumor cerebri. The incidence of this complication can vary depending on different GH indications.\n\nWhat this study adds?\n\nChildren with intracranial hypertension could be asymptomatic, so the diagnosis should be based on fundus examination and not on patient’s symptoms. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. A previous history of pseudotumor cerebri should be investigated.\n\nIntroduction\n\nPseudotumor cerebri syndrome (PTCS) is a condition defined by elevated intracranial pressure (ICP) in the absence of clinical, laboratory or radiologic evidence of infection, vascular abnormality, intracranial space-occupying lesion or hydrocephalus (1,2). It can be primary, or secondary if there are any identifiable risk factors. Primary PTCS most commonly occurs in obese adult women of childbearing age (12-32/100,000). However, it is a rare condition in childhood (0.5-0.9/100,000) with an identifiable risk factor in 53-77% of paediatric cases (3,4,5). Papilledema is a hallmark in PTCS, which is not a benign disorder; there is a risk of severe and permanent visual loss. Even patients with mild visual loss experience reduction in quality of life (6).\n\nGrowth hormone (GH) replacement therapy was first associated with PTCS by The Food and Drug Administration in 1993 (7). Since then, multiple publications have described this association. Reeves and Doyle (8) found that the prevalence in the GH treated population was approximately 100 times greater than in the general paediatric population. This complication usually occurs in the first weeks after initiating treatment (approximately 2-12 weeks) and the papilledema (optic disc swelling from raised ICP) resolves on stopping treatment (8,9).\n\nPseudopapilledema is an elevated optic disc with obscured margins that may occur in hyperopic eyes and in the presence of buried optic disc drusen, rather than from raised ICP. Optic disc drusen are acellular deposits located within the optic disc. Sometimes it can be very difficult to differentiate between pseudopapilledema and papilledema, requiring the opinion of a suitably experienced ophthalmologist and complementary tests (10).\n\nThe aim of this study was to investigate the incidence of PTCS in children treated with GH in a paediatric hospital and to identify risk factors for this complication. A secondary aim was to identify which children really need fundus examination during GH treatment in order to detect this complication.\n\nMethods\n\nA prospective pilot study was conducted in paediatric patients who started GH treatment from February 2013 to September 2017. Inclusion criteria were patients under 16 years of age prescribed GH by the Paediatric Endocrinology Department. Exclusion criteria were: absence of fundus examination prior to or at 3-4 months from starting treatment; severe optic disc atrophy where optic disc swelling would not develop; and cases where GH was prescribed by the Paediatric Nephrology Department. Predisposing pathology for intracranial hypertension was not considered an exclusion criterion, as fundus examinations were conducted before initiating treatment to rule out prior pathology of the optic nerve. The following variables were recorded: previous medical history; anthropometric data; and compliance with treatment.\n\nFundus was explored prior to and after 3-4 months of starting treatment or at any time when severe constant headache, vomiting or other presenting symptoms suggestive of intracranial hypertension arose. Prior fundus examination identified possible cases of pseudopapilledema and avoided possible confusion between this entity and newly developed papilledema in subsequent fundus follow-up examinations.\n\nFundus examination was carried out with indirect ophthalmoscopy and retinography was taken in cases of pseudopapilledema to facilitate follow up. In cases when papilledema was detected, GH was stopped and fundus examination was repeated four weeks later. If papilledema persisted, the patient was referred for neurological assessment, lumbar puncture and possible medical treatment with acetazolamide. Once papilledema resolved, if GH treatment was still considered necessary, treatment was re-initiated at a lower dose and progressively increased until the objective dose was achieved, with monthly ophthalmology visits until four months were completed at the target GH dose.\n\nCerebral magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis was performed in all patients with GH deficiency, prior to treatment. Initial GH doses were as indicated: 0.028-0.035 mg/kg/day for patients with GH deficiency and small for gestational age (SGA), 0.042 mg/kg/day for those with mutations in the SHOX gene and 1 mg/m2/day for patients with Prader-Willi syndrome (PWS).\n\nEthics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383). All subjects (or their parents or guardians) gave their written informed consent.\n\nStatistical Analysis\n\nIn this case series, simple descriptive statistics were sufficient to delineate our populations. Variables are expressed as number, mean and percent (%) or range, as appropriate.\n\nResults\n\nThere were 306 patients to whom GH was prescribed by the Paediatric Endocrinology Department between February 2013 and September 2017. Only 289 patients were enrolled in this study, 17 were excluded because of loss of ophthalmological follow up.\n\nThe mean age was nine years (range 1-16) and 53% of the patients were male. The patients were categorized according to their indication for GH treatment: 244 patients (84.4%) with GH deficiency; 36 patients (12.5%) with short stature associated with SGA; six patients (2%) with a mutation in the SHOX gene; and three (1%) with PWS. Patients diagnosed with chronic kidney disease were not included in the study as their indication for GH treatment and follow up was made by the Paediatric Nephrology Department.\n\nIn the first visit, prior to starting GH treatment, there were 546 eyes with normal optic discs, 16 eyes with pale optic discs, 11 eyes with pseudopapilledema, two eyes with optic disc and chorioretinal coloboma and one eye with dysplastic optic disc. Pale optic discs and optic disc and chorioretinal coloboma were secondary to the patient background pathology, suprasellar cerebral tumours and CHARGE anomaly respectively. In the follow up visit, five patients had optic disc swelling, suggesting papilledema, despite there being no symptoms of intracranial hypertension. None of the patients who presented with headache, who were visited urgently, presented with papilledema on fundus examination.\n\nTable 1 outlines the characteristics of the five patients with papilledema. All these patients had GH deficiency: three had hypothalamic-pituitary axis abnormalities on brain MRI; two were congenital cases; and one was secondary to a suprasellar tumour. The patient with a suprasellar tumour had a ventriculoperitoneal shunt and was treated with external radiotherapy. The only patient with an isolated GH deficiency with normal MRI, had developed primary PTCS five years before and he was obese. The incidence of obesity in children without PTCS in our population is 10.3%.\n\nThe papilledema resolved on discontinuing GH treatment in four patients, whereas in the remaining patient, a lumbar puncture confirmed the diagnosis and was also therapeutic. The opening pressure was 25 cm H2O. The glucose was 61 mg/dL (38-82); protein 20 mg/dL (15-45) and there were neither leukocytes nor red blood cells present in the cerebrospinal fluid (CSF). Medical treatment was not required. In four cases GH treatment was reintroduced at a lower dose with progressive incremental doses, without the reappearance of papilledema.\n\nDiscussion\n\nGH treatment is a risk factor for developing secondary PTCS although the mechanism is little understood. Two hypotheses have been proposed. The first is that GH could have a physiological antidiuretic effect, causing retention of sodium and water and expansion in blood volume, and reducing CSF resorption by the arachnoid villi. The second hypothesis proposes that GH would cross the blood-brain barrier, resulting in raised cerebral levels of GH and its mediator, insulin-like growth factor 1, and finally increasing CSF production (11,12,13,14).\n\nGH was initially obtained from human pituitary gland, and was given at lower doses and frequency, and prescribed in fewer clinical situations. Since 1985, when recombinant human GH became commercially available, more patients were treated with larger doses and more often. Since then, indications for GH treatment have increased, as well as the potential adverse effects (15).\n\nIn our study, there were five patients with papilledema (1.7%), a higher incidence compared with the expected incidence in the general paediatric population (8,9,11,13). All of them had GH deficiency. Other indications for GH treatment did not appear to cause papilledema in this series, although these results may be biased due the small populations with these other indications.\n\nAs all the patients with papilledema were found to have GH deficiency, we analysed this group, classifying patients into three subgroups (Table 2):\n\n1. Isolated GH deficiency (no other associated hormone deficiencies) with normal hypothalamic-pituitary axis anatomy on MRI.\n\n2. Isolated GH deficiency or associated with other hormone deficiencies with altered hypothalamic-pituitary axis anatomy on MRI and/or past history of cerebral radiotherapy.\n\n3. GH deficiency in patients with genetic or chromosomal diseases.\n\nWhen considering patients who presented with papilledema, three completed criteria for subgroup 2, presenting with hypothalamic-pituitary axis abnormalities and external radiotherapy treatment in one case for a suprasellar tumour. These three patients in subgroup 2 had an intracranial hypertension, but not technically a PTCS, because the brain MRI was not normal. One other patient was classified as subgroup 3 for a non-specific genetic disease. Only one patient presented with an isolated GH deficiency with normal cerebral MRI, however this patient had had primary PTCS five years earlier. The patient with a suprasellar tumour also had a ventriculoperitoneal shunt, suggesting that the presence of a shunt is not protective against a rise in ICP induced by GH therapy.\n\nFor each GH indication, the incidence of this adverse effect can vary. Reeves and Doyle (8), reported higher incidences in patients with renal failure and Turner syndrome. Souza and Collet-Solberg (11), also detected a higher incidence in patients with chronic kidney disease. Darendeliler et al (16) proposed that patients with Turner syndrome, organic GH deficiency, PWS and chronic renal insufficiency might be more prone to develop papilledema when receiving GH. In our study, patients with renal disease were excluded, as the GH was not prescribed by the Paediatric Endocrinology Department. However, we have conducted a retrospective study of these patients with renal disease on GH treatment during the same time period and have also detected a higher incidence of papilledema, as described in the literature.\n\nThe association between the dose of GH and the risk of PTCS is not clearly established. Malozowski et al (15) reported that higher doses and increased frequency of administration since the introduction of recombinant human GH in 1985 may be contributing to the development of PTCS in some patients. However, Reeves and Doyle found no relationship between the GH dose and PTCS development (8). One of our patients received GH at the usual dose without complications, later on it was withdrawn due to lack of therapeutic effect. Interestingly, papilledema appeared three months after restarting GH at a higher dose. Patients with PWS and mutations in the SHOX gene, who received higher doses of GH did not present with papilledema, although these subgroups were small in this study. Even though there is no evidence that the GH dose is directly related with this complication, we recommend starting at lower dose and increasing it progressively, in order to minimize this complication.\n\nPatients with a previous history of PTCS may experience recurrence at rates reported to vary between 6-22% (4,17,18,19). There is usually a triggering factor, such as weight gain or the introduction of known medications associated with secondary PTCS (20). In our series, the only patient with a previous history of PTCS, presented with papilledema. This patient was obese, which could have been a further risk factor for primary PTCS recurrence, however his weight had remained stable prior to starting GH treatment, at one month and at two months of treatment, when papilledema was diagnosed. For this reason, we believe it is important to identify patients initiating GH therapy with a previous history of PTCS because of the risk of recurrence. Also, consideration should be taken for starting treatment at a lower dose with progressive increases, accompanied by with careful follow-up including fundus examination during the first months of treatment.\n\nHeadache is a common symptom in the general paediatric population, and is also relatively frequent in patients on GH therapy, being the third most prevalent side effect described in KIGS (Pfizer International Growth study database) (16). On the other hand, headache is the main manifestation of intracranial hypertension at any age. However, in the paediatric population, headache is less common and 33% of children with PTCS may be totally asymptomatic (21,22), and diagnosis is only made on the observation of papilledema on fundus examination. It is important to highlight that papilledema is a cause of visual morbidity, including irreversible vision loss, independent of the patient symptoms. In our series, all patients with papilledema were asymptomatic, whereas no patients examined urgently for headache presented with papilledema.\n\nStopping GH is usually enough to treat this complication. Once papilledema has resolved GH can be reintroduced at a lower dose and progressively increased until the required dose is achieved to prevent recurrence and optimum growth. In the four patients where GH was reintroduced there were no recurrences of papilledema.\n\nStudy Limitations\n\nThe strengths of our study are the prospective design and the number of patients included in it. As children may be asymptomatic, prospective studies are the only way to establish the real incidence of this complication. The main limitation of our study is that patients with kidney diseases were not included and this group of patients has been reported to be at greatest risk of this complication in a different series.\n\nConclusion\n\nIn this study, we have shown that GH therapy is a risk factor for intracranial hypertension and the at-risk group were patients with GH deficiency and hypothalamic-pituitary axis abnormalities on MRI or genetic or chromosomal diseases. Patients may be totally asymptomatic, so fundus examination should be systematically implemented in this at-risk group, irrespective of the presence or absence of symptoms.\n\nWe thank Dr. Susana Noval for her valuable contribution in the analysis and interpretation of data and Dr. Silvia Muñoz for critical review of the manuscript.\n\nTable 1 Characteristics of patients treated with growth hormone who developed papilledema\n\nTable 2 Distribution of patients with growth hormone deficiency according to our classification in subgroups\n\nEthics\n\nEthics Committee Approval: Ethics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383, date: 17.05.2019).\n\nInformed Consent: All subjects (or their parents or guardians) gave their written informed consent.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Concept/Design: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Data Collection or Processing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Analysis or Interpretation: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Literature Search: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Writing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n==== Refs\nReferences\n\n1 Friedman DI Liu GT Digre KB Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children Neurology 2013 81 1159 1165 23966248\n2 Rangwala LM Liu GT Pediatric Idiopathic Intracranial Hypertension Surv Ophthalmol 2007 52 597 617 18029269\n3 Matthews YY Dean F Lim MJ Mclachlan K Rigby AS Solanki GA White CP Whitehouse WP Kennedy CR Pseudotumor cerebri syndrome in childhood: incidence, clinical profile and risk factors in a national prospective population-based cohort study Arch Dis Child 2017 102 715 721 28356250\n4 Ko MW Liu GT Pediatric idiopathic intracranial hypertension (Pseudotumor cerebri) Horm Res Paediatr 2010 74 381 389 20962512\n5 Scott IU Siatkowski RM Eneyni M Brodsky MC Lam BL Idiopathic intracranial hypertension in children and adolescents Am J Ophthalmol 1997 124 253 255 9262557\n6 Digre KB Bruce BB McDermott MP Galetta KM Balcer LJ Wall M; NORDIC Idiopathic Intracranial Hypertension Study Group Quality of life in idiopathic intracranial hypertension at diagnosis: IIH treatment trial results Neurology 2015 84 2449 2456 25995055\n7 Malozowski S Tanner A Wysowski D Fleming GA Growth hormone, insulin-like growth factor I, and benign intracranial hypertension N Engl J Med 1993 329 665 666 8341354\n8 Reeves GD Doyle DA Growth hormone treatment and pseudotumor cerebri: coincidence or close relationship? J Pediatr Endocrinol Metab 2002 15(Suppl 2) 723 730 12092686\n9 Rogers AH Rogers GL Bremer DL McGregor ML Pseudotumor cerebri in children receiving recombinant human growth hormone Ophthalmology 1999 106 1186 1189 10366091\n10 Mollan SP Markey KA Benzimra JD Jacks A Matthews TD Burdon MA Sinclair AJ A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension Pract Neurol 2014 14 380 390 24809339\n11 Souza FM Collet-Solberg PF Adverse effects of growth hormone replacement therapy in children Arq Bras Endocrinol Metab 2011 55 559 565\n12 Johansson JO Larson G Andersson M Elmgren A Hynsjö L Lindahl A Lundberg PA Isaksson OG Lindstedt S Bengtsson BA Treatment of growth hormone-deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters Neuroendocrinology 1995 61 57 66 7537355\n13 Darendeliler F Safety of Growth Hormone Treatment J Clin Res Pediatr Endocrinol 2009 1(Suppl 1) 36 43\n14 Saenger P Metabolic consequences of growth hormone treatment in paediatric practice Horm Res 2000 53(Suppl 19) 60 69 10895045\n15 Malozowski S Tanner LA Wysowski DK Fleming GA Stadel BV Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone J Pediatr 1995 126 996 999 7776116\n16 Darendeliler F Karagiannis G Wilton P Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database Horm Res 2007 68(Suppl 5) 41 47 18174706\n17 Soiberman U Stolovitch C Balcer LJ Regenbogen M Constantini S Kesler A Idiopathic intracranial hypertension in children Visual outcome and risk of recurrence Childs Nerv Syst 2011 27 1913 1918 21538129\n18 Tibussek D Schneider DT Vandemeulebroecke N Turowski B Messing- Juenger M Willems PH Mayatepek E Distelmaier F Clinical spectrum of the pseudotumor cerebri complex in children Childs Nerv Syst 2010 26 313 321 19902218\n19 Aylward SC Way AL Pediatric Intracranial hypertension: a current review Curr Pain Headache Rep 2018 22 14 29441432\n20 Ko MW Chang SC Ridha MA Ney JJ Ali TF Friedman DI Mejico LJ Volpe NJ Galetta SL Balcer LJ Liu GT Weight gain and recurrence in idiopathic intracrnial hypertension: a case-control study Neurology 2011 76 1564 1567 21536635\n21 Bassan H Berkner L Stolovitch C Kesler A Asymptomatic idiopathic intracranial hypertension in children Acta Neurol Scand 2008 118 251 255 18341683\n22 Aylward SC Reem RE Pediatric Intracranial Hypertension Pediatr Rev 2018 39 121 129\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": null, "issue": "13(2)", "journal": "Journal of clinical research in pediatric endocrinology", "keywords": "idiopathic intracranial hypertension; 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GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423694, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9245320", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE RE INTRODUCED WITH LOWER DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "4", "patientonsetage": "14", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "71", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CAMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423707, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9245323", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REINTRODUCED AT A LOW DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".32", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "3", "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "11", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CAMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423396, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9244268", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".21", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "3", "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423769, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9245321", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REINTRODUCED AT A LOW DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".23", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "3", "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "11", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CAMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423725, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "OBJECTIVE\nTo explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH).\n\n\nMETHODS\nClinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed.\n\n\nRESULTS\nThe child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans-retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died.\n\n\nCONCLUSIONS\nThe latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia.", "affiliations": "Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.;Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.;Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.;Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.", "authors": "Su\|Yan\|Y\|;Zhou\|Xuan\|X\|;Zhang\|Li\|L\|;Zhang\|Rui\|R\|", "chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin; D005047:Etoposide; D003630:Daunorubicin", "country": "China", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0578-1310", "issue": "51(12)", "journal": "Zhonghua er ke za zhi = Chinese journal of pediatrics", "keywords": null, "medline_ta": "Zhonghua Er Ke Za Zhi", "mesh_terms": "D000208:Acute Disease; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D003630:Daunorubicin; D020031:Epstein-Barr Virus Infections; D005047:Etoposide; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D016609:Neoplasms, Second Primary; D018570:Risk Assessment; D016896:Treatment Outcome; D014212:Tretinoin", "nlm_unique_id": "0417427", "other_id": null, "pages": "938-42", "pmc": null, "pmid": "24495767", "pubdate": "2013-12", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "Report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature.", "title_normalized": "report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature" }	[ { "companynumb": "CN-WATSON-2014-21043", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074968", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HISTIOCYTOSIS HAEMATOPHAGIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "074968", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute promyelocytic leukaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SU Y, ZHOU X, ZHANG L, ZHANG R. [REPORT OF A CASE WITH SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA AFTER THERAPY FOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND REVIEW OF LITERATURE]. ZHONGHUA ER KE ZA ZHI. 2013;51(12):938-42. CHINESE", "literaturereference_normalized": "report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140930", "receivedate": "20140930", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10484859, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "CN-CORDEN PHARMA LATINA S.P.A.-CN-2016COR000220", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CUMULATIVE DOSE = 3520 MG/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "HISTIOCYTOSIS HAEMATOPHAGIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute promyelocytic leukaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SU Y, ZHOU X, ZHANG L, ZHANG R. REPORT OF A CASE WITH SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA AFTER THERAPY FOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND REVIEW OF LITERATURE. ZHONGHUA ER KE ZA ZHI. 2013;51 (12):938-942", "literaturereference_normalized": "report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20160928", "receivedate": "20160928", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12789239, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "BACKGROUND\nThe compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient.\n\n\nMETHODS\nA 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance.\n\n\nCONCLUSIONS\nIt is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.", "affiliations": "Diakonissenkrankenhaus und Paulinenhilfe gGmbH, Diakonie-Klinikum Stuttgart, Rosenbergstraße 38, 70176, Stuttgart, Germany.;Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.;Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.;Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany. [email protected].", "authors": "Jung\|Susanne\|S\|;Michel\|Manuela\|M\|;Stamminger\|Thomas\|T\|;Michel\|Detlef\|D\|http://orcid.org/0000-0003-2188-1815", "chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C109367:UL54 protein, Human herpesvirus 5; C090238:UL56 protein, cytomegalovirus; D014764:Viral Proteins; D015678:Viral Structural Proteins; C000588473:letermovir; D004259:DNA-Directed DNA Polymerase; D000077562:Valganciclovir", "country": "England", "delete": false, "doi": "10.1186/s12879-019-4016-1", "fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 401610.1186/s12879-019-4016-1Case ReportFast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient Jung Susanne [email protected] 1Michel Manuela [email protected] 2Stamminger Thomas [email protected] 2http://orcid.org/0000-0003-2188-1815Michel Detlef 0049 (0) 731 500 [email protected] 21 0000 0004 0560 4858grid.477279.8Diakonissenkrankenhaus und Paulinenhilfe gGmbH, Diakonie-Klinikum Stuttgart, Rosenbergstraße 38, 70176 Stuttgart, Germany 2 grid.410712.1Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany 8 5 2019 8 5 2019 2019 19 3888 8 2018 24 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient.\n\nCase presentation\nA 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance.\n\nConclusion\nIt is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.\n\nKeywords\nAntiviral resistanceCytomegalovirusLetermovirGenotypingAllogenic hematopoietic-cell transplantationAcute myeloid leukemiaissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCytomegalovirus (CMV) is still one of the reasons for causing severe complications after allogeneic hematopoietic-cell transplantation [1, 2]. Ganciclovir (GCV) and valganciclovir (valGCV) are routinely used for treating CMV infection in solid-organ transplantation. However, after hematopoietic-cell transplantation, GCV and valGCV are avoided due to the possibility of myelosuppression [3–5]. All traditional anti-CMV agents like GCV, foscarnet, and cidofovir target the viral DNA polymerase [6]. In contrast, the compound letermovir (LMV) inhibits CMV replication by binding to components of the viral terminase complex and therefore offers a different mode of action [7–9]. In a recently published phase III study, CMV-seropositive transplant recipients received LMV at either a dose of 240 mg per day for patients taking cyclosporine A or 480 mg per day for patients without cyclosporine co-medication (https://www.accessdata.fda.gov/drugsatfda_docs/labe/2017/209939orig1s000,209940orig1s000lbl.pdf) [10]. The lack of cross-resistance with other anti-CMV compounds, the absence of myelosuppression as well as the positive results from the phase III study led to the recent approval of letermovir for the prophylaxis of CMV infection in CMV-seropositive adult hematopoietic-cell transplant recipients.\n\nGenotypic resistance testing was performed directly from patient specimens. Therefore, fragments of 2100 bp of the open reading frame (ORF) UL56 and 800 bp of the ORF UL89 were amplified by polymerase chain reaction followed by Sanger sequencing. The sequencing analyses of UL56 and UL89 allow detection of all known mutations conferring LMV resistance. Genotyping of the viral polymerase UL54 and the UL97 kinase were performed as previously described [11].\n\nCase presentation\nThe 44-year-old male acute myeloid leukemia (AML) patient received an unmanipulated graft from an unrelated donor (CMV D−/R+) after conditioning with the FLAMSA protocol. The patient received acyclovir (ACV, 400 mg twice per day) continuously, except between days + 43 to + 70 and day + 110 to + 145 (summarized in Fig. 1). For maintenance of immunosuppression, the patient received cyclosporine A per os (measured blood concentrations 180–220 μg/L), mycophenolate (360 mg twice daily), and prednisolone.Fig. 1 Time course of antiviral treatments and events. The CMV DNA loads (detection limit of 50 international units per ml (IU/ml)) were determined on serum samples. CMV DNA loads below the lower limit of quantization (125 IU/ml) are not to scale. The durations and the daily dosages of anti-CMV treatments with valganciclovir (450 mg or 900 mg twice a day) and letermovir are shown as black and grey boxes, respectively. Acyclovir (400 mg twice a day) was administered, when valGCV was paused. First detection of mutation C325Y (cytosine at amino acid 325 to tyrosine) in the specimens is depicted by a black star. The retrospective analysis revealed that the mutation was already present in earlier specimens shown by white stars. CsA, cyclosporine A; LMV, letermovir; valGCV, valganciclovir. ACV, acyclovir\n\n\n\nIt was planned to start LMV prophylaxis directly after the transplantation. However, due to a delay in delivery, administration of LMV could only be initiated at day + 34, under the assumption that CMV viral load was still below detection limit (50 IU/ml in serum). The compound was given at 240 mg once per day per os, along with cyclosporine. In retrospect, it turned out that the virus DNA load at the last check on day + 28 was 190 IU/ml in serum. Over the next 8 days, increasing CMV loads were measured up to 39.600 IU/ml. Therefore, letermovir treatment was discontinued and the patient was switched to valganciclovir (valGCV, 900 mg twice per day) at day + 42. Treatment was maintained for 4 weeks until CMV DNA was negative. At this time, the patient suffered from an intestinal graft-versus-host disease (GvHD) and a mucositis. Therefore, prednisolone was administered at day + 46 for 7 days with 10 mg and then was reduced to 1 mg until discontinuation at day + 82.\n\nAs neutropenia occurred during valGCV therapy, stimulation with G-CSF was necessary. After discontinuation of valGCV, neutropenia was resolved and LMV secondary prophylaxis was started at day + 70 with 240 mg once per day. At this time point CMV DNA was not detectable. At day + 80, mycophenolate was discontinued. For 4 weeks, CMV DNA remained undetectable or at the limit of quantitation of 125 IU/ml. At day + 97, tapering of cyclosporine A was initiated. However, several days later, the patient failed to maintain virologic suppression. CMV viral loads rapidly increased to 236.400 IU/ml in serum samples, between days + 104 and + 110. In order to avoid neutropenia, valGCV treatment with a reduced dosage of 450 mg twice per day was initiated at day + 110. Concomitantly, LMV dosage was increased to 480 mg per day. During the next 4 weeks, CMV viral loads decreased to 1.200 IU/ml. ValGCV treatment, which meanwhile necessitated daily stimulation with G-CSF, was discontinued.\n\nHowever, CMV DNA levels increased up to 33.000 IU/ml during the following 2 weeks. Therefore, genotyping of the CMV terminase UL56 as well as the other relevant genes (UL97 kinase, viral polymerase UL54, and UL89) was initiated. Thereby, a mutation corresponding to amino acid 325 (C325Y, cytosine at amino acid 325 to tyrosine) of UL56 was detected (see Fig. 1). This mutation is associated with a high resistance to LMV in vitro [12]. Therefore, LMV was discontinued at day + 167.\n\nNo further mutation was detected. Retrospective analysis revealed that the UL56 mutation C325Y was already present at day + 117, within 6 weeks after the start of the second letermovir administration. Unfortunately, no other patient specimens were available in order to further elucidate the time point of emergence of the mutation.\n\nSince then CMV DNA loads remained at a low level of 1300 to 2500 IU/ml. Due to the lack of clinical symptoms and increasing CD4 T-cells since day + 145, no further anti-CMV therapy was carried out.\n\nUntil today, the patient is clinically stable and participates in a professional reintegration.\n\nDiscussion and conclusions\nRecent clinical studies indicated that letermovir might be an important addition to the current strategies for prevention of active CMV infection and disease after allogeneic hematopoietic-cell transplantation and it may be useful for salvage therapies in solid organ recipients [13, 14]. However, since the approval of the compound at the end of 2017, several patients have been reported who developed genotypically confirmed resistance to LMV while on therapy [15–18]. Thereby, LMV resistance emerged both in solid organ transplant and in hematopoietic stem cell transplant recipients. In nearly all cases which have been reported, LMV was used for salvage treatment, with considerable viral loads and for longer exposure times. In one case a breakthrough of CMV disease in a HSCT recipient occurred after more than 4 months of letermovir prophylaxis [18]. Contrary to the later, in the present case, we observed a rapid breakthrough of a resistant CMV upon secondary prophylaxis with LMV. Our patient has been re-challenged with the compound after a first short time exposure of 8 days. Thus, the question arose whether the selection of LMV-resistant viruses has already occurred during the first period of administration, because at that time virus loads were very high. On the other hand, re-administration of the drug resulted in successful suppression of virus replication for at least 30 days. Then, however, the resistant CMV subpopulation apparently prevailed. Unfortunately, due to the lack of appropriate patient specimens the question concerning the exact time point of emergence of LMV resistance cannot be answered unequivocally. Additional studies are needed to decide whether the re-exposure to letermovir during repeated periods of CMV reactivation poses a particular risk for the development of antiviral drug resistance.\n\nAnother question is, whether the dosage of LMV was too low for virus suppression at the time when cyclosporine was tapered. In a phase II prophylaxis trial, a single case of breakthrough CMV viremia on LMV prophylactic treatment had been published. Thereby, the UL56 mutation V236 M emerged on a daily dose of 60 mg suggesting that low-dose prophylaxis may confer letermovir resistance [19]. However, although cyclosporin is known to alter LMV pharmacokinetics, a dosage of 240 mg letermovir even in the absence of CsA has been reported to be sufficient for complete suppression of viremia [19, 20].\n\nWe cannot exclude that individual reasons in this specific patient (e.g. compliance issues, nausea or atypical metabolism) led to low drug levels since no pharmacokinetic monitoring of LMV is available. Nonetheless, it is presently unclear whether higher doses of the drug would be more effective or safe during prolonged use since a recent study reported two patients who developed genotypically confirmed resistance to LMV while on therapy with 720 mg and 960 mg daily, respectively [16].\n\nIn vitro studies with serial viral passage in the presence of the compound have been associated with relatively rapid selection of several different UL56 mutations, particularly within codons 25 and 231 to 369 [21, 22]. Thereby, the different mutations led to diverse levels of resistance, ranging from a 5-fold increase in EC50 for V231L to > 5000-fold for C325Y [21, 22]. Remarkably, in all reports published after the approval of letermovir, the amino acid 325 in UL56 was exclusively affected [15–18]. In our case the mutation is also located at this codon. This suggests that amino acid 325 of UL56 may represent a hot spot for the occurrence of resistance upon clinical treatment. The presently available data suggest the necessity for fast genotyping for early detection of relevant mutations before treatment failure is evident.\n\nAccording to the currently available data, letermovir should, if possible, only be used within the scope of the approval. Administration in patients at high risk with active CMV infections and considerable virus loads requires caution and close clinical and virological monitoring concerning the emergence of drug-resistant virus variants. Furthermore, LMV administration at high virus loads combined with (short time) drug exposures may foster the rapid selection of resistant CMV variants.\n\nAbbreviations\nallo-HCTHematopoietic-cell transplantation\n\nAMLAcute myeloid leukemia\n\nCMVHuman cytomegalovirus\n\nLMVLetermovir\n\nPCRPolymerase chain reaction\n\nUL54Unique long open reading frame 54\n\nUL56Unique long open reading frame 56\n\nUL89Unique long open reading frame 89\n\nUL97Unique long open reading frame 97\n\nAcknowledgements\nThe consent of the patient for publication of this case is highly appreciated. DM thanks Dr. Peter Lischka and the reviewers for their constructive comments.\n\nFunding\nThe authors have received no funding for the preparation of this manuscript. The authors declare that they have no conflicts of interests. The information has not been presented on any meeting.\n\nAvailability of data and materials\nThe datasets used and/or analyzed for the case study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll authors read and approved the final manuscript. SJ and DM have been involved in acquisition and interpretation of data. SJ has been involved in patient clinical care and reviewing medical records. MM and DM carried out the CMV genotyping and contributed to analysis. TS and DM drafted the manuscript. TS reviewed and revised this paper, and gave final approval to submit for publication.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nD.M. was consultant for virological diagnosis for AiCuris GmbHCo.KG. The authors have received no funding for the preparation of this manuscript. The authors declare that they have no conflicts of interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Teira P Battiwalla M Ramanathan M Barrett AJ Ahn KW Chen M Green JS Saad A Antin JH Savani BN Lazarus HM Seftel M Saber W Marks D Aljurf M Norkin M Wingard JR Lindemans CA Boeckh M Riches ML Auletta JJ Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis Blood 2016 127 2427 2438 10.1182/blood-2015-11-679639 26884374 \n2. Ljungman P Hakki M Boeckh M Cytomegalovirus in hematopoietic stem cell transplant recipients Hematol Oncol Clin North Am 2011 25 151 169 10.1016/j.hoc.2010.11.011 21236396 \n3. 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Chou S Approach to drug-resistant cytomegalovirus in transplant recipients Curr Opin Infect Dis 2015 28 293 299 10.1097/QCO.0000000000000170 26098499\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2334", "issue": "19(1)", "journal": "BMC infectious diseases", "keywords": "Acute myeloid leukemia; Allogenic hematopoietic-cell transplantation; Antiviral resistance; Cytomegalovirus; Genotyping; Letermovir", "medline_ta": "BMC Infect Dis", "mesh_terms": "D000085:Acetates; D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004259:DNA-Directed DNA Polymerase; D024882:Drug Resistance, Viral; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009154:Mutation; D011799:Quinazolines; D055502:Secondary Prevention; D000077562:Valganciclovir; D019562:Viral Load; D014764:Viral Proteins; D015678:Viral Structural Proteins", "nlm_unique_id": "100968551", "other_id": null, "pages": "388", "pmc": null, "pmid": 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "360", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1800 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MEASURED BLOOD CONCENTRATIONS 180-220 MICROGRAM/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pathogen resistance", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JUNG S, MICHEL M, STAMMINGER T, MICHEL D. FAST BREAKTHROUGH OF RESISTANT CYTOMEGALOVIRUS DURING SECONDARY LETERMOVIR PROPHYLAXIS IN A HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENT. BMC-INFECT-DIS 2019?19:388.", "literaturereference_normalized": "fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190613", "receivedate": "20190613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16425459, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-ROCHE-2329759", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021304", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PER OS (MEASURED BLOOD CONCENTRATIONS 180-220 PG/L)", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "021304", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR 7 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG TWICE PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR [ACICLOVIR]" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021304", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT DAY + 110", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "360 MG TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "720", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JUNG S, MICHEL M, STAMMINGER T, MICHEL D. FAST BREAKTHROUGH OF RESISTANT CYTOMEGALOVIRUS DURING SECONDARY LETERMOVIR PROPHYLAXIS IN A HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENT.. BMC INFECT DIS. DOI: 10.1186/S12879-019-4016-1. 2019 MAY 08?19 (1):388:-.", "literaturereference_normalized": "fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190909", "receivedate": "20190531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16376545, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "Persistence of various symptoms in patients who have recovered from coronavirus disease 2019 (COVID-19) was recently defined as 'long COVID' or 'post-COVID syndrome' (PCS). This article reports a case of a 58-year-old woman who, although recovering from COVID-19, had novel and persistent symptoms including neurological complications that could not be explained by any cause other than PCS. In addition to a low inflammatory response, persistence of immunoglobulin G anticardiolipin autoantibody positivity and eosinopenia were found 1 year after acute COVID-19 infection, both of which have been defined previously as independent factors associated with the severity of COVID-19. The pathophysiological mechanism of PCS is unknown, but the possibility of persistence of the virus, especially in the nervous system, could be suggested with a post-infectious inflammatory or autoimmune reaction.", "affiliations": "Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France. Electronic address: [email protected].;Service de Neurologie, Pôle de Neurosciences Cliniques, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service de Médecine Interne et d'Immunologie Clinique, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix Marseille Université, C2VN, INSERM UMR_S 1263, Marseille, France.;Service de Médecine Interne, Aix-Marseille Université, AP-HM, Hôpital La Timone, Marseille, France.;Institut Hospitalo-Universitaire Méditerranée Infection, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Aix Marseille Université, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille Université, IRD, MEPHI, Institut Hospitalo-Universitaire Méditerranée Infection, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix Marseille Université, C2VN, INSERM UMR_S 1263, Marseille, France.", "authors": "Bertin\|Daniel\|D\|;Kaphan\|Elsa\|E\|;Weber\|Samuel\|S\|;Babacci\|Benjamin\|B\|;Arcani\|Robin\|R\|;Faucher\|Benoit\|B\|;Ménard\|Amélie\|A\|;Brodovitch\|Alexandre\|A\|;Mege\|Jean Louis\|JL\|;Bardin\|Nathalie\|N\|", "chemical_list": null, "country": "Canada", "delete": false, "doi": "10.1016/j.ijid.2021.09.079", "fulltext": null, "fulltext_license": null, "issn_linking": "1201-9712", "issue": "113()", "journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases", "keywords": "COVID-19; anticardiolipin antibodies; antiphospholipid antibodies; long COVID syndrome; post-COVID syndrome", "medline_ta": "Int J Infect Dis", "mesh_terms": null, "nlm_unique_id": "9610933", "other_id": null, "pages": "23-25", "pmc": null, "pmid": "34614444", "pubdate": "2021-12", "publication_types": "D002363:Case Reports", "references": null, "title": "Persistent IgG anticardiolipin autoantibodies are associated with post-COVID syndrome.", "title_normalized": "persistent igg anticardiolipin autoantibodies are associated with post covid syndrome" }	[ { "companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2022-01449", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "065398", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "1", "drugtreatmentdurationunit": "803", "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "065125", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "1", "drugtreatmentdurationunit": "803", "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "210543", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "1", "drugtreatmentdurationunit": "803", "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200101" } }, "primarysource": { "literaturereference": "Bertin D, Kaphan E, Weber S, Babacci B, Arcani R, Faucher B, et al. Persistent IgG anticardiolipin autoantibodies are associated with post-COVID syndrome. International Journal of Infectious Diseases. 2021;113:23-25", "literaturereference_normalized": "persistent igg anticardiolipin autoantibodies are associated with post covid syndrome", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220207", "receivedate": "20220207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20435568, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220424" } ]
{ "abstract": "Metamizole was the second most common drug prescribed in Germany in 2018 despite the known risk of agranulocytosis and the strict indication. According to Stammschulte et al. up to 25 % of all prescriptions are off-label use. Although mandatory according to the prescribing information of metamizole, regular blood cell counts are not performed in up to 50 % of the patients with long-term use of this drug.\n\n\n\nRetrospective analysis of eight cases metamizole-induced agranulocytosis over a period of five years (2016-2020) in the university ENT department in Erlangen. Five patients were men and three women. Mean age of diagnosis was 52,4 years (± 25,6).\n\n\n\nAgranulocytosis after use of metamizole is a serious adverse drug reaction that may affect patients of all ages. Frequently, only distinct clinical symptoms such as temperature of unknown origin, dysphagia and tonsillitis in combination with abscesses in the head and neck area result in the detection of a metamizole-induced agranulocytosis. An agranulocytosis provokes partially radical surgery and/ or intensive-care measures and could lead to sepsis with organ failure or even to death.\n\n\n\nThese patient cases show that agranulocytosis is a dangerous or even deadly adverse drug reaction after use of metamizole. Although the risk of agranulocytosis appears to increase with duration of use, we would recommend patient education as well as documentation of even a single administration of metamizole. This may facilitate early diagnosis of metamizole-induced agranulocytosis and thus prevent the onset of severe complications with possible lethal outcome.", "affiliations": "Hals-Nasen-Ohren-Klinik, Kopf- und Halschirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.;Hals-Nasen-Ohren-Klinik, Kopf- und Halschirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.;Radiologisches Institut, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.;Hals-Nasen-Ohren-Klinik, Kopf- und Halschirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.", "authors": "Schinz\|Katharina\|K\|;Waldfahrer\|Frank\|F\|;Wüst\|Wolfgang\|W\|;Iro\|Heinrich\|H\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004177:Dipyrone", "country": "Germany", "delete": false, "doi": "10.1055/a-1190-4445", "fulltext": null, "fulltext_license": null, "issn_linking": "0935-8943", "issue": "99(10)", "journal": "Laryngo- rhino- otologie", "keywords": null, "medline_ta": "Laryngorhinootologie", "mesh_terms": "D000380:Agranulocytosis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002675:Child, Preschool; D004177:Dipyrone; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D012189:Retrospective Studies", "nlm_unique_id": "8912371", "other_id": null, "pages": "707-712", "pmc": null, "pmid": "32588405", "pubdate": "2020-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Agranulocytosis after use of metamizole - an underestimated risk?", "title_normalized": "agranulocytosis after use of metamizole an underestimated risk" }	[ { "companynumb": "DE-TEVA-2020-DE-1861122", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXEPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "071239", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXEPIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075347", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DIPYRONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPYRONE" } ], "patientagegroup": "5", "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess neck", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agranulocytosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCHINZ K, WALDFAHRER F, WUST W, IRO H. AGRANULOCYTOSIS AFTER USE OF METAMIZOLE - AN UNDERESTIMATED RISK?. [GERMAN]. LARYNGORHINOOTOLOGIE 2020?99(10):707-712.", "literaturereference_normalized": "agranulocytosis after use of metamizole an underestimated risk", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201223", "receivedate": "20201223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18653488, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271954", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METAMIZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METAMIZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXEPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXEPIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Agranulocytosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCHINZ K, WALDFAHRER F, WUST W, IRO H. AGRANULOCYTOSIS AFTER USE OF METAMIZOLE - AN UNDERESTIMATED RISK?. LARYNGORHINOOTOLOGIE. 2020?99(10):707-712", "literaturereference_normalized": "agranulocytosis after use of metamizole an underestimated risk", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201222", "receivedate": "20201222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18645813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]
{ "abstract": "Backgroung: This study investigated the efficacy and safety of TNF antagonists in sarcoid uveitis in unselected cases. Design: This is a multicentre study on patients with sarcoidosis who received TNF antagonists in pneumology and internal medicine departments in France. We present here the subgroup of patients with biopsy-proven sarcoid uveitis included in the nationwide registry STAT (Sarcoidosis treated with TNF AnTagonists). Results: Among the 132 patients included in this multicenter study, 18 patients with refractory uveitis were treated as a first-line TNF antagonist with infliximab (n=14), adalimumab (n=3) and certolizumab (n=1). Before anti-TNF initiation, the median duration of sarcoidosis was 42 months and 83% of the patients have been treated with at least one immunosuppressive drug. Six patients switched for a second-line TNF antagonist. After a mean time under treatment of 29 months, the treatment resulted in a significant decrease of the ophthalmic extrapulmonary Physician Organ Severity Tool (ePOST) (mean score: 4.2 vs. 2.6) scores and a steroid sparing effect (29.4±20.7 vs. 6.2±5.2 mg/d). Overall, the ophthalmic response, either complete or partial, was 67%. Nine patients (50%) presented adverse events, including severe infectious complications in 5 patients, which required anti-TNF treatment interruption in 6 cases (33%). Among the 7 responder patients who discontinued anti-TNF therapy, 71% relapsed. Finally, 12 patients (67%) could continue TNF antagonist treatment. Conclusions: TNF antagonists were efficient in 67% of biopsy-proven refractory sarcoid uveitis. Severe adverse events, mainly infectious complications, were frequent. The high frequency of relapses after anti-TNF-α discontinuation requires a close patient follow-up thereafter. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 74-80).", "affiliations": "Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.;Département de Médecine Interne et d'Immunologie Clinique II, Assistance Publique-Hôpitaux de Paris (AP-HP), CHU Pitié Salpêtrière, Université Pierre et Marie Curie (UPMC), F-75006, Paris, France.;Service de Biostatistique, Hospices Civils de Lyon, F-69003, Lyon, France.;Département de Médecine Interne et d'Immunologie Clinique, AP-HP, CHU Pitié Salpêtrière, Institut E3M, Université Pierre et Marie Curie, F-75006, Paris, France.;Université Claude Bernard, Lyon 1, F-69100, Villeurbanne, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-38700, Grenoble, France.;Département de Médecine Interne, Hôpital Avicenne, Université Paris 13, F-93000, Bobigny, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-21000, Dijon, France.;Département de Pneumologie, Hôpital Avicenne, AP-HP, Université Paris 13, F-93000, Bobigny, France.;Département de Médecine Interne, CHU Gabriel Montpied, F-63000, Clermont-Ferrand, France.;Département de Médecine Interne et d'Immunologie Clinique, AP-HP, CHU Bicêtre, Université Paris Sud, UMR 1184, F-94270, Le Kremlin Bicêtre, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-14033, Caen, France.;Département de Médecine Interne de Gériatrie Thérapeutique, Hôpital Saint-Julien, CHU de Rouen, F-76031 Rouen Cedex, France.;Université Claude Bernard, Lyon 1, F-69100, Villeurbanne, France.;Département d'Ophtalmologie, AP-HP, CHU Pitié Salpêtrière, F-75013, Paris, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-38700, Grenoble, France.;Service de Biostatistique, Hospices Civils de Lyon, F-69003, Lyon, France.;Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.;Département de Médecine Interne et d'Immunologie Clinique II, Assistance Publique-Hôpitaux de Paris (AP-HP), CHU Pitié Salpêtrière, Université Pierre et Marie Curie (UPMC), F-75006, Paris, France.;Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.;Département de Pneumologie, Hôpital Avicenne, AP-HP, Université Paris 13, F-93000, Bobigny, France.;Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.", "authors": "Marquet\|Alicia\|A\|;Chapelon-Abric\|Catherine\|C\|;Maucort-Boulch\|Delphine\|D\|;Cohen-Aubart\|Fleur\|F\|;Pérard\|Laurent\|L\|;Bouillet\|Laurence\|L\|;Abad\|Sébastien\|S\|;Bielefeld\|Philip\|P\|;Bouvry\|Diane\|D\|;André\|Marc\|M\|;Noël\|Nicolas\|N\|;Bienvenu\|Boris\|B\|;Proux\|Alice\|A\|;Vukusic\|Sandra\|S\|;Bodaghi\|Bahram\|B\|;Sarrot-Reynaud\|Françoise\|F\|;Iwaz\|Jean\|J\|;Broussolle\|Christiane\|C\|;Saadoun\|David\|D\|;Jamilloux\|Yvan\|Y\|;Valeyre\|Dominique\|D\|;Sève\|Pascal\|P\|;\|\|\|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.36141/svdld.v34i1.5368", "fulltext": null, "fulltext_license": null, "issn_linking": "1124-0490", "issue": "34(1)", "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "keywords": "TNF antagonists; efficacy; safety; sarcoidosis; uveitis", "medline_ta": "Sarcoidosis Vasc Diffuse Lung Dis", "mesh_terms": null, "nlm_unique_id": "9610928", "other_id": null, "pages": "74-80", "pmc": null, "pmid": "32476825", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "26092330;19585358;23276549;24090799;23988768;22885144;16840744;10209662;22119879;23470459;25325834;23311120;24401994;10430755;27015607;21191712;19386069;23392263;23983404;18256069;24704868;22387045;26120779;19382527", "title": "Efficacy and safety of TNF antagonists in ocular sarcoidosis: data from the French registry STAT.", "title_normalized": "efficacy and safety of tnf antagonists in ocular sarcoidosis data from the french registry stat" }	[ { "companynumb": "FR-JNJFOC-20170931387", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OCULAR SARCOIDOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bacterial sepsis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes virus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prostatitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARQUET A, CHAPELON-ABRIC C, MAUCORT-BOULCH D, COHEN-AUBART F, PERARD L, BOUILLET L, ET AL. EFFICACY AND SAFETY OF TNF ANTAGONISTS IN OCULAR SARCOIDOSIS: DATA FROM THE FRENCH REGISTRY STAT. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2017;34 (1):74-80.", "literaturereference_normalized": "efficacy and safety of tnf antagonists in ocular sarcoidosis data from the french registry stat", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171005", "receivedate": "20171005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14047712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]
{ "abstract": "Traction alopecia (TA) is a form of hair loss caused by continuous and prolonged tension to the hair, most commonly seen in Black/African American women and children who wear hairstyles that pull excessively at the frontotemporal hairline. Dermatologists have recommended the use of intralesional triamcinolone acetonide injections (ILK) to decrease the inflammatory process, however, evidence-based proof is lacking in the literature. In this case series, we evaluate the effectiveness and safety of ILK in the TA management of 6 African American women. A retrospective chart review was done of patients with a diagnosis of TA, who were treated with ILK at an academic dermatology clinic, yielding 6 patients. Management of TA was assessed by comparing the photographs for changes in hair density along the frontotemporal hairline. ILK with a concentration of 5 mg/mL, was administered in areas of low hair density along the frontotemporal hairline at 6 to 8-week intervals, for 3 successive visits. All subjects demonstrated visible increase in hair density along the frontotemporal hairline following their first or second treatment, and no severe adverse effects were observed or reported. The use of ILK is currently an effective and safe method of treating TA, particularly in the early to mid-stages. Common adverse effects are pain, and subsequent transient atrophy at the injection site. The transient atrophy is not an indication to stop treatment. Avoidance of treating dented areas is sufficient to allow it to revert. Patient education is pivotal in the prevention and management of TA. It is imperative that dermatologists caution against grooming practices that exert tension on the hairline.\n\nJ Drugs Dermatol. 2020;19(2)128-130. doi:10.36849/JDD.2020.4635", "affiliations": null, "authors": "Uwakwe\|Laura N.\|LN\|;De Souza\|Brianna\|B\|;Tovar-Garza\|Andrea\|A\|;McMichael\|Amy J.\|AJ\|", "chemical_list": "D014222:Triamcinolone Acetonide", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1545-9616", "issue": "19(2)", "journal": "Journal of drugs in dermatology : JDD", "keywords": null, "medline_ta": "J Drugs Dermatol", "mesh_terms": "D000328:Adult; D000505:Alopecia; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D008875:Middle Aged; D012189:Retrospective Studies; D014222:Triamcinolone Acetonide", "nlm_unique_id": "101160020", "other_id": null, "pages": "128-130", "pmc": null, "pmid": "32129955", "pubdate": "2020-02-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Intralesional Triamcinolone Acetonide in the Treatment of Traction Alopecia", "title_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia" }	[ { "companynumb": "US-JNJFOC-20201144066", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1 INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "021812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." } ], "patientagegroup": "5", "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapeutic response unexpected", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Application site pruritus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MCMICHAEL A, DE SOUZA B, TOVAR-GARZA A, UWAKWE L. INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. JOURNAL OF DRUGS IN DERMATOLOGY. 2020?19(2):128-130.", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201210", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573414, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-JNJFOC-20201144022", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5MG/ML, 3 INJECTION 6-8 WEEK INTERVAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "021812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response unexpected", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UWAKWE L, DE SOUZA B, TOVAR-GARZA A, MCMICHAEL A. INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. JOURNAL OF DRUGS IN DERMATOLOGY. 2020 FEB?19(2):128-130.", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201203", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573658, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-JNJFOC-20201144143", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "021812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "3 INJECTIONS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": "5", "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response unexpected", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UWAKWE L, DE SOUZA B, TOVAR-GARZA A, MCMICHAEL A. INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. JOURNAL OF DRUGS IN DERMATOLOGY. 2020?19 (2):128-130.", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201203", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573426, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-APOTEX-2020AP022466", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209243", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "026", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TOPICAL SOLUTION", "drugdosagetext": "5 PERCENT, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "UWAKWE LN, DE SOUZA B, TOVAR-GARZA A, MCMICHAEL AJ. INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. J-DRUGS-DERMATOL. 2020?19(2):128-130", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201216", "receivedate": "20201216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18623292, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]
{ "abstract": "Epidural steroid injections are widely used for the treatment of lumbago and sciatica although their efficacy has not yet been demonstrated in a convincing way. Moreover, systemic complications, although rare, have been documented. The present case report illustrates that even a single low-dose epidural injection may induce Cushing's syndrome and even steroid myopathy.", "affiliations": "Department of Internal Medicine, University Hospital, Katholieke Universiteit Leuven, Belgium.", "authors": "Boonen\|S\|S\|;Van Distel\|G\|G\|;Westhovens\|R\|R\|;Dequeker\|J\|J\|", "chemical_list": "D014221:Triamcinolone", "country": "England", "delete": false, "doi": "10.1093/rheumatology/34.4.385", "fulltext": null, "fulltext_license": null, "issn_linking": "0263-7103", "issue": "34(4)", "journal": "British journal of rheumatology", "keywords": null, "medline_ta": "Br J Rheumatol", "mesh_terms": "D000368:Aged; D001416:Back Pain; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D007268:Injections, Epidural; D009135:Muscular Diseases; D014221:Triamcinolone", "nlm_unique_id": "8302415", "other_id": null, "pages": "385-6", "pmc": null, "pmid": "7788158", "pubdate": "1995-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Steroid myopathy induced by epidural triamcinolone injection.", "title_normalized": "steroid myopathy induced by epidural triamcinolone injection" }	[ { "companynumb": "BE-MACLEODS PHARMACEUTICALS US LTD-MAC2022036258", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "209535", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MILLIGRAM, SINGLE, LOW-DOSE INJECTION", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sciatica", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cushing^s syndrome", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Boonen S, Distel VG, Westhovers R, Dequeker J.. Steroid myopathy induced by epidural triamcinolone injection. British Journal of Rheumatology. 1995;34(4):385-386", "literaturereference_normalized": "steroid myopathy induced by epidural triamcinolone injection", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20220630", "receivedate": "20220630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 21028261, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]
{ "abstract": "To investigate the histopathological findings in ketamine-associated uropathy (KU) and their clinical association.\n\n\n\nThirty-eight KU patients had received history investigation and video urodynamic study. Twelve of them were clinically mild KU who were admitted for cystoscopic hydrodistention. The other 26 patients were severe KU who were admitted for enterocystoplasty with or without ureter reimplantation. Bladder and ureter specimens were harvested during operation, and a single pathologist reviewed all specimens under hematoxylin and eosin stain. The severity of histopathological findings was graded with a 4-point scale (0: none, 1: mild, 2: moderate, and 3: severe) RESULTS: Inflammatory cells infiltrations and nerve hyperplasia were found in the mucosa, muscle, and subserosal layers of KU bladders and ureter. In the mild KU bladder mucosa, the predominant component of the infiltrating inflammatory cells was lymphocytes. In contrast, neutrophils, eosinophils, lymphocytes, and plasma cells infiltration were noted in the mucosa of almost all severe KU bladders. Clinical severe KU was significantly correlated with severe to moderate lymphocytes, plasma cells, neutrophils, eosinophils infiltration, and nerve hyperplasia in bladder mucosa. KU patients with moderate or severe neutrophils or lymphocytes infiltration in bladder mucosa had significantly more severe bladder pain and smaller bladder capacity.\n\n\n\nThe histological findings of KU showed whole-layer inflammation and nerve hyperplasia in bladder mucosa. The severity of inflammatory cell infiltration in the bladder mucosa is associated with clinical symptoms. A histopathological examination might be a useful tool to discriminate the KU severity in patients.", "affiliations": "Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.", "authors": "Jhang\|Jia-Fong\|JF\|;Hsu\|Yung-Hsiang\|YH\|;Jiang\|Yuan-Hong\|YH\|;Lee\|Cheng-Ling\|CL\|;Kuo\|Hann-Chorng\|HC\|0000-0001-7165-4771", "chemical_list": "D007649:Ketamine", "country": "United States", "delete": false, "doi": "10.1002/nau.23514", "fulltext": null, "fulltext_license": null, "issn_linking": "0733-2467", "issue": "37(5)", "journal": "Neurourology and urodynamics", "keywords": "fibrosis; histology; pathogenesis; surgery; upper tract", "medline_ta": "Neurourol Urodyn", "mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D017699:Pelvic Pain; D014513:Ureter; D014563:Urodynamics; D014570:Urologic Diseases; D013520:Urologic Surgical Procedures; D055815:Young Adult", "nlm_unique_id": "8303326", "other_id": null, "pages": "1764-1772", "pmc": null, "pmid": "29441609", "pubdate": "2018-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Histopathological characteristics of ketamine-associated uropathy and their clinical association.", "title_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association" }	[ { "companynumb": "TW-MYLANLABS-2018M1063121", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321864, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063085", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321884, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063060", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321877, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063109", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321868, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063023", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15312418, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063037", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316198, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063072", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321886, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063024", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15315686, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063091", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321866, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063048", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321876, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063029", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316199, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063082", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321889, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063080", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321869, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063049", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063042", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316192, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063125", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321872, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063071", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321870, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063047", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316195, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063069", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321881, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063106", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321871, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063031", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063032", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316211, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063027", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316193, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063095", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15312413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]
{ "abstract": "Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study.", "affiliations": "Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, 89-1, Enya, Izumo-City 693-8501, Japan.;Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1, Asahi, Takamatsu-City 760-8557, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Dentistry and Dental Surgery, Tsuyama Chuo Hospital, 1756, Kawasaki, Tsuyama-City 708-0841, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.", "authors": "Obata\|Kyoichi\|K\|0000-0002-6569-7406;Okui\|Tatsuo\|T\|0000-0002-7640-3274;Ono\|Sawako\|S\|;Umemori\|Koki\|K\|;Ryumon\|Shoji\|S\|;Ono\|Kisho\|K\|;Yao\|Mayumi\|M\|;Yoshioka\|Norie\|N\|;Ibaragi\|Soichiro\|S\|;Sasaki\|Akira\|A\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/diagnostics11081375", "fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11081375\ndiagnostics-11-01375\nCase Report\nComparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review\nhttps://orcid.org/0000-0002-6569-7406\nObata Kyoichi 1\nhttps://orcid.org/0000-0002-7640-3274\nOkui Tatsuo 2\nOno Sawako 3\nUmemori Koki 1\nRyumon Shoji 1\nOno Kisho 1\nYao Mayumi 4\nYoshioka Norie 1\nIbaragi Soichiro 1\nSasaki Akira 1\nGenina Elina A. Academic Editor\n1 Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan; [email protected] (K.U.); [email protected] (S.R.); [email protected] (K.O.); [email protected] (N.Y.); [email protected] (S.I.); [email protected] (A.S.)\n2 Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, 89-1, Enya, Izumo-City 693-8501, Japan\n3 Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1, Asahi, Takamatsu-City 760-8557, Japan; [email protected]\n4 Department of Dentistry and Dental Surgery, Tsuyama Chuo Hospital, 1756, Kawasaki, Tsuyama-City 708-0841, Japan; [email protected]\n* Correspondence: [email protected] (K.O.); [email protected] (T.O.); Tel.: +81-86-235-6702 (K.O.); +81-853-20-2301 (T.O.)\n30 7 2021\n8 2021\n11 8 137512 7 2021\n28 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study.\n\nmethotrexate\nlymphoproliferative disorders\nEpstein-Barr virus\nmucocutaneous ulcer\nrheumatoid arthritis\n==== Body\n1. Introduction\n\nMethotrexate (MTX) is an immunosuppressive antifolate that was approved as a therapeutic agent for rheumatoid arthritis (RA) by the FDA in 1988. MTX is the anchor drug in RA treatment because of its high efficacy rate, continuation rate, and inhibitory effect on bone destruction and improvement of quality of life [1,2]. However, MTX also has various side effects, such as bone marrow suppression, increased risk of interstitial pneumonia, and gastrointestinal tract disorders [1,3,4,5]. In 1991, Ellman et al. reported MTX-associated lymphoproliferative disorder (MTX-LPD) as a lymphoma that occurred in RA patients using MTX, with more than 100 cases reported at that time [6]. In 2008, MTX-LPD was classified as one of the “other iatrogenic immunodeficiency-associated lymphoproliferative disorders” in the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue [7]. The progression of RA is considered to be a risk factor for the onset of MTX-LPD, however, the pathogenesis of MTX-LPD remains poorly understood [8].\n\nEpstein-Barr virus (EBV) was detected in approximately half of MTX-LPD cases by blood exam, immunohistochemistry, and in situ hybridization. Latently EBV-infected B-cells, which are normally suppressed, are thought to be reactivated by the immunosuppressive action of MTX, allowing MTX-LPD to develop in EBV-infected patients [9]. EBV-infected MTX-LPD patients usually have a good prognosis upon withdrawal of MTX. Dojcinov et al. reported EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease that can be histopathologically diagnosed as a lymphoma with ulcers localized to the skin and mucosa [10]. In 2017, EBV-MCU was newly added to the WHO Classification [11]. The use of immunosuppressive drugs is a major risk factor for the development of EBV-MCU and MTX is the most frequently reported causal agent [12]. Immunosenescence due to ageing and primary immunodeficiency are also known risk factors of EBV-MCU. Currently, reports of EBV-MCU and MTX-LPD with lesions in the oral mucosa are increasing. However, there are few studies that have aggregated and compared MTX-LPD and EBV-MCU in the oral mucosa. In addition, it is not clear how the pathogenesis and pathophysiology of MTX-LPD and EBV-MCU differ in the oral mucosa. Also, MTX-LPD and EBV-MCU does not occur in all patients with risk factors and it is reasonable to assume that there are some additional risk factors that have yet to be discovered.\n\nHere, we report our experience with the treatment of EBV-MCU and MTX-LPD in the oral mucosa and provide a comprehensive review of the clinical features.\n\n2. Materials and Methods\n\nThis case series was composed of 10 patients with MTX-LPD or EBV-MCU occurring in the oral mucosa who visited the Department of Oral and Maxillofacial Surgery, Okayama University Hospital (Okayama, Japan) and the Department of Dentistry and Oral Surgery, Tsuyama Chuo Hospital (Okayama, Japan) during the nine year period from 2012 to 2021. The patients were identified retrospectively and evaluated for age, sex, autoimmune disease and immunosuppressive therapy details, site of onset, EBV infection, histological findings, treatment, and prognosis.\n\n3. Results\n\nTable 1 summarizes the detailed characteristics of 10 patients with MTX-LPD and EBV-MCU in our department and at Tsuyama Chuo Hospital. The average age of patients was 75.1 ± 8.05 years (range 58–87 years) and the male-to-female ratio was 1:4, revealing a predominance of females. Eight patients were referred from general dentists (Case No. 1–6, 9, 10), one was referred from the general hospital dentist (Case No. 8), and one was referred from other departments in our hospital (Case No. 7). All patients were receiving immunosuppressive therapy with MTX for RA; one had an additional autoimmune disease of interstitial pneumonia (Case No. 6). The average period since the diagnosis of RA was 20.0 years (range 5–40 years), and the duration of MTX treatment was 12.7 years (range 5–30 years). Immunosuppressive agents used other than MTX were as follows: prednisolone (PSL) in five patients (Case No. 1, 3, 4, 8, 9), tacrolimus (TAC) in two patients (Case No. 5, 6), and bucillamine in one patient (Case No. 7). The primary site was the gingiva in all cases and the maxillary to mandibular ratio was 1:1 (maxillary: Case No. 2–5, 9; mandibular: Case No. 1, 6–8, 10). One patient had a lesion on the lung as well as the oral mucosa (Case No. 3). All patients were confirmed to be infected with EBV by blood test and histopathological examination. In all cases, partial biopsy under local anesthesia was performed to suspect malignancy. Immunohistochemistry staining showed CD20-positive atypical large lymphocytes in all cases; CD3, CD5, and CD10-positive lymphocytes were not detected in many cases. EBV-encoded small RNA in situ hybridization (EBER-ISH) showed positivity in all cases. Therefore, the histopathological diagnosis was diffuse large B-cell lymphoma with EBV infection in all cases. All patients achieved complete clinical remission with discontinued MTX, without chemotherapy or radiotherapy. Tacrolimus was initiated in two patients after withdrawal of MTX to prevent reactivation of RA (Case No. 1, 4). Below, we present two cases as typical examples.\n\n3.1. Case 1\n\nThe patient was a 75-year-old Japanese man who visited our department complaining of a painful right mandibular gingiva after first molar extraction. He had had RA for 40 years and had been treated with several immunosuppressive drugs, including MTX (8 mg/week for 20 years), PSL (5 mg/day for 10 years), and golimumab (50 mg/month for 3 years). The intraoral examination showed redness and ulceration of the right mandibular gingiva. There was exposure of necrotic bone in the extraction wound (Figure 1A). Head and neck computed tomography (CT) showed bone destruction from perilesional alveolar bone to the mandibular canal (Figure 1B), but no lymph node abnormality was detected. A blood examination revealed EBV infection [EBV viral capsid antigen (EBV-VCA) IgG = 320, IgM < 10, IgA < 10, EBV nuclear antigen (EBNA) = 20] and a high level of soluble interleukin-2 receptor (sIL-2R = 1224). Fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) indicated the presence of increased uptake in the right mandibular (maximum standardized uptake value: SUVmax = 11.9; Figure 1C) and the right superior internal jugular nodes (SUVmax = 3.78). The biopsy material showed diffuse proliferation of atypical lymphocytes in the subepithelium (Figure 1E). Immunohistochemistry staining showed that the atypical large-sized lymphocytes were positive for CD20 (Figure 1F) and negative for CD3, CD5, and CD10; the Ki-67 labeling index was high (Figure 1G). The result of EBER-ISH was positive (Figure 1H) and the histopathological diagnosis was EBV-MCU (Figure 1E–H).\n\nThe patient’s primary physician changed MTX to TAC. The lesion decreased and symptoms disappeared within two weeks. FDG-PET/CT at one year since the withdrawal of MTX showed no increased uptake anywhere. At 20 months after the withdrawal of MTX, the patient was in good condition without recurrence (Figure 1D).\n\n3.2. Case 5\n\nThe patient was a 73-year-old Japanese woman who visited our department desiring an examination for bone exposure of the left maxillary gingiva. She had RA for 11 years and had been treated with immunosuppressive drugs, including MTX (14 mg/week for 6 years) and TAC (1.5 mg/day for 1 year). The intraoral examination showed painless ulceration of the gingiva on the palatal side of the first molar with bone exposure (Figure 2A). CT showed cortical bone destruction around the lesion and exposure of the first molar palatal root (Figure 2B). Blood examination for sIL-2R and EBV infection were not performed. FDG-PET/CT indicated only the presence of increased uptake around the lesion (SUVmax = 11.9; Figure 2C). The biopsy material showed diffuse proliferation of lymphocytes with a background of inflammatory cell infiltration (Figure 2E); the lymphocytes were large and atypical (Figure 2F). Immunohistochemistry staining showed that the atypical large-sized lymphocytes were positive for CD20 (Figure 2G), 30, and negative for CD3. EBER-ISH was positive (Figure 2H). The histopathological diagnosis was MTX-LPD (in the current definition, EBV-MCU).\n\nThe patient’s primary physician discontinued MTX and the lesion gradually became epithelialized. FDG-PET/CT at seven months after the withdrawal of MTX showed no increased uptake anywhere. At six years after the withdrawal of MTX, the patient was in good condition (Figure 2D).\n\n4. Discussion\n\nAlthough EBV-MCU was newly registered as a subtype of mature B-cell neoplasm in the 2017 WHO classification, it was treated as MTX-LPD until then [7,11]. Lymphoproliferative is a descriptive term that sets this disease group apart from physiological lymphadenopathy and lymphocytosis. The WHO classifies lymphoproliferative disorders (LPD) according to etiology, i.e., LPD associated with primary immune disorders, lymphomas associated with HIV infection, post-transplant LP disorders, and other iatrogenic immunodeficiency-associated LP disorders, including MTX-LPD [7]. Previously, the last of the four classes was identified solely with MTX-LPD because MTX was thought to be the only causative drug for this disease. However, the category has been revised to a broader concept because it was found that immunosuppressive drugs other than MTX can also cause LPD [11,13].\n\nA previous study found that 40–50% of MTX-LPDs develop in extranodal sites, with lesion sites throughout the body, such as the gastrointestinal tract, skin, lung, and head and neck region, including the gingiva, tongue, and mouth floor [7]. EBV infection has been detected in about half of MTX-LPDs and many EBV-positive MTX-LPD cases have shown resolution or reduction of lesions with MTX withdrawal. The prognosis of the latter type of case is relatively good, while cases without response to drug withdrawal require chemotherapy and have poor outcomes [7,11,14].\n\nEBV is a virus belonging to the family of Herpesviridae. More than 90% of infections occur via saliva or sexual secretion in adulthood. Initial infection often occurs in infancy, however, these infections usually only cause mild symptoms, if any. In the case of initial infection after adolescence, infectious mononucleosis with fever, pharyngitis, and generalized lymphadenopathy develops. After initial infection, EBV continues to infect B-cells or epithelial cells of the nasopharynx, although the immune mechanism induces a latent infection state in which virus is not produced. However, in an immunosuppressive state caused by an autoimmune disease or the use of an immunosuppressive drug, reactivation of latent EBV-infected B-cells and subsequent proliferation of viral particles induces various diseases. Diseases caused by reactivation of EBV-infected B-cells include chronic active EBV infection and EBV-positive diffuse large B-cell lymphoma; EBV-MCU is also one of these pathological conditions [15,16].\n\nIn terms of research on EBV-MCU, Sinit reported that the most common risk factor for developing EBV-MCU was the use of immunosuppressive drugs, with MTX being the most commonly associated drug (46%), followed by azathioprine, mycophenolate, prednisone, rituximab, and cyclosporine A. The most common reason for immunosuppressive drug use was autoimmune disease (64%), followed by organ or stem-cell transplantation and hematologic malignancies. The most common scenario was an RA patient being treated with MTX (20% of cases). The sites of onset were the oral and oropharyngeal mucosa, gastrointestinal tract, and skin [12]. The high frequency of onset in the oral mucosa was attributed to the mode of EBV infection (lytic vs. latent infection) and the chronic irritation associated with colonization by anaerobic bacteria. During lytic infection, EBV easily colonizes oral mucosa. In this infection mode, the infected B-cells sequestered in the lymphoid tissues of Waldeyer’s ring, etc., are activated due to immunosuppression. After cell death, the lysed B-cells release infectious viral particles, and the mucosal epithelial cells of the oral cavity and ductal epithelial cells of the salivary gland become infected. In addition, the oral mucosa is often chronically irritated by dental caries, periodontal disease, inadequate crown-bridge restorations, dentures, occlusion, etc., leading to the occurrence of cell-level microtrauma. Due to these factors, EBV-MCU is thought to occur frequently in the oral mucosa [12,17,18]. We conjectured that EBV-MCU may be triggered by immunosuppression caused by MTX and that oral peculiarities may be strongly involved in the development of the disease. A disease with a similar pathogenic mechanism is Merkel cell carcinoma. Merkel cell carcinoma has been demonstrated to be triggered by iatrogenic immunosuppression due to the biologics employed in autoimmune diseases therapy, and Merkel cell polyomavirus is reactivated when certain conditions are combined [19]. Therefore, EBV-MCU does not occur in all patients using MTX. We suspect that risk factors such as the degree of infection of the mucosal epithelial cells of the oral cavity and ductal epithelial cells of the salivary gland, and the presence of chronic irritation of the oral mucosa, are strongly involved in the development of EBV-MCU.\n\nWhen MTX-LPD or EBV-MCU develop, treatment for autoimmune disease becomes difficult because immunosuppressive drugs need to be withdrawn or changed. In particular, after the withdrawal of MTX in RA patients, the majority of patients experience a reactivation of RA. The latest guidelines suggest the use of rituximab or tacrolimus for patients with RA reactivation [20]. Satou et al. reported that rituximab may be effective to prevent regrowth of EBV-MCU [21]. MTX was withdrawn in all 10 cases we experienced, and although RA worsened in some patients, it was controlled with rituximab or tacrolimus.\n\nThe 10 cases we experienced had the following characteristics. (1) All patients were being treated for RA with MTX. Immunosuppressive drugs used in combination with MTX included prednisolone. (2) EBV infection was positive in all cases by in situ hybridization and, in some cases, by blood test. (3) In all patients, withdrawal of immunosuppressive drugs without chemotherapy or surgery was selected. (4) Regarding prognosis, a complete or partial response was obtained in all cases without additional treatment. A total of three patients were diagnosed with MTX-LPD before the WHO approved the concept of EBV-MCU. However, we determined that all of the cases could be considered EBV-MCU. This is supported by the report of Yamakawa et al. that 42% of MTX-LPD patients and 13% of elderly LPD patients among all LPD patients are rediagnosed as having EBV-MCU [9]. We also previously reported that cases diagnosed as MTX-LPD in the oral mucosa were highly likely to be EBV-MCU because such cases had a higher rate of EBV infection, a lower rate of ectopic cases, and a better prognosis than MTX-LPD at other sites in the body [22]. Therefore, we considered that most of the LPDs with EBV infection that develop in the oral mucosa of patients using MTX are likely to be EBV-MCU. However, despite speculation that various factors are involved in the onset of LPD and that they interact in a complicated manner, few studies pursuing this possibility have been performed. It is a topic worthy of future research.\n\n5. Conclusions\n\nAll the patients we encountered were being treated for RA using MTX and were positive for EBV infection. In addition, all patients had a good prognosis with the withdrawal of immunosuppressive drugs. We consider that EBV-positive LPD in the oral mucosa of a patient using MTX is likely to be EBV-MCU.\n\nAuthor Contributions\n\nConceptualization, K.O. (Kyoichi Obata) and T.O.; data curation, K.O. (Kyoichi Obata), K.U., S.R., M.Y. and N.Y.; formal analysis, K.O. (Kyoichi Obata), S.O. and K.O. (Kisho Ono); funding acquisition, K.O. (Kyoichi Obata); supervision, T.O., S.I. and A.S.; writing-original draft, K.O. (Kyoichi Obata); writing-review and editing, K.O. (Kyoichi Obata), T.O. and S.I. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was partly supported by a Grant-in-Aid for Early-Career Scientists (JP20K18668 to Obata K.) from the Japan Society for the promotion of Sciences, Japan.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences (protocol No: 2108-002, 24 June 2021).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nAll supporting data are provided in the current manuscript.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAbbreviations\n\nCT\tcomputed tomography\t\nEBER-ISH\tEpstein-Barr virus-encoded small RNA in situ hybridization\t\nEBNA\tEpstein-Barr virus nuclear antigen\t\nEBV\tEpstein-Barr virus\t\nEBV-MCU\tEpstein-Barr virus-positive mucocutaneous ulcer\t\nEBV-VCA\tEpstein-Barr virus capsid antigen\t\nFDG-PET/CT\tfluorodeoxyglucose-positron emission tomography/computed tomography\t\nLPD\tlymphoproliferative disorders\t\nMTX\tmethotrexate\t\nMTX-LPD\tmethotrexate-associated lymphoproliferative disorders\t\nPSL\tprednisolone\t\nRA\trheumatoid arthritis\t\nsIL-2R\tsoluble interleukin-2 receptor\t\nSUVmax\tmaximum standardized uptake value\t\nTAC\ttacrolimus\t\n\nFigure 1 Case 1. (A) Pre-treatment intraoral photograph: necrotic bone was exposed in the right mandibular first molar extraction wound with redness and ulceration in the surrounding gingiva. (B) Coronal CT: bone destruction of the mandible. (C) Horizontal FDG-PET/CT: positive uptake around the lesion. (D) Post-treatment intraoral photograph: the wound where the necrotic bone was removed became epithelialized and the lesion completely disappeared. (E) Hematoxylin and eosin staining showing diffuse proliferation of atypical lymphocytes in the subepithelium. (F–H) Immunochemistry staining showing positivity for CD20 (F), a high Ki-67 labeling index (G), and positivity for EBER-ISH (H).\n\nFigure 2 Case 5. (A) Pre-treatment intraoral photograph (mirror image): a painless ulceration with bone exposure on the palatal side of the maxillary left first molar. (B) Coronal CT: cortical bone destruction on the palatal side. (C) Horizontal FDG-PET/CT: positive uptake around the lesion. (D) Post-treatment intraoral photograph (mirror image): The ulceration has disappeared and become epithelization. (E–H) Histopathological findings: Hematoxylin and eosin staining showed diffuse proliferation of atypical lymphocytes with a background of inflammatory cell infiltration (E); the lymphocytes were large with prominent nucleoli (F). These cells were positive for CD20 (G) and EBER-ISH (H).\n\ndiagnostics-11-01375-t001_Table 1 Table 1 Characteristics of patients and course with MTX-LPD or EBV-MCU occurring in the oral mucosa.\n\nNo\tAge\tSex\tAutoimmune Disease\tImmunosuppressive Therapy\t\nRA\tOther\tDuration\n(Year)\tMTX\tDose\n(mg/week)\tDuration\n(Year)\tOther\t\n1\t75\tM\t+\t-\t40\t+\t8\t>20\tPSL\t\n2\t80\tM\t+\t-\tN/A\t+\t6–8\t6\t-\t\n3\t58\tF\t+\t-\t10\t+\t2–4\t10\tPSL\t\n4\t67\tF\t+\t-\t28\t+\tN/A\t25\tPSL\t\n5\t73\tF\t+\t-\t11\t+\t14\t6\tTAC\t\n6\t74\tF\t+\tIP\t12\t+\t10\t11\tTAC\t\n7\t77\tF\t+\t-\t24\t+\t10\t11\tBUC\t\n8\t79\tF\t+\t-\t40\t+\t2.5\t30\tPSL\t\n9\t81\tF\t+\t-\t5\t+\t8\t5\tPSL\t\n10\t87\tF\t+\t-\t10\t+\t6\t10\t-\t\nPrimary\nSite\tMultiple\nSite\tEBV\nInfection\tImmunophenotype\tHistology\tTherapy\nand\nResponse\tFollow Up\nPeriod\n(Month)\t\nPositive\tNegative\t\nMandibular\ngingiva\t-\t+\tCD20\tCD3, 5\tDLBCL\tWM\n-> CR\t24\t\nMaxillary\ngingiva\t-\t+\tCD20\tN/A\tDLBCL\tWM\n-> CR\t92\t\nMaxillary\ngingiva\t+ (lung)\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t36\t\nMaxillary\ngingiva\t-\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t30\t\nMaxillary\ngingiva\t-\t+\tCD20, 30\tCD3\tDLBCL\tWM\n-> CR\t27\t\nMandibular\ngingiva\t-\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t20\t\nMandibular\ngingiva\t-\t+\tCD20, 79a\tCD3, 5\tDLBCL\tWM\n-> CR\t13\t\nMandibular\ngingiva\t-\t+\tCD20, 79a\tCD3, 5\tDLBCL\tWM\n-> CR\t7\t\nMaxillary\ngingiva\t-\t+\tCD20, 79a\tCD3, 5\tDLBCL\tWM\n-> CR\t31\t\nMandibular\ngingiva\t-\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t12\t\nBUC = bucillamine, CR = complete remission, DLBCL = diffuse large B-cell lymphoma, EBV = Epstein-Barr virus, IP = interstitial pneumonia, MTX = methotrexate, PSL = prednisolone, RA = rheumatoid arthritis, TAC = tacrolimus, WM = withdrawal of MTX.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Pittaluga S. Jaffe E.S. EBV Positive Mucocutaneous Ulcer—A study of 26 cases associated with various sources of immunosuppression Am. J. Surg. Pathol. 2010 34 405 417 10.1097/PAS.0b013e3181cf8622 20154586\n11. Gaulard P. Swerdlow S.H. Harris N.L. Sundstrom C. Jaffe E. EBV-positive mucocutaneous ulcer World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Harald S. Jurgen T. IARC Publications Lyon, France 2017 307 308\n12. Sinit R.B. Horan K.L. Dorer R.K. Aboulafia D.M. Epstein-Barr Virus–Positive Mucocutaneous Ulcer: Case Report and Review of the First 100 Published Cases Clin. Lymphoma Myeloma Leuk. 2019 19 e81 e92 10.1016/j.clml.2018.10.003 30442566\n13. Hasserjian R.P. Chen S. Perkins S.L. de Leval L. Kinney M.C. Barry T.S. Said J. Lim M.S. Finn W.G. Medeiros L.J. Immunomodulator agent-related lymphoproliferative disorders Mod. Pathol. 2009 22 1532 1540 10.1038/modpathol.2009.131 19767727\n14. Ichikawa A. Arakawa F. Kiyasu J. Sato K. Miyoshi H. Niino D. Kimura Y. Takeuchi M. Yoshida M. Ishibashi Y. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: Histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression Eur. J. Haematol. 2013 91 20 28 10.1111/ejh.12116 23560463\n15. Kataoka Y. Matsue T. Katagiri H. Hashiba T. Hanzawa M. Tsunoda R. A case of Epstein-Barr virus-positive mucocutaneous ulcer arising in the lower gingiva Jpn. J. Oral Maxillofac. Surg. 2020 66 157 161 10.5794/jjoms.66.157\n16. Kim H.-J. Ko Y.H. Kim J.E. Lee S.-S. Lee H. Park G. Paik J.H. Cha H.J. Choi Y.-D. Han J.H. Epstein-barr virus-associated lymphoproliferative disorders: Review and update on 2016 WHO classification J. Pathol. Transl. Med. 2017 51 352 358 10.4132/jptm.2017.03.15 28592786\n17. Dugan J.P. Coleman C.B. Haverkos B. Opportunities to target the life cycle of Epstein-Barr Virus (EBV) in EBV-associated lymphoproliferative disorders Front. Oncol. 2019 9 127 10.3389/fonc.2019.00127 30931253\n18. McGinness J.L. Spicknall K.E. Mutasim D.F. Azathioprine-induced EBV-positive mucocutaneous ulcer J. Cutan. Pathol. 2012 39 377 381 10.1111/j.1600-0560.2011.01829.x 22236092\n19. Rotondo J.C. Bononi I. Puozzo A. Govoni M. Foschi V. Lanza G. Gafà R. Gaboriaud P. Touzé F.A. Selvatici R. Merkel cell carcinomas arising in autoimmune disease affected patients treated with biologic drugs including anti-TNF Clin. Cancer Res. 2017 23 3929 3934 10.1158/1078-0432.CCR-16-2899 28174236\n20. Fraenkel L. Bathon J.M. England B.R. Clair E.W.S. Arayssi T. Carandang K. Deane K.D. Genovese M. Huston K.K. Kerr G. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Arthritis Rheumatol. 2021 73 1108 1123 10.1002/art.41752 34101376\n21. Satou A. Banno S. Hanamura I. Takahashi E. Takahara T. Nobata H. Katsuno T. Takami A. Ito Y. Ueda R. EBV-positive mucocutaneous ulcer arising in rheumatoid arthritis patients treated with methotrexate: Single center series of nine cases Pathol. Int. 2019 69 21 28 10.1111/pin.12745 30615240\n22. Obata K. Okui T. Kishimoto K. Ibaragi S. Sasaki A. Methotrexate-Associated Lymphoproliferative Disorder Developed Ectopically in the Maxillary Gingiva and Bilateral Lungs Case Rep. Med. 2020 2020 5 9 10.1155/2020/4814519 32411253\n\n", "fulltext_license": "CC BY", "issn_linking": "2075-4418", "issue": "11(8)", "journal": "Diagnostics (Basel, Switzerland)", "keywords": "Epstein-Barr virus; lymphoproliferative disorders; methotrexate; mucocutaneous ulcer; rheumatoid arthritis", "medline_ta": "Diagnostics (Basel)", "mesh_terms": null, "nlm_unique_id": "101658402", "other_id": null, "pages": null, "pmc": null, "pmid": "34441310", "pubdate": "2021-07-30", "publication_types": "D002363:Case Reports", "references": "20154586;30442566;24334644;19767727;30615240;34101376;30931253;22313647;15901903;24246254;1787499;21044440;28174236;23560463;32411253;22236092;30243154;28592786", "title": "Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review.", "title_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review" }	[ { "companynumb": "JP-ACCORD-238049", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. 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Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics-(Basel) 2021;11(8):1-10.. 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220218", "receivedate": "20220218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20489087, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001457", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, ONCE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "20", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "801", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GOLIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, ONCE A MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "801", "medicinalproduct": "GOLIMUMAB" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484227, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001456", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 TO 8 MG PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "6", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel).. 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220221", "receivedate": "20220221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20494698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326913", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": "30", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001453", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, ONCE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "11", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484226, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326907", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "6", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K et al. Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review. Diagnostics. 2021;11(8):1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220324", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20509326, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326915", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "14 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "14", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucocutaneous ulceration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;Jul 30; 11(8):1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505009, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238052", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUCILLAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUCILLAMINE" } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811629, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-ACCORD-238053", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326906", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505012, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326919", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20504682, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238046", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CHANGED MTX TO TAC", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GOLIMUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GOLIMUMAB" } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N,IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19810572, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001455", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (FOR 25 YEARS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326912", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "25", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K et al. Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review. Diagnostics. 2021;11:1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505010, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-MYLANLABS-2022M1012454", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics-(Basel) 2021;11(8):1-10.. 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220218", "receivedate": "20220218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20489085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238050", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "14", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19810575, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001449", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM PER WEEK (FOR 10 YEARS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484225, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-ACCORD-238051", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001450", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326910", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-4 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucocutaneous ulceration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20509323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-ACCORD-238048", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6?8 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "6", "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19810573, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326914", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucocutaneous ulceration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20504683, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001452", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, ONCE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "11", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUCILLAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUCILLAMINE" } ], "patientagegroup": null, "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326917", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "11", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K et al. Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review. Diagnostics. 2021;11:1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20504993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238054", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Transcatheter aortic valve implantation is a feasible therapeutic option for selected patients with severe aortic stenosis and high or prohibitive risk for standard surgery. Lung transplant recipients are often considered high-risk patients for heart surgery because of their specific transplant-associated characteristics and comorbidities. We report a case of successful transfemoral transcatheter aortic valve replacement in a lung transplant recipient with a symptomatic severe aortic stenosis, severe left ventricular dysfunction, and end-stage renal failure 9 years after bilateral lung transplantation.", "affiliations": "Department of Pulmonary Medicine, University Hospital and University of Bern, Bern, Switzerland; Academic Department of Sleep and Breathing, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom. Electronic address: [email protected].;Cardiology, Cardiovascular Department, University Hospital and University of Bern, Bern, Switzerland.;Service de Pneumologie et Centre Transplantation, University Hospital and University of Lausanne, Lausanne, Switzerland.;Cardiology, Cardiovascular Department, University Hospital and University of Bern, Bern, Switzerland.;Department of Pulmonary Medicine, University Hospital and University of Bern, Bern, Switzerland.", "authors": "Brill\|Anne-Kathrin\|AK\|;Gloekler\|Steffen\|S\|;Aubert\|John-David\|JD\|;Wenaweser\|Peter M\|PM\|;Geiser\|Thomas\|T\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4975", "issue": "97(6)", "journal": "The Annals of thoracic surgery", "keywords": null, "medline_ta": "Ann Thorac Surg", "mesh_terms": "D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D006328:Cardiac Catheterization; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "15030100R", "other_id": null, "pages": "e159-60", "pmc": null, "pmid": "24882332", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Transcatheter aortic valve implantation in a lung transplant recipient.", "title_normalized": "transcatheter aortic valve implantation in a lung transplant recipient" }	[ { "companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-95141", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Aortic stenosis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "End stage renal disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exercise tolerance decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary function test decreased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRILL AK, GLOEKLER S, AUBERT JD, WENAWESER PM, GEISER T. 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TRANSCATHETER AORTIC VALVE IMPLANTATION IN A LUNG TRANSPLANT RECIPIENT. 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TRANSCATHETER AORTIC VALVE IMPLANTATION IN A LUNG TRANSPLANT RECIPIENT. 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TRANSCATHETER AORTIC VALVE IMPLANTATION IN A LUNG TRANSPLANT RECIPIENT. ANN-THORAC-SURG. 2014;97(6):E159-E160", "literaturereference_normalized": "transcatheter aortic valve implantation in a lung transplant recipient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20150404", "receivedate": "20150404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10985122, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "The viral infection causing COVID-19 most notably affects the respiratory system but can result in extrapulmonary clinical manifestations as well. Rhabdomyolysis-associated acute kidney injury (AKI) in the setting of COVID-19 is an uncommon complication of the infection. There is significant interest in this viral infection given its global spread, ease of transmission, and varied clinical manifestations and outcomes. This case report and literature review describes the symptoms, laboratory findings, and clinical course of a patient who developed AKI secondary to rhabdomyolysis and COVID-19, which will help clinicians recognize and treat this condition.", "affiliations": "Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.;Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.;Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.;Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.", "authors": "Chetram\|Vishaka K\|VK\|https://orcid.org/0000-0003-4375-389X;Ahmad\|Akram I\|AI\|;Farid\|Saira\|S\|;Sood\|Tanuj\|T\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2021/5528461", "fulltext": "\n==== Front\nCase Rep Nephrol\nCase Rep Nephrol\nCRIN\nCase Reports in Nephrology\n2090-6641\n2090-665X\nHindawi\n\n34367704\n10.1155/2021/5528461\nCase Report\nAcute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review\nhttps://orcid.org/0000-0003-4375-389X\nChetram Vishaka K. [email protected]\n\nAhmad Akram I.\nFarid Saira\nSood Tanuj\nDepartment of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA\nAcademic Editor: Bernard G Jaar\n\n2021\n2 8 2021\n2021 552846128 2 2021\n26 7 2021\nCopyright © 2021 Vishaka K. Chetram et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nThe viral infection causing COVID-19 most notably affects the respiratory system but can result in extrapulmonary clinical manifestations as well. Rhabdomyolysis-associated acute kidney injury (AKI) in the setting of COVID-19 is an uncommon complication of the infection. There is significant interest in this viral infection given its global spread, ease of transmission, and varied clinical manifestations and outcomes. This case report and literature review describes the symptoms, laboratory findings, and clinical course of a patient who developed AKI secondary to rhabdomyolysis and COVID-19, which will help clinicians recognize and treat this condition.\n\nMedStar Health\n==== Body\n1. Introduction\n\nThe novel coronavirus which emerged in late 2019, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and responsible for COVID-19, has infected more than 85 million people worldwide and has grown into a global pandemic. The incubation period, disease severity, initial presentation, and laboratory findings are varied [1–4]. Multiorgan complications include respiratory failure, cardiac arrhythmias, cardiomyopathy, encephalopathy, thromboembolic events, and acute kidney injury (AKI) [5–7].\n\nKidney involvement in the setting of COVID-19 manifests as hematuria, proteinuria, and/or an AKI, which is associated with increased mortality and more severe infections [8, 9]. Estimates of the incidence of AKI range from 17% to 37% and between 5–15% require kidney replacement therapy [8, 10]. The etiology of kidney dysfunction remains unexplored and may be the result of direct viral infection, cytokine release, altered hemodynamics, or multifactorial, including rhabdomyolysis. Characterized as a clinical syndrome of muscle weakness, myalgia, tea-coloured urine, and muscle swelling, rhabdomyolysis is defined with a creatine kinase value greater than 1000 IU/L or higher than 5 times the upper limit of normal [11]. Rhabdomyolysis occurs due to trauma, drugs, electrolyte abnormalities, and also rarely, viral infections such as influenza A and B, coxsackievirus, Epstein–Barr, herpes simplex, parainfluenza, adenovirus, echovirus, HIV, cytomegalovirus, and most recently, COVID-19 [12, 13]. Thus, our aim in this case report is to present the symptoms, laboratory findings, and clinical course of a patient who presented with AKI secondary to rhabdomyolysis and COVID-19 and provide a literature review of the reported cases.\n\n2. Case Report\n\nA 62 year-old-African American male patient presented to the emergency department with a 3-day history of general feeling of malaise, poor appetite, decreased urine output, and blood in his urine. His comorbidities include hypertension, morbid obesity (BMI of 39.6), and suboptimally controlled type II diabetes. He was socially distancing alone at home and reported no known sick contacts. He denied taking any anticoagulation medication and had no symptoms of urinary urgency or dysuria. He also denied recent strenuous activity, alcohol ingestion, or taking any over-the-counter supplements. Home medications included aspirin 81 mg, glargine 25 units daily, hydrochlorothiazide-lisinopril 12.5mg–20 mg daily, pioglitazone 30 mg, and simvastatin 20 mg daily.\n\nOn presentation, he was febrile to 38.1°C with a heart rate of 103, respiratory rate of 20, blood pressure of 91/58 mmHg, and saturating well on room air. Physical examination yielded a patient with a large body habitus and mild respiratory distress. Pertinent initial laboratory findings revealed a sodium of 132 mmol/L, potassium 4.5 mmol/L, magnesium 2.0 mg/dL, phosphorus 8.9 mg/dL, corrected calcium 4.4 mg/dL, BUN 54 mg/dL, creatinine 4.90 mg/dL (baseline of 1.1 mg/dL), glucose 372 mg/dL, aspartate aminotransferase (AST) 1077 units/L (baseline of 16 units/L), alanine aminotransferase (ALT) of 158 units/L (baseline of 24 units/L), alkaline phosphatase 45 units/L, total bilirubin 0.4 mg/dL, glomerular filtration rate (GFR) 14 mL/min, and lactic acid of 2.1 mmol/L. Urine albumin-to-creatinine ratio one month prior to presentation was 30 mg/g. Creatinine kinase was 327, 629 units/L, and peaked on presentation. Hemoglobin A1C glycosylated was 12.9%. D-dimer was 2.01 mcg/mL FEU. Arterial blood gas showed a pH of 7.35, CO2 of 31 mmHg, and bicarbonate of 17.1 mmol/L. C-reactive protein (CRP) was 136.39 mg/L, and thyroid-stimulating hormone (TSH) was 1.397 uIU/mL. Hepatitis viral panel was obtained and negative. Urine toxicology was negative. Urine analysis showed a moderate amount of blood and 19/hpf red blood cells. The progression of creatinine and creatinine kinase is depicted in Figure 1, respectively.\n\nPoint-of-care ultrasound of the bladder showed <100 mL of urine. Ultrasound of the abdomen showed hepatomegaly with fatty infiltration and no acute cholecystitis or choledocholithiasis, as well as no hydronephrosis. The initial chest radiograph was significant for multifocal patchy airspace disease suggestive of atypical pneumonia or viral infection including COVID-19 (Figure 2).\n\nInitial COVID-19 RNA PCR was negative. Respiratory viral panel for influenza and respiratory syncytial virus (RSV) was also negative. He was given a bolus of 2 L lactated ringer (LR) and started on maintenance LR at 200 mL/hour as well as sevelamer 2400 mg three times a day. For the first 48 hours, he was anuric. He also received ceftriaxone and azithromycin for community-acquired pneumonia coverage. His anion gap and metabolic acidosis resolved shortly after administration of IV fluids. Following the first 48 hours, his urine output increased to 600 mL over 24 hours on the third day and was red tinged. Urine output decreased to 210 mL and 150 mL per 24 hours on hospitalization days four and five, respectively. On the third day of his hospitalization, given the elevated D-dimer and concerning chest radiograph findings, COVID-19 PCR was repeated and found to be positive.\n\nDespite his positive test, the patient did not have respiratory symptoms and continued to oxygenate well on room air. On day 3, continuous renal replacement therapy (CRRT) was initiated due to persistent low urine output, worsening kidney indices, and volume overload. He received 3 consecutive days of CRRT while maintenance fluids were continued at 100 mL per hour. His urine output gradually increased, and CRRT was interrupted. By day 5, his creatine kinase downtrended to 57, 074 units/L with improved serum creatinine to 5.46 mg/dL. At the end of the first week of his hospitalization, his urine appeared clear and total 24-hour output was 700 mL. Given his improvement in urine output and downward trend in creatinine, CRRT was stopped.\n\nOn day 8 of his hospitalization, his oxygen levels desaturated to 87% while walking to the bathroom and he was placed on 2 L supplemental oxygen via a nasal cannula. Maintenance fluids were also discontinued at this time, and he developed a fever to 38.1°C. Chest X-ray showed worsening bilateral infiltrates (Figure 3).\n\nAt this point in his clinical course, his blood pressures remained elevated, ranging from 170/80 to 200/90, and antihypertensive medication doses were progressively increased up to amlodipine 10 mg daily and hydralazine 100 mg thrice a day. On day 12, the patient went into acute hypoxic respiratory failure, developed tachycardia with a heart rate of 120s beats per minute and tachypnea with a respiratory rate of 30. An arterial blood gas (ABG) was obtained which showed a pH of 7.41, CO2 29 mmHg, bicarbonate 18.4 mmol/L, and PaO2 of 82 mmHg. He was placed on BiPAP at 60% FiO2, broad-spectrum antibiotics for pneumonia coverage, and heparin drip for suspected pulmonary embolism and was transferred to the intensive care unit (ICU).\n\nIn the ICU, he was started on a 10-day course of dexamethasone and weaned to a high-flow nasal cannula after 2 days. Remdesevir was never given due to kidney dysfunction. He was also intermittently treated with diuretics. By day 14 of his hospitalization, his daily urine output was 2.9 L and clear in color. He received an echocardiogram which showed an ejection fraction of 65–70% with no valvular or diastolic dysfunction. Ultrasound of the lower extremities was negative for deep vein thrombosis. As his respiratory status improved, he was weaned to 6 L supplemental oxygen via a nasal cannula and was transferred out of the ICU. The patient gradually improved as he completed the 10-day course of dexamethasone, and at the time of discharge, 26 days after his presentation, his creatinine gradually decreased to 1.16 mg/dL and he was sent home, on room air.\n\n3. Discussion\n\nCOVID-19-related kidney dysfunction occurs in a number of ways [14] and can manifest as (1) prerenal AKI from volume depletion or cardiorenal syndrome, (2) acute tubular injury in the setting of circulatory collapse, (3) thrombotic microangiopathy secondary to hypercoagulation, (4) collapsing glomerulopathy in APOL1 gene variants, and (5) myoglobin cast nephropathy due to rhabdomyolysis. Emerging literature has connected COVID-19 to the development of rhabdomyolysis and acute kidney injury, but only few cases have been reported (Table 1) and the physiology link remains unknown.\n\nThe proposed hypotheses include direct invasion of muscle tissue, release of toxic cytokines, namely, TNF-alpha, and destruction of muscle cell membranes by circulating toxins [25]. Approximately 5% of hospitalized COVID-19 patients develop an AKI [26], and up to 40% of those are admitted to the ICU [27]. Studies have indicated that the development of stage II or III AKI incurs a poor prognosis with mortality rates as high as 70% in those requiring kidney replacement therapy [26, 28, 29]. The patient in this case report developed stage III AKI secondary to his rhabdomyolysis which was the presenting symptom of COVID-19. Although he required kidney replacement therapy, he fortunately obtained complete recovery despite a prolonged hospital course and also requiring ICU level of care.\n\nRhabdomyolysis has been described as a late complication of COVID-19 [30], but in our case, it was the presenting clinical manifestation even before respiratory symptoms developed and in light of a negative initial COVID-19 test. Of the reported cases, the classic triad of weakness, myalgia, and tea-coloured urine was not seen in any patients and only 7 of 16 reported one symptom, most commonly myalgia. In this case report, the patient presented with tea-coloured urine, decreased urine output, and general malaise and weakness. Myalgia is a common complaint of viral infections, including influenza. Thus, in patients presenting with myalgia and respiratory symptoms or high suspicion of COVID-19, we recommend evaluating serum creatine kinase and serum creatinine and closely monitoring urine output. The development of rhabdomyolysis and AKI does not appear to have a predilection in patients with certain comorbidities or age. Additionally, it appears that peak creatinine kinase is not associated with in-hospital mortality. In this case, peak creatine kinase was 327, 629 units/L, the second highest of the reported cases, and the patient recovered completely. This contrasts with the cases reported by Singh et al. where peak creatinine kinase was less than <10,000 units/L and patients died during their hospitalization.\n\nThe favourable outcome of our patient may be linked to early identification and IV fluid therapy.\n\nRegarding management of rhabdomyolysis, the mainstay continues to be correction of intravascular volume depletion and prevention of intratubular cast formation with fluid resuscitation. The initial recommended rate is 1 L/hour followed by 500 mL/hour thereafter with either isotonic saline or lactate ringers, although there is no strong evidence supporting either of these IV fluid formulations [31]. The goal of therapy is increased urine output; however, clinicians should be cognizant of volume overload in the setting of oliguria [32]. Additionally, electrolyte abnormalities such as hyperkalemia, hyperphosphatemia, and hypercalcemia or hypocalcaemia should be monitored closely and addressed quickly. Further evidence is needed on target therapies to prevent rhabdomyolysis-associated AKI [33].\n\nA potential limitation to this report is that the patient was taking 20 mg simvastatin as a home medication, a notable cause of myopathy and rhabdomyolysis. Statin-induced rhabdomyolysis is rare and occurs in <0.1% of cases [34]. Furthermore, in larger, follow-up studies, rhabdomyolysis-associated acute kidney failure only developed when statins were used in combination with cyclosporine, gemfibrozil, protease inhibitors, niacin, digoxin, and some antimicrobials [35], none of which this patient was taking at the time. Lastly, although myopathy can occur at any time during treatment with a statin, the onset of symptoms is usually within months of initiation of therapy. Approximately 2/3 of patients experience myopathy in the first six months of starting therapy [36], and the patient in this case report had been on statin therapy for eighteen months without changes in dose. Pioglitazone has been associated with rhabdomyolysis [37], although it appears to be at higher doses (75 mg/day) and rare. Risk factors for thiazolidinedione-induced rhabdomyolysis include concomitant therapy with fibrate, alcohol abuse, and asymptomatic mild creatinine phosphokinase elevation prior to initiating therapy. The patient in this report was on a lower dose of pioglitazone (30 mg/day) and had no further additional risk factors. Other causes of rhabdomyolysis were excluded with thyroid function tests and urine toxicology.\n\nIn summary, this is a unique presentation and complication of COVID-19 in a patient who initially tested negative for the virus. This case was unique in that the patient had a favourable prognosis and although being being admitted to the ICU, recovered completely. Most described cases presented with respiratory symptoms or were diagnosed with COVID-19 and were subsequently found to have rhabdomyolysis and kidney dysfunction, unlike the case in this report. This case report also details the clinical presentation, hospital course, and treatment which adds to the existing literature on the phenomenon. It is imperative for clinicians to be aware of the potential for COVID-19 patients to develop rhabdomyolysis, initiate early treatment, and minimize the kidney dysfunction.\n\nAcknowledgments\n\nThis work was funded by MedStar Health.\n\nConsent\n\nWritten informed consent was obtained prior to the preparation of this manuscript.\n\nDisclosure\n\nThe funder was not involved in the manuscript writing, editing, approval, or decision to publish.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to declare.\n\nFigure 1 Trend of creatinine kinase and creatinine.\n\nFigure 2 Chest X-ray showing multifocal patchy airspace disease, COVID-19.\n\nFigure 3 Chest X-ray on day 14 showing worsening bilateral infiltrates.\n\nTable 1 Summary of the reported cases.\n\n \tDemographics\tClinical Presentation\tComorbidities\tPertinent labs\tClinical course and outcome\t\nTaxbro et al. [15]\t38-year-old male\t1 week of fever, myalgia, nausea, emesis, dry cough, dyspnea, and abdominal pain\tType 2 diabetes\nGout\tCRP: 145 mg/dL\nCreatinine: 51 mmol/L\nD-dimer: 0.19 mg/dL\nNo reported CK\tComplete recovery after ICU admission requiring intubation\nLOS: 23 days\t\nValente-Acosta et al. [16]\t71-year-old male\t1 week of dry coughing, mild dyspnoea and fever, and myalgia and arthralgia, predominantly in his legs\tBenign prostatic hyperplasia\tCRP: 2.9 mg/dL\nCreatinine: 1.68 mg/dL\nLDH: 541 U/L\nD-dimer: 983 ng/mL\nCK peak: 8,720 U/L\tComplete recovery after ICU admission requiring intubation\nLOS: 16 days\t\nSingh et al. [17]\t34-year-old male\tFever, cough, dyspnea, and weakness\tPrediabetes\t—\nCreatinine 0.89 mg\\dl\n—\n—\nCK peak: 5,454 U/L\tDied in hospital\nLOS: not reported\t\n71-year-old male\tFever, cough, and dyspnea\tHypertension\nSchizophrenia\nSeizures\t—\nCreatinine: 4.1 mg/dL\n—\n—\nCK peak: 10,247 U/L\tDied in hospital\nLOS: not reported\t\n88-year-old male\tConfusion\tDiabetes\nHypertension\t—\nCreatinine: 2.25 mg/dL\n—\n—\nCK peak: 2,628 U/L\tDied in hospital\nLOS: not reported\t\n36-year-old male\tFever, cough, and dyspnea\tNone\t—\nCreatinine: 1.03 mg/dL\n—\n—\nCK peak: 5,531 U\\L\tDied in hospital\nLOS: not reported\t\n39-year-old male\tMyalgias, fever, cough, and dyspnea\tHypertension\t—\nCreatinine: 3.8 mg/dL\n—\n—\nCK peak: 4,330 U/L\tDied in hospital\nLOS: not reported\t\n\t\nHusain et al. [18]\t38-year-old male\tSever, cough, dyspnea, and myalgia\tNot reported\tCRP: 98.3 mg/dL\nCreatinine: 1.5 mg/dL\nLDH: 398 U/L\n—\nCK peak: 33,000 U/L\tComplete recovery after ICU admission\nLOS: 3 months\t\nChedid et al. [19]\t51-year-old male\t2 days of diffuse myalgias, dry cough, and mild chills\tHypertension\nType 2 diabetes OSA\nCKD II\tCRP: 98.3 mg/dL\nCreatinine: 2.48 mg/dL\nLDH: 2150 U/L\n—\nCK peak: 464,000 U/L\tDialysis as outpatient\nLOS: not reported\t\nSingh et al. [20]\t67-year-old male\tFever and dyspnea\tHypertension\t—\nCreatinine: 1.16 mg/dL\nLDH: 459 U/L\nD-dimer: 0.62 ng/mL\nCK peak: 19,773 U/L\tDied in hospital\nLOS: 21 days\t\n39-year-old male\tFever, myalgia, dyspnea, and altered mental status\tHypertension\tCRP: 98.3 mg/dL\nCreatinine: 3.8 mg/dL\nLDH: 907 U/L\nD-dimer: 1.92 ng/mL\nCK: 4,330 U/L\tDied in hospital\nLOS: 1 day\t\n\t\nAlejandro et al. [21]\t89-year-old male\tDyspnea, fever, cough, and malaise\tHypertension, coronary artery disease, and heart failure with preserved ejection fraction\tCreatinine: 2.0 mg/dL\nLDH: 805 U/L\n—\nCK: 2,751 U/L\tComplete recovery\nLOS: 12 days\t\nPellegrini et al. [22]\t34-year-old male\t2 days of emesis, sore throat, nonproductive cough, and dyspnea\tNot reported\tCRP: 3.3 mg/dL\nCreatinine: 1.4 mg/dL\nLDH: 854 U/L\n—\nCK: 73,922 U/L\tComplete recovery\nLOS: 8 days\t\nChong and Saha [23]\t37-year-old male\t2 days of dyspnea and fatigue\tNot reported\t—\nCreatinine: 5.0 mg/dL\n—\n—\nCK peak: 35,000 U/L\tDied in hospital\nLOS: 12 day\t\nChan et al. [24]\t75-year-old female\t4 days of weakness and decrease in appetite\tCoronary artery disease, hypertension, and GERD\t—\nCreatinine: 1.2 mg/dL\n—\n—\nCK: 2,767 U/L\tComplete recovery\nLOS: not reported\t\n71-year-old male\tGeneralized weakness and leg twitching\tHypertension, seizure, CKD, and overactive bladder\t—\nCreatinine: 5.6 mg/dL\n—\n—\nCK: 1,859 U/L\tHospitalized as inpatient\nLOS: undetermined\t\n\t\nChetram et al., 2021 (this manuscript)\t62-year-old male\t3-day history of general feeling of malaise, poor appetite, decreased urine output, and blood in his urine\tHypertension, type II diabetes, obesity\tCRP: 136.39 mg/L\nCreatinine: 4.9 mg/dL\n—\nD-dimer: 2.01 mcg/dL\nCK peak: 327,629 U/L\tComplete recovery\nLOS: 26 days\n==== Refs\n1 Wu Z. McGoogan J. M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China JAMA 2020 323 13 p. 1239 10.1001/jama.2020.2648\n2 Zhou F. Yu T. Du R. 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Pioglitazone-induced acute rhabdomyolysis Diabetes Care 2009 32 7 p. e84 10.2337/dc09-0593 2-s2.0-67650070836\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-665X", "issue": "2021()", "journal": "Case reports in nephrology", "keywords": null, "medline_ta": "Case Rep Nephrol", "mesh_terms": null, "nlm_unique_id": "101598418", "other_id": null, "pages": "5528461", "pmc": null, "pmid": "34367704", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "19564463;8729203;19328397;33125416;33005556;25043142;32878841;30644084;15572716;33824868;33308501;32416116;33022818;32587121;32690987;32555134;32091533;32414522;32671722;32031570;33059350;32109013;32320003;32171076;16344427;27301374;30617905;32247631;32775814;33016619;12622602;32771219;33252915;32197060", "title": "Acute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review.", "title_normalized": "acute kidney injury secondary to rhabdomyolysis and covid 19 a case report 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE\\LISINOPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM CHLORIDE\\POTASSIUM CHLORIDE\\SODIUM CHLORIDE\\SODIUM LACTATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLILITER, INTERVAL 1 HOUR", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACTATED RINGERS SOLUTION" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SEVELAMER" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2400 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SEVELAMER" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXYGEN" }, "drugadditional": null, "drugadministrationroute": "045", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 LITER", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "011", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYGEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDRALAZINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, TID", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDRALAZINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Chetram VK, Ahmad AI, Farid S, Sood T. Acute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review. Case Reports in Nephrology. 2021", "literaturereference_normalized": "acute kidney injury secondary to rhabdomyolysis and covid 19 a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211112", "receivedate": "20211112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20061390, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-TEVA-2021-US-1975084", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIOGLITAZONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077210", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 2 diabetes mellitus", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIOGLITAZONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "76052", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM DAILY; FOR LAST 18 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "087668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "10", "drugtreatmentdurationunit": "804", "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "81", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INSULIN GLARGINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 UNITS DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 2 diabetes mellitus", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN GLARGINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE\\LISINOPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE\\LISINOPRIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDRALAZINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THRICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDRALAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Chetram VK, Ahmad AI, Farid S, Sood T. Acute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review. Case-Rep-Nephrol 2021;:.", "literaturereference_normalized": "acute kidney injury secondary to rhabdomyolysis and covid 19 a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211122", "receivedate": "20211111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20059490, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20220304" } ]
{ "abstract": "Pulmonary infiltrates in immunosuppressed patients are common. Yields from bronchoscopy with bronchoalveolar lavage (BAL) has been reported to be between 31 and 65%. The clinical impact of pneumocystis and viral Polymerase chain reaction (PCR) testing on BAL has not been extensively evaluated in a mixed immunosuppressed patient population.\n\n\n\nWe performed a retrospective chart review of immunosuppressed adults with pulmonary infiltrates who underwent BAL at the University of Rochester Medical Center. Only one BAL per patient was included. We compared the rate of positive PCR testing to conventional testing. We then investigated factors associated with positive PCR testing. Finally, we assessed for changes in antimicrobial therapy after bronchoscopy.\n\n\n\nThree hundred and fifty-nine patients underwent BAL with 249 patients having pneumocystis PCR testing and 142 having viral PCR testing. Pneumocystis identification occurred in 43 patients and viral species identification occurred in 56 patients. PCR testing increased pneumocystis identification compared to microscopy, 14% vs. 5%, p = 0.01, and viral identification compared to culture, 25% vs. 6%, p = 0.0001. Of the patients with positive pneumocystis PCR testing 49% had antibiotics stopped, 66% were started on anti-pneumocystis therapy, and only 6% did not receive treatment. There was no difference in the number of patients with antibiotics stopped based on viral PCR testing results.\n\n\n\nPCR testing increases BAL yield in immunosuppressed patients compared to conventional testing. Pneumocystis identified by PCR only may cause a self-limited infection and may not require antimicrobial therapy. PCR testing should be included in the evaluation of pulmonary infiltrates in immunosuppressed patients.", "affiliations": "Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA. Electronic address: [email protected].;Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.;Wegmans School of Nursing, St. John Fisher College, Rochester, NY, USA.;Department of Microbiology and Immunology, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.;Division of Transplant Infectious Disease, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA; Division of Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.;Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.", "authors": "Lachant\|Daniel J\|DJ\|;Croft\|Daniel P\|DP\|;McGrane Minton\|Heather\|H\|;Hardy\|Dwight J\|DJ\|;Prasad\|Paritosh\|P\|;Kottmann\|R Matthew\|RM\|", "chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000998:Antiviral Agents", "country": "England", "delete": false, "doi": "10.1016/j.rmed.2018.10.021", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-6111", "issue": "145()", "journal": "Respiratory medicine", "keywords": "BAL; Immunosuppressed; PCR; Pneumocystis; Viral", "medline_ta": "Respir Med", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000998:Antiviral Agents; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D011010:Pneumocystis; D016720:Pneumocystis Infections; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "8908438", "other_id": null, "pages": "35-40", "pmc": null, "pmid": "30509714", "pubdate": "2018-12", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "20837876;23509331;8610948;10524989;15135373;23990137;22814461;9508424;9383232;2817582;12114367;16061360;14769756;8265840;22491773;16652305;17803871;28382762;18576286;15819805;23922610;25009050;25062720;25122864;15752442;15072757;19265086;9154883;26378282;18024536;25448310;15190141;19684637", "title": "The clinical impact of pneumocystis and viral PCR testing on bronchoalveolar lavage in immunosuppressed patients.", "title_normalized": "the clinical impact of pneumocystis and viral pcr testing on bronchoalveolar lavage in immunosuppressed patients" }	[ { "companynumb": "US-009507513-1811USA003953", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RIBAVIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020903", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REBETOL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LACHANT DJ, CROFT DP, MINTON H, HARDY DJ, PRASAD P, KOTTMANN R. THE CLINICAL IMPACT OF PNEUMOCYSTIS AND VIRAL PCR TESTING ON BRONCHOALVEOLAR LAVAGE IN IMMUNOSUPPRESSED PATIENTS. RESPIRATORY MEDICINE. 2018?145:35-40", "literaturereference_normalized": "the clinical impact of pneumocystis and viral pcr testing on bronchoalveolar lavage in immunosuppressed patients", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20181128", "receivedate": "20181128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15667925, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]
{ "abstract": "The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.", "affiliations": "Department of Neurosurgery, Shunan Memorial Hospital.", "authors": "Anda\|Takeo\|T\|;Honda\|Masaru\|M\|;Ishihara\|Tokuhiro\|T\|;Kamei\|Toshiaki\|T\|", "chemical_list": "D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D009570:Nitriles; D011974:Receptors, LH; D014105:Tosyl Compounds; D007987:Gonadotropin-Releasing Hormone; C053541:bicalutamide; D016729:Leuprolide", "country": "Japan", "delete": false, "doi": "10.2176/nmc.cr2012-0417", "fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 2420110010.2176/nmc.cr2012-0417nmc-54-327Case ReportProgression of Intracranial Meningioma during Luteinizing Hormone-Releasing Hormone Agonist Treatment for Prostate Cancer: Case Report ANDA Takeo 1HONDA Masaru 1ISHIHARA Tokuhiro 2KAMEI Toshiaki 31 Department of Neurosurgery, Shunan Memorial Hospital, Kudamatsu, Yamaguchi;2 Department of Pathology, Tokuyama Medical Association Hospital, Shunan, Yamaguchi;3 Department of Pathology, Yamaguchi Grand Medical Center, Hofu, YamaguchiAddress reprint requests to: Takeo Anda, MD, Department of Neurosurgery, Shunan Memorial Hospital, 1-10-1 Ikunoyaminami, Kudamatsu, Yamaguchi 744-0033, Japan. e-mail: [email protected] of Interest Disclosure\n\nNone. Two authors who are the members of Japan Neuro-surgical Society have already submitted the conflict of interest self-declaration to the society.\n\n4 2014 8 11 2013 54 4 327 330 6 12 2012 6 2 2013 © 2014 The Japan Neurosurgical Society2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.\n\nmeningiomaluteinizing hormone-releasing hormone receptorleuprorelin acetateprostate cancer\n==== Body\nIntroduction\nSome sex hormone receptors have been verified in meningioma cells, and several hormones have been reported to affect the growth of meningioma. In this report, the authors present a patient with meningioma whose tumor growth could have been related to a luteinizing hormone-releasing hormone (LH-RH) agonist administration.\n\nCase Report\nI. History\nA 70-year-old man underwent gastrectomy for early stage gastric cancer, and remained well after that for 7 years. He received a brain check-up at another hospital in November 2007, and no intracranial abnormalities were detected (Fig. 1). In April 2008, early stage prostate cancer (T1C, N0, M0) was detected. Prostatectomy was performed, and leuprorelin acetate and bicalutamide were administered prophylactically to the patient. Monthly treatment was then maintained. In December 2010, he suffered from headache and a brain magnetic resonance imaging (MRI) at another hospital demonstrated an intracranial mass lesion. He was referred to our hospital on January 31, 2011.\n\nII. Examination\nNo neurological deficits were observed. Brain MRI revealed a large extraaxial parasagittal mass near the bregma which compressed bilateral frontal lobes and extended into the falx and skull. It showed iso-intense on T1-weighted images (WI) and high-intense on T2WI, and was homogeneously enhanced after intravenous injection of contrast materials. The diameter of the tumor reached 5 cm (Fig. 2). Hyperostosis of the skull near the mass was identified by skull X-ray. Many feeding arteries originating from bilateral pial arteries and branches of external carotid arteries were recognized on cerebral angiogram. The superior sagittal sinus (SSS) was segmentally occluded near the bregma. Prostate-specific antigen (PSA) was 0 ng/ml, carcinoembryonic antigen (CEA) was 1.8 ng/ml, and Ca19-9 was 9.7 U/ml. The tumor was regarded as a parasagittal meningioma invading the falx, SSS, and skull. An operation was performed on March 14, 2011.\n\nIII. Operation\nUnder general anesthesia, the medial frontoparietal bone was removed in a divided manner. At the same time, a part of the tumor which invaded the skull was also removed. Then, the dura around the tumor was cut, and the border between the tumor and its dural attachment was separated, and the tumor surface was dissected from the brain while interrupting the pial supply. The tumor was pinkish and fragile and tended to bleed. Internal decompression was suitably done, and the tumor was removed in a piecemeal manner. Almost all the tumor attachment, affected falx, and SSS were removed. A part of the attachment near the intact cortical bridging vein was left as it was coagulated. The extent of tumor removal was judged as Simpson grade 2. Dural plasty using Goatex, and cranioplasty using a titanium plate were performed. The tumor was histopathologically proved to be a meningothelial meningioma without atypical or anaplastic features. The molecular immunology borstel-1 (MIB-1) staining index was 5% or less. Cytoplasmic immunoreactivity for the luteinizing hormone-releasing hormone (LH-RH) receptor was detected (Fig. 3). The used primary antibody was mouse monoclonal anti-LH-RH receptor antibody (Thermo, Fremont, California, USA).\n\nIV. Postoperative course\nThere were no perioperative events, and no neurological deficits were recognized. Administration of leuprorelin acetate was ceased. On July 11, 2012, sixteen months after the operation, brain MRI demonstrated no tumor recurrence (Fig. 4).\n\nDiscussion\nThis patient's intracranial tumor was histologically diagnosed as meningothelial meningioma and it showed no evidence of malignant features. It is very rare for a small benign meningioma not detected by MRI to grow into a large mass 5 cm in diameter, and invade the falx and SSS and skull in the course of less than 3 years. Because bony and dural sinus invasion by meningioma is reportedly not related to its biological malignancy,1–3) the rapid tumor progression in such a short time in this patient is not consistent with typical benign meningiomas. The authors suspect that maintenance of hormone treatment for prostate cancer led to rapid growth of the meningioma.\n\nThere are many reports referring to sex steroid hormone receptors in meningiomas. Meningioma occurs in females twice as frequently as in males. Progesterone receptors were found in 83% of meningiomas,4) and discontinuation of a progesterone agonist induced regression of meningioma.5) Antiprogestational therapy showed efficacy for unresectable meningioma.6)\n\n\nReceptors of gonadotropin-releasing hormone, namely LH-RH were identified immunohistochemically in the cytoplasm of 95.1% of meningiomas resected.7) Another report demonstrated that LH-RH increased proliferation of meningioma cells in vitro.8)\n\n\nLeuprorelin acetate, an LH-RH agonist, exhibits antiandrogenic effect if administered to males, so it is often used for patients with prostate cancer. The authors found a few reports referring to leuprorelin acetate administered and a meningioma developing in patients with prostate cancer. Fallanca et al. reported two cases. A 70-year-old man had undergone hormonal therapy with leuprorelin (7.5 mg/month) and bicalutamide (150 mg/day) for 3 years after radical prostatectomy and radiotherapy for prostate cancer. Subsequently, abnormal tracer uptake in the lumboaortic lymph nodes and lumbosacral vertebral body and the posterior cranial fossa were found by a (11C) choline positron emission tomography/computed tomography (PET/CT) scan. The lesions in the skeletal bone and lymph nodes were thought to be metastasis, but the latest was highly suggestive of meningioma on enhanced MRI. Hormonal treatment was discontinued and chemotherapy with docetaxel was started. After two cycles of chemotherapy, PET/CT showed that the intensity of abnormal tracer uptake in the metastatic lesion was increasing but was stable in the posterior cranial fossa meningioma.9) This article quoted other two cases described in a case report written by Lee and Terris.10) Both patients developed neurological symptoms during LH-RH agonist treatment after surgery for prostate cancer. In one patient, meningioma was found on radiological imaging, and in the other, who had undergone surgery for meningioma, tumor recurrence was documented.\n\nBicalutamide is an androgen receptor antagonist, and is often administered to patients with prostate cancer. An effect of this drug on the development of meningioma is regarded as unlikely.\n\nAs mentioned above, leuprorelin acetate, an LH-RH agonist, could conceivably play a role in the rapid growth of meningioma. This hypothesis is consistent with the immunoreactivity for the LR-RH receptor in the tumor cells of this patient. Nevertheless, there have been only a few reports of this kind. This may be because there may be very few male patients with prostate cancer who have meningioma simultaneously as it predominantly occurs in females. Also, PSA, a strong tumor marker for prostate cancer at present, was not popular before. So, some patients with prostate cancer in early stage might be overlooked. Further clinical experience and investigation are needed.\n\nConclusion\nThe authors documented a 70-year-old man with prostate cancer whose meningioma had grown to 5 cm in diameter over 3 years during hormone treatment for prostate cancer. In this patient, leuprorelin acetate, an LH-RH agonist, could have contributed to the rapid growth of meningioma.\n\nThe authors thank the laboratory technician, Ms. Tomoko Hayaki, for her assistance in the immunohistochemistory of the tumor specimen.\n\nFig. 1 A: T2-weighted axial magnetic resonance (MR) imaging demonstrating no apparent intracranial abnormalities. B: MR sagittal scout imaging demonstrating no apparent abnormalities.\n\nFig. 2 A: Gadolinium-enhanced T1-weighted coronal magnetic resonance imaging (MRI) demonstrating an extramedullary homogenously enhanced tumor at the parasagittal region expanding into the falx and skull bone. B: Gadolinium-enhanced T1-weighted sagittal MRI.\n\nFig. 3 Photomicrographs of the resected tumor. A: Whorl arrangements are seen in places. Necrosis is not identified. Hematoxylin and eosin (H&E) staining, original magnification ×200. B: Tumor cells are largely uniform and have oval nuclei. Mitoses are not identified. H&E staining, original magnification ×400. C: Molecular immunology borstel (MIB)-1 staining index is 5%. Immunohistochemical stain for Ki-67, original magnification ×400. D: The cytoplasm of tumor cells is immunopositive for the LH-RH receptor. Immunohistochemical stain for the LH-RH receptor, original magnification ×400. LH-RH: luteinizing hormone-releasing hormone.\n\nFig. 4 No recurrent tumor is identified 16 months after the operation. A: Gadolinium-enhanced T1-weighted coronal magnetic resonance imaging (MRI). B: Gadolinium-enhanced T1-weighted sagittal MRI.\n==== Refs\nReferences\n1) \nDiMeco F Li KW Casali C Ciceri E Giombini S Filippini G Broggi G Solero CL : \nMeningiomas invading the superior sagittal sinus: surgical experience in 108 cases . \nNeurosurgery \n55 : \n1263 –\n1272 ; \ndiscussion 1272–1274 , \n2004 \n15574208 \n2) \nMoon HS Jung S Jung TY Cao VT Moon KS Kim IY : \nPossible role of matrix metalloproteinase in osteolytic intracranial meningiomas . \nJ Korean Neurosurg Soc \n47 : \n11 –\n16 , \n2010 \n20157372 \n3) \nRaza SM Gallia GL Brem H Weingart JD Long DM Olivi A : \nPerioperative and long-term outcomes from the management of parasagittal meningiomas invading the superior sagittal sinus . \nNeurosurgery \n67 : \n885 –\n893 ; \ndiscussion 893 , \n2010 \n20802356 \n4) \nHsu DW Efird JT Hedley-Whyte ET : \nProgesterone and estrogen receptors in meningiomas: prognostic considerations . \nJ Neurosurg \n86 : \n113 –\n120 , \n1997 \n8988089 \n5) \nShimizu J Matsumoto M Yamazaki E Yasue M : \nSpontaneous regression of an asymptomatic meningioma associated with discontinuation of progesterone agonist administration . \nNeurol Med Chir (Tokyo) \n48 : \n227 –\n230 , \n2008 \n18497498 \n6) \nGrunberg SM : \nRole of antiprogestational therapy for meningiomas . \nHum Reprod \n9 (Suppl 1 ): \n202 –\n207 , \n1994 \n7962466 \n7) \nHirota Y Tachibana O Uchiyama N Hayashi Y Nakada M Kita D Watanabe T Higashi R Hamada J Hayashi Y : \nGonadotropin-releasing hormone (GnRH) and its receptor in human meningiomas . \nClin Neurol Neurosurg \n111 : \n127 –\n133 , \n2009 \n18980792 \n8) \nDurmaz R Deliorman S Isiksoy S Uyar R Tel E : \nLuteinizing hormone releasing hormone increases proliferation of meningioma cells in vitro . \nArchives Physiol Biochem \n107 : \n286 –\n291 , \n1999 \n\n9) \nFallanca F Giovacchini G Picchio M Bettinardi V Messa C Fazio F : \nIncidental detection by [11C]choline PET/CT of meningiomas in prostate cancer patients . \nQ J Nucl Med Mol Imaging \n53 : \n417 –\n421 , \n2009 \n19282812 \n10) \nLee KL Terris MK : \nLuteinizing hormone-releasing hormone agonists and meningioma: a treatment dilemma . \nUrology \n62 : \n351 , \n2003\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0470-8105", "issue": "54(4)", "journal": "Neurologia medico-chirurgica", "keywords": null, "medline_ta": "Neurol Med Chir (Tokyo)", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005743:Gastrectomy; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D016729:Leuprolide; D008279:Magnetic Resonance Imaging; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D009363:Neoplasm Proteins; D009376:Neoplasms, Hormone-Dependent; D016609:Neoplasms, Second Primary; D009570:Nitriles; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D011974:Receptors, LH; D013274:Stomach Neoplasms; D014105:Tosyl Compounds", "nlm_unique_id": "0400775", "other_id": null, "pages": "327-30", "pmc": null, "pmid": "24201100", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12893358;20157372;10779825;7962466;8988089;19282812;20802356;18497498;15574208;18980792", "title": "Progression of intracranial meningioma during luteinizing hormone-releasing hormone agonist treatment for prostate cancer: case report.", "title_normalized": "progression of intracranial meningioma during luteinizing hormone releasing hormone agonist treatment for prostate cancer case report" }	[ { "companynumb": "PHHY2015JP082244", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BICALUTAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BICALUTAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "74728", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUPRORELIN" } ], "patientagegroup": null, "patientonsetage": "70", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exostosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningioma", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ANDA T, HONDA M, ISHIHARA T, KAMEI T.. PROGRESSION OF INTRACRANIAL MENINGIOMA DURING LUTEINIZING HORMONE-RELEASING HORMONE AGONIST TREATMENT FOR PROSTATE CANCER: CASE REPORT. NEUROLOGIA MEDICO-CHIRURGICA. 2014;54(4):327-30", "literaturereference_normalized": "progression of intracranial meningioma during luteinizing hormone releasing hormone agonist treatment for prostate cancer case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150715", "receivedate": "20150715", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11274144, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" } ]
{ "abstract": "BACKGROUND Several cases of herpes simplex virus type 1 meningoencephalitis (HSVE) have been reported in patients receiving steroids, but the exact contribution of steroids to the disorder remains unclear because other risk factors, such as chemotherapy, brain radiation, or surgery, were present in almost all cases. CASE REPORT We report the case of a 76-year-old man who developed HSVE following the administration of pulse-dose steroids. The patient had occupational asbestos exposure and a chronic interstitial lung disease of unclear etiology (sarcoidosis versus hypersensitivity pneumonitis) and was admitted for acute-on-chronic respiratory failure requiring mechanical ventilation. After a negative infectious workup and several days of antibiotics without improvement, pulse-dose steroids were administered. In the following days, the patient developed a fever and worsening encephalopathy. A lumbar puncture showed elevated nucleated cells and positive polymerase chain reaction for herpes simplex virus 1 in the cerebrospinal fluid, confirming the diagnosis of HSVE. Acyclovir treatment was initiated, but the patient later died as a result of persistent severe encephalopathy and respiratory failure with an inability to wean mechanical ventilation. CONCLUSIONS Clinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids, taking into account associated factors of immunosuppression. A high level of awareness should be especially maintained in critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.", "affiliations": "Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.", "authors": "Horn\|Jeffrey\|J\|;Mullholand\|Jon B\|JB\|;Ashraf\|Saad\|S\|;Shore\|David\|D\|;Van de Louw\|Andry\|A\|", "chemical_list": "D000212:Acyclovir; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.12659/AJCR.933847", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34716288\n10.12659/AJCR.933847\n933847\nArticles\nHerpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review\nHorn Jeffrey A B C D E F\nMullholand Jon B. A B C D E F\nAshraf Saad A B F\nShore David A B C D\nVan de Louw Andry A B C D E F\nDivision of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA\nCorresponding Author: Andry Van de Louw, e-mail: [email protected]\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nFinancial support: None declared\n\nConflict of interest: None declared\n\n2021\n30 10 2021\n22 e933847-1e933847-6\n03 7 2021\n11 9 2021\n01 10 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 76-year-old\n\nFinal Diagnosis: Herpes simplex virus type 1 (HSV-1) encephalitis\n\nSymptoms: Encephalopathy\n\nMedication: —\n\nClinical Procedure: Lumbar puncture\n\nSpecialty: Critical Care Medicine\n\nObjective:\n\nUnusual or unexpected effect of treatment\n\nBackground:\n\nSeveral cases of herpes simplex virus type 1 meningoencephalitis (HSVE) have been reported in patients receiving steroids, but the exact contribution of steroids to the disorder remains unclear because other risk factors, such as chemotherapy, brain radiation, or surgery, were present in almost all cases.\n\nCase Report:\n\nWe report the case of a 76-year-old man who developed HSVE following the administration of pulse-dose steroids. The patient had occupational asbestos exposure and a chronic interstitial lung disease of unclear etiology (sarcoidosis versus hypersensitivity pneumonitis) and was admitted for acute-on-chronic respiratory failure requiring mechanical ventilation. After a negative infectious workup and several days of antibiotics without improvement, pulse-dose steroids were administered. In the following days, the patient developed a fever and worsening encephalopathy. A lumbar puncture showed elevated nucleated cells and positive polymerase chain reaction for herpes simplex virus 1 in the cerebrospinal fluid, confirming the diagnosis of HSVE. Acyclovir treatment was initiated, but the patient later died as a result of persistent severe encephalopathy and respiratory failure with an inability to wean mechanical ventilation.\n\nConclusions:\n\nClinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids, taking into account associated factors of immunosuppression. A high level of awareness should be especially maintained in critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.\n\nKeywords:\n\nCritical Care\nEncephalitis, Herpes Simplex\nSteroids\n==== Body\npmcBackground\n\nHerpes simplex virus (HSV) is the most common infectious cause of sporadic encephalitis worldwide, with HSV-1 being the most common strain to cause HSV encephalitis (HSVE) [1]. After primary mucocutaneous infection, HSV remains latent in sensory ganglia and 60–90% of the world’s population is estimated to be seropositive for HSV [1]. Possible pathogenic mechanisms for HSVE include reactivation of latent HSV in the trigeminal ganglia, with subsequent spread of infection to the temporal and frontal lobes, primary central nervous system (CNS) infection, and perhaps reactivation of latent virus within the brain parenchyma itself [1]. The introduction of acyclovir has decreased mortality rates from 70% to 15% [2], but early diagnosis and treatment initiation are major determinants of mortality [2].\n\nImmunocompromised individuals seem to be at higher risk for severe HSV infections including meningoencephalitis [3], but the precise contribution of steroids remains unclear. Owing to their anti-inflammatory and immunomodulatory effects, glucocorticoids might in theory increase the rate of viral replication, but experimental animal models have yielded conflicting results regarding their effect on replication and clearance of HSV in the CNS [4,5]. Case reports have shown temporal associations between steroids and HSVE, but the relative contribution of steroids remains unclear because other factors, such as concomitant chemotherapy [6,7] or direct insult to the CNS (radiation [8], surgery [9,10]) or close structures (eye [11,12]), may have contributed to the HSVE in most of these cases. Here, we present a case of HSV-1 meningoencephalitis that developed following pulse-dose steroids for the treatment of interstitial lung disease in a patient with no history of chemotherapy or CNS insult. This case highlights the potential risk of pulse-dose steroids in patients with associated risk factors (age, critical illness immune paralysis, lymphopenia) and the need to rule out CNS infection in case of persistent, unexplained encephalopathy in critically ill patients. Informed consent for publication was obtained from the patient’s next of kin.\n\nCase Report\n\nA 76-year-old man was admitted with acute-on-chronic hypoxic respiratory failure. He had a past medical history of ischemic cardiomyopathy with reduced ejection fraction, atrial fibrillation, and ventricular tachycardia requiring a pacemaker and amiodarone, and he was on home oxygen owing to chronic hypoxic respiratory failure. The patient had a significant smoking history and occupational asbestos exposure. A year prior to admission he underwent the following procedures for dyspnea: (1) a pulmonary function test that showed normal spirometry, decreased lung volumes, and severely impaired diffusion capacity, consistent with restrictive lung disease; (2) a chest computed tomography (CT) scan that revealed perilymphatic nodular opacities (some calcified), ground glass opacities, and lower lobe predominant septal thickening; and (3) unre-markable bronchoscopy and broncho-alveolar lavage. A repeat chest CT a month prior to admission revealed worsening inter-stitial lung disease concerning for sarcoidosis versus chronic hypersensitivity pneumonitis. On admission, the patient was afebrile with a normal neurological exam. Significant laboratory values included white blood cell count 11.4×109/L (lymphocytes 0.66×109/L), procalcitonin 0.15 ng/mL, C-reactive protein 10.3 mg/dL, and brain natriuretic peptide 5374 pg/ mL. A chest CT showed no acute pulmonary embolus, but new ground glass and consolidative opacities were observed in both upper lobes. The patient was started on antibiotics for presumed community-acquired pneumonia and diuretics for heart failure exacerbation. He required intubation and mechanical ventilation on day 3 for worsening acute hypoxic respiratory failure. An extensive infectious workup, including 2 bronchoscopies with broncho-alveolar lavage, was entirely negative (bacterial and fungal cultures, multiplex polymerase chain reaction (PCR) for respiratory viral panel performed on a nasal swab and broncho-alveolar lavage fluids, Pneumocystis jirovecii PCR, acid fast bacillus cultures). Serum levels of immunoglobulins were normal for IgA and IgM and elevated for IgE (388 IU/mL, normal values <100 IU/mL) and IgG (1631 IU/mL, normal values 700–1600 IU/mL). An echocardiogram showed an ejection fraction of 45%, which was unchanged from prior examination. On day 5, given the lack of respiratory improvement after several days of antibiotics and diuretics, methylprednisolone at 46 mg/d was started to treat possible cryptogenic organizing pneumonia versus amiodarone-induced lung toxicity versus sarcoidosis. No improvement was subsequently observed and on day 11 steroid dosage was increased to 1000 mg/d for 3 days.\n\nOn day 13, the patient became febrile with worsening hyper-leukocytosis; urine culture was positive for Candida albicans, blood culture for Candida parapsilosis, and sputum culture for methicillin-sensitive Staphylococcus aureus. The patient was started on caspofungin.\n\nWithin the next few days, attempts to wean sedation and mechanical ventilation were unsuccessful. The patient was intermittently following commands during sedation holidays, but he was very tachypneic with patient/ventilator dyssynchrony, requiring sedation to be maintained. On day 18, the patient was noted to be minimally responsive to commands, which was a worsening of his mental status from previous days. He was febrile again and his white blood cell count was 20.1×109/L. A head CT scan was unremarkable, but a brain MRI could not be obtained due to the pacemaker. A lumbar puncture was performed, and cerebrospinal fluid studies were significant for nucleated cells of 36/μL (92% neutrophils), red blood cells of 8000/μL, glucose 73 mg/dL (normal 40–70 mg/dL), protein 46 mg/dL (normal 15–45 mg/dL), and lactate 2.8 mmol/L (normal 1.1–2.4 mmol/L). Bacterial cultures were negative, but PCR results for HSV-1 were positive.\n\nThe patient was started on acyclovir 10 mg/kg every 8 h for HSV-1 meningoencephalitis. Steroids were tapered and eventually discontinued. The patient’s mental status did not improve, and severe patient/ventilator dyssynchrony persisted with an inability to wean mechanical ventilation. The patient was transitioned to comfort care and died on day 25. Of note, he had remained significantly lymphopenic during the entire Intensive Care Unit (ICU) stay (lymphocyte count consistently below 0.8×109/L with a nadir of 0.01×109/L) with a CD4 count of 66/mm3 and a CD4/CD8 ratio of 1.84. Screening for HIV and viral hepatitis yielded negative results.\n\nAn autopsy was performed, and significant lung findings included interstitial fibrosis most compatible with silicosis, pulmonary congestion, acute bronchopneumonia in the right lower lobe, and subacute infarction with necrosis and cavitation in left upper lobe. The neuropathology did not reveal any acute process.\n\nDiscussion\n\nThis case illustrates how important and challenging the discussion of the benefit/risk ratio is prior to administering pulse-dose steroids in critically ill patients. Steroids were administered in our patient, with the dosage subsequently being increased because of the lack of improvement after treatment of presumed pneumonia and heart failure exacerbation. The steroid treatment was also used because diagnoses of sarcoidosis or hypersensitivity pneumonitis were considered based on previous medical history and chest imaging. However, the autopsy ruled out these diagnoses.\n\nThe risk of developing severe HSV infection after high-dose steroids is difficult to ascertain. In patients with systemic lupus erythematosus treated with various immunosuppressive drugs, the risk of severe HSV infection is increased [3]; steroids have been specifically associated with increased rates of opportunistic infections and herpes zoster infection in this population. The hypothesis of an increased risk of HSV infection due to steroids is therefore reasonable, but it has not been conclusively proven so far. Multiple cases of steroid-associated HSVE have been reported and are summarized in Table 1 [6–8,10–24]. In almost all cases, the presence of other potential triggers of HSVE, such as immunosuppressive drugs or direct CNS injury (surgery, radiation, eye injury), prevents any definite conclusion regarding a specific effect of steroids.\n\nOur patient did not have a history of chemotherapy administration or direct CNS injury, but his lymphopenia on presentation was another potential risk factor for HSVE and makes a causal link between steroids and HSVE difficult to assert.\n\nThe lymphopenia consistently present in our patient throughout his admission and very low CD4 count may have indeed increased his risk of developing HSVE. Its cause remains unclear. HIV screening was negative, and the lymphopenia was ascribed on admission to possible sarcoidosis; however, the autopsy did not confirm that diagnosis. After inoculation of HSV in experimental models, antilymphocyte serum allowed the development of viremia and fatal meningoencephalitis [25]. Lymphopenia has been associated with increased risk of infection in general in patients with systemic lupus erythematosus [26], and HSVE complicating drug-induced lymphopenia has been reported [27]. Lymphopenia was present in our patient even before steroid administration, but steroids are known to decrease circulating lymphocyte count and function, especially T cells and the CD4 subset [28], and may have further altered our patient’s immune system.\n\nCritical illness and sepsis per se are associated with lymphopenia, monocyte deactivation, and immune paralysis [29]. Lymphopenia in our patient was not secondary to sepsis because it was present prior to his admission. Pre-existing lymphopenia, critical illness-induced immune paralysis, and steroids may have synergistically led to the development of HSVE. However, despite a high prevalence of lymphopenia and immune paralysis in critically ill patients, regardless of the presence of sepsis [30], the occurrence of ICU-acquired HSVE is very rare [31] and its reality has even been challenged [32]. It is therefore likely that steroids played a key role in our patient even though a causal link with HSVE cannot be proven. Another concern specific to critically ill patients is that alarming neurological signs associated with HSVE may be missed in sedated, mechanically ventilated patients, which could cause delayed diagnosis and increased mortality. From that perspective, implementing daily interruption of sedation in these patients, which has been associated with better outcomes in randomized control trials [33,34], might also allow earlier detection of alarming signs, earlier diagnosis of HSVE, and improved outcome. The presence of fever, reported in 80–90% of patients with HSVE [35], should prompt a lumbar puncture when it is unexplained and associated with persistent altered mental status during sedation interruptions in immunocom-promised patients.\n\nThe fact that our patient also developed a C. parapsilosis fungemia after steroid administration further suggests significant immunosuppression. The patient had several risk factors for candidemia (age, mechanical ventilation, central venous catheter, broad-spectrum antibiotics) [36], and whether steroids may have acted as an independent risk factor remains unclear given previous conflicting results [37,38]. The patient developed candidemia and HSVE a few days apart; the coexistence of HSVE and candidiasis were already reported in 3 HSVE cases by Schiff and Rosenblum [17]. Circulating immune cells of patients with candidemia display a phenotype of immunosuppression with T-cell exhaustion [39], which may have further predisposed our patient to HSVE.\n\nConclusions\n\nIn summary, clinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids in critically ill patients, taking into account factors associated with immuno-suppression. A high level of awareness should be especially maintained for critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.\n\nTable 1. Summary of reported cases of herpes simplex virus meningoencephalitis associated with steroids administration.\n\nAuthor\tYear\tPatient age/sex\tSteroid\tDaily dose, (Prednisone equivalent)\tDuration d\tIndication for steroids\tAssociated risk factors\tHSV-1/2\tLymphopenia\tSurvival\t\nDoherty et al [13]\t2001\t81 y/M\tHydrocortisone\t75 mg\t10\tMyxedema coma\tDirect CNS insult due to myxedema\tN/A\tN/A\tNo\t\nJacobs [8]\t1999\t42 y/F\tDexametha-sone\t50 mg\t30\tBrain metastases (breast)\tWhole brain radiation\tN/A\tN/A\tN/A\t\nJaques et al [9]\t2016\t24 y/M\tDexametha-sone\t50 mg\t8\tBrain tumor\tNeurosurgery\tHSV-1\tN/A\tYes\t\n\t\t53 y/M\tDexametha-sone\t60 mg\t18\tBrain tumor\tNeurosurgery\tHSV-2\tN/A\tYes\t\nTan et al [14]\t2012\t74 y/F\tNot specified\tN/A\tN/A\tPolymyositis\tCyclophosphamide\tN/A\tN/A\tN/A\t\nSermer et al [15]\t2014\t55 y/M\tDexametha-sone\t80 mg\t28\tBrain metastases (lung)\tWhole brain radiation\tHSV-1\tN/A\tYes\t\nBewersdorf et al [16]\t2019\t60 y/F\tPrednisolone\t30 mg\tN/A\tCOPD exacerbation\tIgG deficiency\tHSV-1\tN/A\tYes\t\nSchiff and Rosenblum [17]\t1998\t35 y/F\tDexametha-sone\t120 mg\t21\tCNS lymphoma\tRadiation/neurosurgery\tN/A\tYes\tNo\t\n\t\t24 y/F\tDexametha-sone\t30 mg\t120\tGlioblastoma\tRadiation/neurosurgery/chemotherapy\tHSV-1\tYes\tNo\t\nAlimohamadi et al [6]\t2004\t22 y/F\tPrednisolone\t20 mg\tN/A\tUlcerative colitis\tAzathioprine\tN/A\tNo\tYes\t\nNg et al [24]\t2019\t38 y/F\tNot specified\tN/A\t8\tGlioblastoma\tNeurosurgery\tHSV-1\tNo\tNo\t\nMcLaughlin et al [10]\t2019\t72 y/M\tDexametha-sone\t110 mg\t4\tMeningioma\tNeurosurgery\tHSV-1\tN/A\tYes\t\nOsterman et al [18]\t2020\t48 y/F\tNot specified\tPulse-dose\t5\tSuspected limbic encephalitis\tNone but CSF abnormalities present before steroid administration (HSV PCR negative)\tHSV-1\tN/A\tNo\t\nSilvano et al [19]\t2007\t55 y/M\tDexametha-sone\t50 mg\tN/A\tProphylactic cranial irradiation\tChemotherapy/radiation\tHSV-1\tYes\tNo\t\nRiel-Romero and Baumann [20]\t2003\t15 y/M\tDexametha-sone\t50 mg\tN/A\tGlioma\tTemozolomide/radiation\tHSV-1\tN/A\tN/A\t\nPeng et al [21]\t2007\t61 y/M\tDexametha-sone\t110 mg\t14\tPituitary adenoma\tNeurosurgery/radiation\tN/A\tYes\tYes\t\nWittles et al [12]\t2011\t62 y/F\tPrednisolone\t1 mg/kg/d\t14\tPanuveitis\tAcute retinal necrosis\tN/A\tN/A\tNo\t\nKim et al [11]\t2012\t57 y/M\tMethylpredni-solone\t1250 mg\t5\tRetinal vasculitis\tAcute retinal necrosis\tHSV-1\tN/A\tYes\t\nLizarraga et al [22]\t2013\t32 y/F\tDexametha-sone\t110 mg\t77\tGlomus jugulare paraganglioma\tRadiation\tHSV-1\tN/A\tYes\t\nSaito et al [7]\t2016\t77 y/F\tDexametha-sone\t110 mg\tN/A\tProphylactic antiemetic\tChemotherapy\tHSV-1\tYes\tYes\t\nGraber et al [23]\t2011\t48 y/F\tDexametha-sone\t40 mg\tN/A\tBrain metastases (lung)\tRadiation/chemotherapy\tHSV-2\tNo\tYes\t\n\t\t55 y/M\tDexametha-sone\t80 mg\tN/A\tBrain metastases (melanoma)\tRadiation\tHSV-1\tNo\tNo\t\n\t\t45 y/F\tDexametha-sone\t50 mg\tN/A\tThyroid cancer\tNeurosurgery\tHSV-2\tNo\tNo\t\nCNS – central nervous system; COPD – chronic obstructive pulmonary disease; CSF – cerebrospinal fluid; F – Female; HSV – herpes simplex virus; IgG – immunoglobulin G; M – Male; N/A – not available; PCR – polymerase chain reaction.\n==== Refs\nReferences:\n\n1. Bradshaw MJ Venkatesan A Herpes simplex virus-1 encephalitis in adults: Pathophysiology, diagnosis, and management Neurotherapeutics 2016 13 3 493 508 27106239\n2. Raschilas F Wolff M Delatour F Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: Results of a multicenter study Clin Infect Dis 2002 35 3 254 60 12115090\n3. Li TH Lai CC Wang WH Risk of severe herpes simplex virus infection in systemic lupus erythematosus: Analysis of epidemiology and risk factors analysis in Taiwan Ann Rheum Dis 2019 78 7 941 46 30954968\n4. Baringer JR Klassen T Grumm F Experimental herpes simplex virus encephalitis. Effect of corticosteroids and pyrimidine nucleoside Arch Neurol 1976 33 6 442 46 180935\n5. Thompson KA Blessing WW Wesselingh SL Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal herpes encephalitis J Neurovirol 2000 6 1 25 32 10786994\n6. Alimohamadi SM Malekzadeh R Mirmadjless SH Herpes simplex virus encephalistis during immunosuppressive treatment of ulcerative colitis MedGenMed 2004 6 4 7\n7. Saito M Kiyozaki H Obitsu T Herpes simplex virus-1 encephalitis induced by chemoradiotherapy and steroids in an esophageal cancer patient: A case report BMC Cancer 2016 16 233 26988237\n8. Jacobs DH Herpes simplex virus encephalitis following corticosteroids and cranial irradiation Neurology 1999 52 5 1108 9 10102451\n9. Jaques DA Bagetakou S L’Huillier AG Herpes simplex encephalitis as a complication of neurosurgical procedures: Report of 3 cases and review of the literature Virol J 2016 13 83 27216026\n10. McLaughlin DC Achey RL Geertman R Grossman J Herpes simplex reactivation following neurosurgery: Case report and review of the literature Neurosurg Focus 2019 47 2 E9\n11. Kim SJ Kang SW Joo EY An unusual case of herpes simplex viral encephalitis following acute retinal necrosis after administration of a systemic steroid J Epilepsy Res 2012 2 1 21 24 24649457\n12. Wittles KN Goold LA Gilhotra JS Herpes simplex encephalitis presenting after steroid treatment of panuveitis Med J Aust 2011 195 2 87 88 21770880\n13. Doherty MJ Baxter AB Longstreth WT Jr Herpes simplex virus encephalitis complicating myxedema coma treated with corticosteroids Neurology 2001 56 8 1114 15 11320194\n14. Tan IL McArthur JC Venkatesan A Nath A Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised Neurology 2012 79 21 2125 32 23136265\n15. Sermer DJ Woodley JL Thomas CA Hedlund JA Herpes simplex encephalitis as a complication of whole-brain radiotherapy: A case report and review of the literature Case Rep Oncol 2014 7 3 774 79 25722668\n16. Bewersdorf JP Koedel U Patzig M Challenges in HSV encephalitis: Normocellular CSF, unremarkable CCT, and atypical MRI findings Infection 2019 47 2 267 73 30506479\n17. Schiff D Rosenblum MK Herpes simplex encephalitis (HSE) and the immunocompromised: A clinical and autopsy study of HSE in the settings of cancer and human immunodeficiency virus-type 1 infection Hum Pathol 1998 29 3 215 22 9496822\n18. Osterman A Ruf VC Domingo C Travel-associated neurological disease terminated in a postmortem diagnosed atypical HSV-1 encephalitis after high-dose steroid therapy – a case report BMC Infect Dis 2020 20 1 150 32070282\n19. Silvano G Lazzari G Resta F A herpes simplex virus-1 fatal encephalitis following chemo-radiotherapy, steroids and prophylactic cranial irradiation in a small cell lung cancer patient Lung Cancer 2007 57 2 243 46 17368625\n20. Riel-Romero RM Baumann RJ Herpes simplex encephalitis and radiotherapy Pediatr Neurol 2003 29 1 69 71 13679127\n21. Peng T Blakeley J Cingolani E Herpes simplex encephalitis in a patient with recurrent pituitary adenoma receiving radiation therapy Am J Clin Oncol 2007 30 6 664 65 18091066\n22. Lizarraga KJ Alexandre LC Ramos-Estebanez C Merenda A Are steroids a beneficial adjunctive therapy in the immunosuppressed patient with herpes simplex virus encephalitis? Case Rep Neurol 2013 5 1 52 55 23626565\n23. Graber JJ Rosenblum MK DeAngelis LM Herpes simplex encephalitis in patients with cancer J Neurooncol 2011 105 2 415 21 21637964\n24. Ng S Le Corre M Aloy E Herpes simplex encephalitis shortly after surgery for a secondary glioblastoma: A case report and review of the literature World Neurosurg 2019 129 13 17 31150854\n25. Zisman B Hirsch MS Allison AC Selective effects of anti-macrophage serum, silica and anti-lymphocyte serum on pathogenesis of herpes virus infection of young adult mice J Immunol 1970 104 5 1155 59 4315460\n26. Ng WL Chu CM Wu AK Lymphopenia at presentation is associated with increased risk of infections in patients with systemic lupus erythematosus QJM 2006 99 1 37 47 16371405\n27. Perini P Rinaldi F Puthenparampil M Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient Mult Scler Relat Disord 2018 26 68 70 30227312\n28. Slade JD Hepburn B Prednisone-induced alterations of circulating human lymphocyte subsets J Lab Clin Med 1983 101 3 479 87 6219171\n29. Boomer JS To K Chang KC Immunosuppression in patients who die of sepsis and multiple organ failure JAMA 2011 306 23 2594 605 22187279\n30. Hohlstein P Gussen H Bartneck M Prognostic relevance of altered lymphocyte subpopulations in critical illness and sepsis J Clin Med 2019 8 3 353\n31. Algahtani H Shirah B Hmoud M Subahi A Nosocomial herpes simplex encephalitis: A challenging diagnosis J Infect Public Health 2017 10 3 343 47 27686257\n32. Jouan Y Grammatico-Guillon L Guillon A Nosocomial herpes simplex encephalitis: does it really exist? J Infect Public Health 2018 11 1 142 28209321\n33. Girard TD Kress JP Fuchs BD Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial Lancet 2008 371 9607 126 34 18191684\n34. Kress JP Pohlman AS O’Connor MF Hall JB Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation N Engl J Med 2000 342 20 1471 77 10816184\n35. Whitley RJ Herpes simplex encephalitis: Adolescents and adults Antiviral Res 2006 71 2–3 141 48 16675036\n36. Guery BP Arendrup MC Auzinger G Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis Intensive Care Med 2009 35 1 55 62 18972101\n37. Dimopoulos G Ntziora F Rachiotis G Candida albicans versus nonalbicans intensive care unit-acquired bloodstream infections: differences in risk factors and outcome Anesth Analg 2008 106 2 523 29 18227310\n38. Poissy J Damonti L Bignon A Risk factors for candidemia: A prospective matched case-control study Crit Care 2020 24 1 109 32188500\n39. Spec A Shindo Y Burnham CA T cells from patients with Candida sepsis display a suppressive immunophenotype Crit Care 2016 20 15 26786705\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "22()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000212:Acyclovir; D000368:Aged; D020803:Encephalitis, Herpes Simplex; D018259:Herpesvirus 1, Human; D006801:Humans; D008297:Male; D008590:Meningoencephalitis; D008775:Methylprednisolone", "nlm_unique_id": "101489566", "other_id": null, "pages": "e933847", "pmc": null, "pmid": "34716288", "pubdate": "2021-10-30", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": 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"reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract candidiasis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. American Journal of Case Reports. 2021;22(e933847):1-6", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211129", "receivedate": "20211129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20124988, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" }, { "companynumb": "US-AUROBINDO-AUR-APL-2021-046672", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, 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"1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sarcoidosis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ventricular tachycardia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYGEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Respiratory failure", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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Mullholand JB, Ashraf S, Shore D, Van de Louw A.. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review.. 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Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. American Journal of Case Reports. 2021;22(1):10.12659/AJCR.933847", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211124", "receivedate": "20211116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20074286, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2021JUB00418", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "46 MG/D", "drugenddate": null, "drugenddateformat": null, "drugindication": "Organising pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "46", "drugstructuredosageunit": "003", "drugtreatmentduration": "6", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/D", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Herpes simplex meningoencephalitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A.. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review.. Am J Case Rep. 2021;22(1)", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211119", "receivedate": "20211119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20092192, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-TEVA-2021-US-1982309", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, 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"reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract candidiasis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. 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Herpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review. 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Herpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review. 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"801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. Am-J-Case-Rep 2021;22(1):e933847-1-e933847-6.", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211123", "receivedate": "20211123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20101673, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "Rothia mucilaginosa (R. mucilaginosa), formerly named Stomatococcus mucilaginosus, is a facultatively anaerobic, encapsulated gram-positive coccus, which forms part of the normal oropharyngeal and is rarely considered to be a pathogen in immunocompetent patients, although it can produce, on rare occasions, serious infections like bacteremia, endocarditis and respiratory infections; such as pneumonia, pleural empyema or superinfection of bronchiectasis. We present the case of a 74-year-old male diagnosed with right basal pneumonia of torpid evolution with a poor initial response to different antibiotics, with clinical and radiological worsening and the appearance of bilateral bronchopneumonia with pseudonodular images. R. mucilaginosa in pure culture was isolated in three sputum cultures and in bronchial suction. The patient was finally treated with Linezolid with a good clinical response and normalisation of the thorax radiography, confirming the disappearance of R. mucilaginosa in subsequent sputum cultures. As there are few documented cases of pneumonia due to R. mucilaginosa, we believe that presenting this case will be of interest.", "affiliations": "Hospital Clínico Universitario Lozano Blesa. [email protected].", "authors": "De Escalante Yangüela\|B\|B\|;Gracia Gutiérrez\|A\|A\|;Gracia Tello\|B\|B\|;Alastrué Del Castaño\|V\|V\|;Bueno Juana\|E\|E\|;Algárate Cajo\|S\|S\|", "chemical_list": null, "country": "Spain", "delete": false, "doi": "10.23938/ASSN.0090", "fulltext": null, "fulltext_license": null, "issn_linking": "1137-6627", "issue": "40(3)", "journal": "Anales del sistema sanitario de Navarra", "keywords": null, "medline_ta": "An Sist Sanit Navar", "mesh_terms": "D000368:Aged; D001996:Bronchopneumonia; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D008835:Micrococcaceae", "nlm_unique_id": "9710381", "other_id": null, "pages": "479-483", "pmc": null, "pmid": "29149111", "pubdate": "2017-12-29", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bilateral bronchopneumonia due to Rothia mucilaginosa.", "title_normalized": "bilateral bronchopneumonia due to rothia mucilaginosa" }	[ { "companynumb": "ES-MYLANLABS-2019M1050563", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076276", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE ESCALANTE YANGUELA B, GRACIA GUTIERREZ A, GRACIA TELLO B, ALASTRUE DEL, BUENO JUANA E, ALGARATE CAJO S.. BILATERAL BRONCHOPNEUMONIA DUE TO ROTHIA MUCILAGINOSA", "literaturereference_normalized": "bilateral bronchopneumonia due to rothia mucilaginosa", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190531", "receivedate": "20190531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16379758, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "ES-CIPLA LTD.-2018ES21949", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076890", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE ESCALANTE YANGUELA B, GRACIA GUTIERREZ A, GRACIA TELLO B, ALASTRUE DEL, BUENO JUANA E, ALGARATE CAJO S. BILATERAL BRONCHOPNEUMONIA DUE TO ROTHIA MUCILAGINOSA", "literaturereference_normalized": "bilateral bronchopneumonia due to rothia mucilaginosa", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181024", "receivedate": "20181024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15544361, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "Stevens-Johnson Syndrome (SJS) is a rare but severe dermatological condition that typically occurs after the ingestion of medications such as nonsteroidal drugs, antibiotics, and anticonvulsants. Extracutaneous manifestations of the syndrome can occur and may involve the conjunctiva, trachea, buccal mucosa, gastrointestinal tract, and genitourinary tract. Cholestatic liver disease, which may precede the skin manifestations of SJS, has been reported to occur in SJS, but the medical literature has only 10 case reports describing this phenomenon (1-9). We report the case of a 19-year-old female with SJS and cholestatic liver disease. A discussion of the underlying pathophysiology of SJS and its treatment follows.", "affiliations": "Department of Internal Medicine, Section of General Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.", "authors": "Morelli\|M S\|MS\|;O'Brien\|F X\|FX\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen", "country": "United States", "delete": false, "doi": "10.1023/a:1012351231143", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-2116", "issue": "46(11)", "journal": "Digestive diseases and sciences", "keywords": null, "medline_ta": "Dig Dis Sci", "mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D005260:Female; D006801:Humans; D007052:Ibuprofen; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "7902782", "other_id": null, "pages": "2385-8", "pmc": null, "pmid": "11713940", "pubdate": "2001-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "2064763;8934797;276660;6224935;7477195;7794310", "title": "Stevens-Johnson Syndrome and cholestatic hepatitis.", "title_normalized": "stevens johnson syndrome and cholestatic hepatitis" }	[ { "companynumb": null, "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "72169", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (TWO DAYS, UNSPECIFIED DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Headache", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETOROLAC" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Urinary tract infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cholestasis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cholecystitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malaise", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Scleral discolouration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Conjunctival hyperaemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash papular", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dermatitis bullous", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash macular", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash vesicular", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pain", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Morelli MS, O Brien FX. Stevens-Johnson syndrome and cholestatic hepatitis. DIGESTIVE DISEASES AND SCIENCES. 2001;46:2385-8", "literaturereference_normalized": "stevens johnson syndrome and cholestatic hepatitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220228", "receivedate": "20080325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 6606808, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "IT-ZAMBON-202103375COR", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "208865", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (TWO DAYS, UNSPECIFIED DOSE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Headache", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Urinary tract infection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETOROLAC TROMETHAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETOROLAC" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Morelli MS. Stevens-Johnson syndrome and cholestatic hepatitis. 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN AND TAZOBACTAM" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Morelli MS, O^Brien F. Stevens-Johnson Syndrome and Cholestatic Hepatitis. Digestive Diseases and Sciences. 2001;VOL 46/11:2385 - 2388", "literaturereference_normalized": "stevens johnson syndrome and cholestatic hepatitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220330", "receivedate": "20220316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20601933, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]
{ "abstract": "Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates.\n\n\n\nTo investigate the safety and anti-epileptic effects of intracerebral muscimol infusion into the epileptic focus of patients with DRE.\n\n\n\nIn this phase 1 clinical trial, 3 adult patients with DRE underwent CED into the seizure focus of artificial CSF vehicle followed by muscimol for 12 to 24 h each using a crossover design. Basic pathophysiology of the epileptic focus was examined by assessing the infusions' effects on seizure frequency, electroencephalogram (EEG) spike-wave activity, and power-spectral EEG frequency.\n\n\n\nInter-ictal neurological function remained normal in all patients. Pathological examination of resected specimens showed no infusion-related brain injuries. Seizure frequency decreased in 1 of 3 patients during muscimol infusion but was unchanged in all patients during vehicle infusion. Mean beta frequencies did not differ significantly before, during, or after infusion periods. Infused fluid provided insufficient MRI-signal to track infusate distribution. In the 2 yr after standard epilepsy surgery, 1 patient had temporary reduction in seizure frequency and 2 patients were seizure-free.\n\n\n\nCED of muscimol into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. This study did not confirm that intracerebral muscimol infusion effectively suppressed seizures. A surrogate tracer is recommended to track infusion distribution to the epileptic focus and surrounding structures in future studies using CED to suppress the seizure focus.", "affiliations": "Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.;Electroencephalography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Electroencephalography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.", "authors": "Heiss\|John D\|JD\|;Argersinger\|Davis P\|DP\|;Theodore\|William H\|WH\|;Butman\|John A\|JA\|;Sato\|Susumu\|S\|;Khan\|Omar I\|OI\|", "chemical_list": "D000927:Anticonvulsants; D009118:Muscimol", "country": "United States", "delete": false, "doi": "10.1093/neuros/nyy480", "fulltext": null, "fulltext_license": null, "issn_linking": "0148-396X", "issue": "85(1)", "journal": "Neurosurgery", "keywords": "Convection; epilepsy; epileptic focus; muscimol", "medline_ta": "Neurosurgery", "mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001921:Brain; D018481:Convection; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D057967:Infusions, Intraventricular; D008279:Magnetic Resonance Imaging; D008297:Male; D009118:Muscimol", "nlm_unique_id": "7802914", "other_id": null, "pages": "E4-E15", "pmc": null, "pmid": "30407567", "pubdate": "2019-07-01", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": "16381190;12700290;9396606;10516265;418955;10507396;27995127;9950503;7539062;7278491;16304999;9322847;152602;8304553;17054693;11240604;1449242;2203963;9652621;10443891;24410126;8134351", "title": "Convection-Enhanced Delivery of Muscimol in Patients with Drug-Resistant Epilepsy.", "title_normalized": "convection enhanced delivery of muscimol in patients with drug resistant epilepsy" }	[ { "companynumb": "US-CIPLA LTD.-2019US06433", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IMMUNE GLOBULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RASMUSSEN ENCEPHALITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULINS NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, TID, EXTENDED-RELEASE CAPSULES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM, QD (EVERY MORNING)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, PRN (3 TO 4 TIMES DAILY AS NEEDED)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISS JD, ARGERSINGER DP, THEODORE WH, BUTMAN JA, SATO S, KHAN OI.. CONVECTION-ENHANCED DELIVERY OF MUSCIMOL IN PATIENTS WITH DRUG-RESISTANT EPILEPSY. NEUROSURGERY. 2019?85 (1):E4 TO E15", "literaturereference_normalized": "convection enhanced delivery of muscimol in patients with drug resistant epilepsy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190920", "receivedate": "20190920", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16830639, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-CIPLA LTD.-2019US06434", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISS JD, ARGERSINGER DP, THEODORE WH, BUTMAN JA, SATO S, KHAN OI. CONVECTION-ENHANCED DELIVERY OF MUSCIMOL IN PATIENTS WITH DRUG-RESISTANT EPILEPSY. NEUROSURGERY. 2019?85 (1):E4 TO E15", "literaturereference_normalized": "convection enhanced delivery of muscimol in patients with drug resistant epilepsy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190923", "receivedate": "20190923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16837542, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "West Nile virus infection can pose a diagnostic challenge to clinicians, especially in geographic areas where human cases of this disease have never been encountered before. In August 2016, the first human case of West Nile virus infection was diagnosed in Cyprus. An elderly non immunosuppressed patient with a history of recent travel, presented with a clinical picture of rapidly progressing ascending paralysis mimicking Guillain-Barré syndrome. Neuroinvasive West Nile virus disease was diagnosed by detecting West Nile virus nucleic acid in the patient's cerebrospinal fluid. Public health measures were taken raising awareness regarding this disease and its prevention. Clinical vigilance to consider West Nile virus as a possible emerging pathogen in the appropriate clinical setting is warranted and could benefit individual patients.", "affiliations": "Nicosia General Hospital Intensive Care Clinic, Nicosia, Cyprus. Electronic address: [email protected].;Nicosia General Hospital Intensive Care Clinic, Nicosia, Cyprus. Electronic address: [email protected].;Nicosia General Hospital Intensive Care Clinic, Nicosia, Cyprus; Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].;Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].;Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].;Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].", "authors": "Paphitou\|Niki I\|NI\|;Tourvas\|Aristomenis\|A\|;Floridou\|Dora\|D\|;Richter\|Jan\|J\|;Tryfonos\|Christina\|C\|;Christodoulou\|Christina\|C\|", "chemical_list": "D012367:RNA, Viral", "country": "England", "delete": false, "doi": "10.1016/j.jiph.2017.02.003", "fulltext": null, "fulltext_license": null, "issn_linking": "1876-0341", "issue": "10(6)", "journal": "Journal of infection and public health", "keywords": "Cyprus; Emerging diseases; Neuroinvasive disease; Public health; West Nile virus", "medline_ta": "J Infect Public Health", "mesh_terms": "D000368:Aged; D002555:Cerebrospinal Fluid; D003535:Cyprus; D006801:Humans; D008297:Male; D012367:RNA, Viral; D014901:West Nile Fever; D014902:West Nile virus", "nlm_unique_id": "101487384", "other_id": null, "pages": "891-893", "pmc": null, "pmid": "28233724", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The first human case of neuroinvasive West Nile virus infection identified in Cyprus.", "title_normalized": "the first human case of neuroinvasive west nile virus infection identified in cyprus" }	[ { "companynumb": "CY-BAUSCH-BL-2017-032379", "fulfillexpeditecriteria": "1", "occurcountry": "CY", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GUILLAIN-BARRE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "018604", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GUILLAIN-BARRE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMPICILLIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GUILLAIN-BARRE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PAPHITOU N, TOURVAS A, FLORIDOU D, RICHTER J, TRYFONOS C, CHRISTODOULOU C. THE FIRST HUMAN CASE OF NEUROINVASIVE WEST NILE VIRUS INFECTION IDENTIFIED IN CYPRUS. JOURNAL OF INFECTION AND PUBLIC HEALTH. 2017;10(6):891-893.", "literaturereference_normalized": "the first human case of neuroinvasive west nile virus infection identified in cyprus", "qualification": "3", "reportercountry": "CY" }, "primarysourcecountry": "CY", "receiptdate": "20171128", "receivedate": "20171128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14232746, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "CY-GLAXOSMITHKLINE-CY2017180284", "fulfillexpeditecriteria": "1", "occurcountry": "CY", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "018603", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GUILLAIN-BARRE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GUILLAIN-BARRE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPICILLIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GUILLAIN-BARRE SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMPICILLIN" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PAPHITOU NI, TOURVAS A, FLORIDOU D, RICHTER J, TRYFONOS C, CHRISTODOULOU C. THE FIRST HUMAN CASE OF NEUROINVASIVE WEST NILE VIRUS INFECTION IDENTIFIED IN CYPRUS. JOURNAL OF INFECTION AND PUBLIC HEALTH. 2017; 10(6):891-893. DOI: 10.1016/J.JIPH.2017.02.003", "literaturereference_normalized": "the first human case of neuroinvasive west nile virus infection identified in cyprus", "qualification": "3", "reportercountry": "CY" }, "primarysourcecountry": "CY", "receiptdate": "20171127", "receivedate": "20171127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14226546, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180321" } ]
{ "abstract": "BACKGROUND\nPseudoaneurysm, the most common complication of femoral artery catheterization, involves the formation of a space between the lumen and the surrounding fibrous tissue through the damaged arterial wall. In patients treated with antiplatelet and anticoagulant agents, the incidence of vascular complications increases with the increasing use of minimally invasive procedures.\nWe experienced 2 cases of procedure-induced pseudoaneurysms. A 79-year-old man with right hemiparesis visited our hospital. Brain magnetic resonance imaging showed acute left middle cerebral artery territory infarction and severe stenosis of the left proximal carotid artery. The patient was prescribed apixaban and underwent carotid stenting through the right femoral artery. Hematoma and tenderness were observed in the right inguinal region after the procedure. The hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL. Another 78-year-old man with left common carotid artery stenosis was admitted. We performed stent implantation through the right femoral artery and administered aspirin and clopidogrel. After the procedure, hematoma and tenderness of the puncture site were observed. The hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL.\n\n\nMETHODS\nEmergency computed tomography confirmed a pseudoaneurysm with a massive hematoma in the right inguinal area. The patients were diagnosed with infection-associated right pseudoaneurysm for which an emergency puncture site repair was performed.\n\n\nMETHODS\nWe performed resection of pseudoaneurysm and repaired puncture site.\n\n\nRESULTS\nThe hemoglobin level was stabilized postoperatively and vital sign remained stable.\n\n\nCONCLUSIONS\nPseudoaneurysm is an important complication of femoral artery puncture. The use of a hemostatic device was not superior to manual compression, and the incidence of this complication was significantly higher in patients who received anticoagulant or antiplatelet agents. A pseudoaneurysm may cause a bad prognosis. Therefore, the early detection of pseudoaneurysm and immediate treatment after femoral arterial puncture are needed.", "affiliations": "Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.", "authors": "Jeon\|Seung-Ho\|SH\|;Kang\|Hyun Goo\|HG\|;Kim\|Hong-Jin\|HJ\|;Seo\|Man-Wook\|MW\|;Shin\|Byoung-Soo\|BS\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000015309", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31027097MD-D-18-0861510.1097/MD.0000000000015309153095300Research ArticleClinical Case ReportFemoral artery pseudoaneurysm after carotid artery stenting Two case reportsJeon Seung-Ho MDaKang Hyun Goo MD, PhDabKim Hong-Jin MDaSeo Man-Wook MD, PhDabShin Byoung-Soo MD, PhDab∗NA. a Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonjub Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Chonbuk, Republic of Korea.∗ Correspondence: Byoung-Soo Shin, Department of Neurology, Chonbuk National University Medical School and Hospital, 20, Geonji-ro, Jeonju, Chonbuk, 54907, Republic of Korea (e-mail: [email protected]).4 2019 26 4 2019 98 17 e1530928 11 2018 13 3 2019 25 3 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nPseudoaneurysm, the most common complication of femoral artery catheterization, involves the formation of a space between the lumen and the surrounding fibrous tissue through the damaged arterial wall. In patients treated with antiplatelet and anticoagulant agents, the incidence of vascular complications increases with the increasing use of minimally invasive procedures.\n\nPatient concerns:\nWe experienced 2 cases of procedure-induced pseudoaneurysms. A 79-year-old man with right hemiparesis visited our hospital. Brain magnetic resonance imaging showed acute left middle cerebral artery territory infarction and severe stenosis of the left proximal carotid artery. The patient was prescribed apixaban and underwent carotid stenting through the right femoral artery. Hematoma and tenderness were observed in the right inguinal region after the procedure. The hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL. Another 78-year-old man with left common carotid artery stenosis was admitted. We performed stent implantation through the right femoral artery and administered aspirin and clopidogrel. After the procedure, hematoma and tenderness of the puncture site were observed. The hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL.\n\nDiagnosis:\nEmergency computed tomography confirmed a pseudoaneurysm with a massive hematoma in the right inguinal area. The patients were diagnosed with infection-associated right pseudoaneurysm for which an emergency puncture site repair was performed.\n\nInterventions:\nWe performed resection of pseudoaneurysm and repaired puncture site.\n\nOutcomes:\nThe hemoglobin level was stabilized postoperatively and vital sign remained stable.\n\nLessons:\nPseudoaneurysm is an important complication of femoral artery puncture. The use of a hemostatic device was not superior to manual compression, and the incidence of this complication was significantly higher in patients who received anticoagulant or antiplatelet agents. A pseudoaneurysm may cause a bad prognosis. Therefore, the early detection of pseudoaneurysm and immediate treatment after femoral arterial puncture are needed.\n\nKeywords\nangiographyclosure devicepseudoaneurysmstentOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nA pseudoaneurysm, the most common complication caused by femoral artery catheter insertion, occurs when a space forms between the blood vessel lumen and the surrounding fibrous tissue through the damaged artery wall.[1] The occurrence of local vascular complications due to a surgical procedure has recently increased with the use of an antiplatelet or anticoagulant along with femoral artery catheter insertion.[2] In particular, pseudoaneurysm frequently occurs at the puncture site below the head of the femur due to insufficient bone support resulting in angiopressure after catheter removal.[3] However, to our knowledge, only a few studies have reported local complications after cerebral angiography. Here we describe 2 cases of femoral artery pseudoaneurysm after cerebral angiography and a review of the relevant literature.\n\n2 Case presentation\n2.1 Case 1\nA 79-year-old man visited our clinic with a 3-day history of weakness of the right hand. He was taking medication for chronic obstructive pulmonary disease. However, he had no hypertension or diabetes and did not smoke. A neurological examination showed no abnormalities except for weakness in the distal portion of the right upper extremity (Medical Research Council Grade 4+). At the time of the visit, his National Institutes of Health Stroke Scale score was 1 point. Acute cerebral infarction was observed in the left middle cerebral artery territory on brain magnetic resonance imaging (MRI). Moreover, severe stenosis was found in the left proximal internal carotid artery on brain magnetic resonance angiography (MRA). In addition, atrial fibrillation was observed on echocardiography performed during the visit. The patient was prescribed apixaban 10 mg/day and underwent balloon angioplasty and carotid artery stent insertion through the right femoral artery. Moreover, puncture site closure was conducted using an Angio-seal closure device.\n\nThe second day after the procedure, hematoma accompanying ecchymosis and tenderness was observed in the right inguinal area. Although the patient's vital signs were stable, his hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL before the surgical procedure. Emergent computed tomography (CT) was performed to identify the cause of the hemoglobin decrease after a fluid infusion and blood transfusion. We confirmed the presence of pseudoaneurysm accompanying a massive hematoma in the right inguinal area (Fig. 1A, B). After pseudoaneurysm removal and puncture site restoration surgery, the vital signs remained stable and the hemoglobin level normalized.\n\nFigure 1 Axial view and angiography of contrast-enhanced computed tomography with right femoral pseudoaneurysm in 2 patients. (Case 1—A and B. Case 2—C and D) Hematoma (H) and pseudoaneurysm (P) communicate with the right common femoral artery through a pseudoaneurysm neck (N). The white arrow indicated a pseudoaneurysm (P) which is communicated with right common femoral artery.\n\n2.2 Case 2\nA 78-year-old man visited our hospital with stenosis of the left common carotid artery detected on brain MRA during a health check examination. The patient was already on antiplatelet treatment and no abnormalities were found in a neurological examination. Although there were no specific findings on brain MRI, the MRA results showed severe stenosis of the left common carotid artery. The patient was administered aspirin 100 mg/day and clopidogrel 75 mg/day and underwent balloon angioplasty and carotid artery stent insertion through the right femoral artery. Moreover, the puncture site was closed using an MYNXGRIP closure device.\n\nThe patient's vital signs and neurological symptoms were stable after the procedure. However, a mild fever (38.2°C) and hematoma accompanying puncture site tenderness were observed the day after the procedure. A laboratory test showed that the hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL. Moreover, the emergent CT revealed that pseudoaneurysm occurred in the right femoral artery (Fig. 1C, D). The patient was diagnosed with an infection-associated pseudoaneurysm for which an emergent pseudoaneurysm resection and puncture site reconstruction were performed. The patient was stable afterward and then discharged.\n\n3 Discussion\nBoth patients described here experienced pseudoaneurysm accompanying an acute hemoglobin level decrease after undergoing cerebral angiography through the femoral artery while taking anticoagulant or antiplatelet agents. We conducted further evaluations of suspected pseudoaneurysm due to the hematoma accompanying the tenderness that expanded in the inguinal area after the femoral artery catheter insertion.\n\nWhen a hematoma accompanying tenderness while the vibration thrill of the femoral artery is felt or bruit is auscultated, further evaluations of pseudoaneurysm should be performed.[3] Color Doppler ultrasonography, the most common test, is used to confirm the presence of a communicating tract and pseudoaneurysm number and size. When a pseudoaneurysm is large, its location and size can be identified more precisely using contrast-enhanced CT or MRI.[4] It was difficult to conduct ultrasounds for these patients due to severe tenderness at the hematoma site, decrease in hemoglobin level, and rapidly expanding hematoma. Therefore, contrast-enhanced CT was conducted immediately.\n\nThe treatment of pseudoaneurysm may vary depending on its size and symptoms. A pseudoaneurysm <2 cm in diameter that is not expanding can be treated conservatively. Among conservative treatments, ultrasound-guided compression repair (UGCR) can be the first option. A thrombus in the pseudoaneurysm lumen compresses the pseudoaneurysm neck and blocks the blood flow. If UGCR fails, embolization, in which thrombin or multiple small coils are injected into the aneurysm neck, is performed.[5] Surgical treatment can be considered when infection, rapid swelling, non-surgical treatment failure, skin necrosis, compression syndrome such as neuropathy, or claudication occurs.[6] Simple wound suturing after hematoma removal may be sufficient, while surgical reconstruction with a patch can be added as needed.[7] In these cases, conservative treatments such as compression using ultrasonography or a simple procedure could not be conducted due to severe pain and they needed emergency operations because of the rapid hematoma expansion, an abrupt decrease in hemoglobin, and symptoms of infection such as fever.\n\nThe use of an arterial puncture closure device such as the MYNXGRIP compared to manual compression did not affect the occurrence of complications. However, the occurrence of pseudoaneurysm was significantly higher for patients taking anticoagulant or antiplatelet agents.[8] Similarly, our patients’ bleeding was controlled using a hemostasis device while they were taking medications and a pseudoaneurysm occurred. This result suggests that it a future large-scale systematic prospective study of the effects and abnormal responses of a hemostasis device on patients taking anticoagulant or antiplatelet agents will be necessary.\n\nPseudoaneurysm is an important complication of femoral artery puncture that may lead to a poor prognosis for patients such as hematoma and infection. If a patient takes anticoagulant or antiplatelet agents, such as in our cases, it will be necessary to control bleeding using sufficient pressure for a sufficient time after femoral artery puncture. Moreover, it is important to identify the pseudoaneurysm as soon as possible by observing the patient carefully and continuously. Additionally, physicians must pay enough attention to these patients. For example, it is recommended that the hematoma development, puncture site, and fever be checked periodically. Thus, if a pseudoaneurysm is suspected, active treatment such as an emergency operation can be performed efficiently.\n\nAuthor contributions\nConceptualization: Seung-Ho Jeon, Hyun Goo Kang, Hong-Jin Kim, Man-Wook Seo, Byoung-Soo Shin.\n\nFormal analysis: Byoung-Soo Shin.\n\nFunding acquisition: Hyun Goo Kang.\n\nInvestigation: Seung-Ho Jeon.\n\nMethodology: Seung-Ho Jeon, Hyun Goo Kang, Hong-Jin Kim, Man-Wook Seo.\n\nSupervision: Hyun Goo Kang, Byoung-Soo Shin.\n\nWriting – original draft: Seung-Ho Jeon, Hyun Goo Kang, Byoung-Soo Shin.\n\nAbbreviations: CT = computed tomography, MRA = magnetic resonance angiography, MRI = magnetic resonance imaging, UGCR = ultrasound-guided compression repair.\n\nS-HJ and HGK contributed equally to this work.\n\nThe patients have given their consents for this case report.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nAll data and material supporting our findings are contained within the manuscript.\n\nFunding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, NRF-2017R1C1B5017293).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Baird R Doran M \nThe false aneurysm . Canad Med Assoc J \n1964 ;91 :281 –4 .14180533 \n[2] Morgan R Belli A-M \nCurrent treatment methods for postcatheterization pseudoaneurysms . J Vasc Interv Radiol \n2003 ;14 :697 –710 .12817037 \n[3] Gupta P Basheer A Sukumaran G \nFemoral artery pseudoaneurysm as a complication of angioplasty. How can it be prevented . Heart Asia \n2013 ;5 :144 –7 .27326111 \n[4] Ouriel K DeWeese JA \nManagement of peripheral arterial aneurysms. Vascular Surgery . 5th ed. 1994 ;Boston, MA : Springer , 377–383 .\n[5] Kang SS Labropoulos N Mansour MA \nPercutaneous ultrasound guided thrombin injection: a new method for treating postcatheterization femoral pseudoaneurysms . J Vasc Surg \n1998 ;27 :1032 –8 .9652465 \n[6] Webber GW Jang J Gustavson S \nContemporary management of postcatheterization pseudoaneurysms . Circulation \n2007 ;115 :2666 –74 .17515479 \n[7] Tisi PV Callam MJ \nSurgery versus non-surgical treatment for femoral pseudoaneurysms . Cochrane Database Syst Rev \n2009 ;2 :CD004981 .19370614 \n[8] Piedad BT Kronzon I \nIatrogenic femoral artery pseudoaneurysm . Curr Treat Options Cardiovasc Med \n2003 ;5 :103 –8 .12686007\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0025-7974", "issue": "98(17)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D017536:Carotid Artery, Common; D002404:Catheterization; D005263:Femoral Artery; D006801:Humans; D008297:Male; D015607:Stents", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e15309", "pmc": null, "pmid": "31027097", "pubdate": "2019-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Femoral artery pseudoaneurysm after carotid artery stenting: Two case reports.", "title_normalized": "femoral artery pseudoaneurysm after carotid artery stenting two case reports" }	[ { "companynumb": "KR-ACCORD-125900", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202925", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vascular pseudoaneurysm", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vessel puncture site haematoma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JEON SH, KANG HG, KIM HJ, SEO MW, SHIN BS. FEMORAL ARTERY PSEUDOANEURYSM AFTER CAROTID ARTERY STENTING: TWO CASE REPORTS. MEDICINE (BALTIMORE). 2019 APR?98(17):E15309.", "literaturereference_normalized": "femoral artery pseudoaneurysm after carotid artery stenting two case reports", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20190506", "receivedate": "20190506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16274558, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]
{ "abstract": "We present a rare case of infantile pyoderma gangrenosum with an extended course and limited response to treatment. Despite extensive examination for an underlying disorder, the case remains idiopathic.", "affiliations": "Jefferson Medical College, Philadelphia, PA.", "authors": "Etzler\|Chloe\|C\|;Cannon\|Sarah\|S\|;Hyde\|Patrice\|P\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1111/pde.12318", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "32(1)", "journal": "Pediatric dermatology", "keywords": null, "medline_ta": "Pediatr Dermatol", "mesh_terms": "D004351:Drug Resistance; D005260:Female; D006801:Humans; D007223:Infant; D017511:Pyoderma Gangrenosum", "nlm_unique_id": "8406799", "other_id": null, "pages": "156-7", "pmc": null, "pmid": "24894462", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Refractory pyoderma gangrenosum in an infant.", "title_normalized": "refractory pyoderma gangrenosum in an infant" }	[ { "companynumb": "US-JNJFOC-20150208978", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYODERMA GANGRENOSUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "2", "patientonsetage": "10", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyoderma gangrenosum", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ETZLER C, CANNON S, HYDE P. REFRACTORY PYODERMA GANGRENOSUM IN AN INFANT. PEDIATRIC DERMATOLOGY 2015;32/1:156-157.", "literaturereference_normalized": "refractory pyoderma gangrenosum in an infant", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150218", "receivedate": "20150218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10815114, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]
{ "abstract": "Objectives: Acute kidney injury (AKI) at onset of adult systemic lupus erythematosus (SLE) is a risk factor for end stage kidney disease (ESKD). However, data on childhood-onset lupus nephritis (LN) with AKI are scarce.Methods: We retrospectively reviewed the complete files of pediatric SLE patients from 1995 to 2010. All patients underwent kidney biopsy promptly after diagnosis.Results: Thirty-six patients (10 males and 26 females) were enrolled. Mean age at diagnosis and observation period were 11.6 ± 2.4 and 8.1 ± 4.4 years, respectively. Seven patients had AKI at onset of SLE. Compared with those without AKI, patients with AKI had significantly higher proportions of pathologically proliferative LN. Only one patient with AKI progressed to ESKD without complete recovery of renal function. Overall and renal survival rates were 100and 97.2%, respectively. There was no significant difference in estimated glomerular filtration rate at the final visit (85ml/min/1.73 m2 in the AKI group vs. 103.2 ml/min/1.73 m2 in the non-AKI group; p = .11).Conclusion: Our study demonstrated favorable renal outcomes in childhood-onset LN with AKI in the near to midterm period. Inducing complete remission may be important for preserving renal function.", "affiliations": "Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.;Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.;Department of Pediatrics, Kakogawa Central City Hospital, Hyogo, Japan.;Department of Pediatrics, Himeji Red-Cross Hospital, Hyogo, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.;Department of Pediatrics, Ryukyu University Graduate School of Medicine, Okinawa, Japan.;Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, Hyogo, Japan.;Clinical Research Center, Wakayama Medical University, Wakayama, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.", "authors": "Ishimori\|Shingo\|S\|;Kaito\|Hiroshi\|H\|;Shima\|Yuko\|Y\|;Kamioka\|Ichiro\|I\|;Hamahira\|Kiyoshi\|K\|;Nozu\|Kandai\|K\|;Nakanishi\|Koichi\|K\|;Tanaka\|Ryojiro\|R\|;Yoshikawa\|Norishige\|N\|;Iijima\|Kazumoto\|K\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/14397595.2018.1532861", "fulltext": null, "fulltext_license": null, "issn_linking": "1439-7595", "issue": "29(6)", "journal": "Modern rheumatology", "keywords": "Acute kidney injury; childhood-onset; lupus nephritis; renal prognosis; systemic lupus erythematosus", "medline_ta": "Mod Rheumatol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008181:Lupus Nephritis; D008297:Male; D012307:Risk Factors; D015996:Survival Rate", "nlm_unique_id": "100959226", "other_id": null, "pages": "970-976", "pmc": null, "pmid": "30289013", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Clinicopathological characteristics and renal outcomes of childhood-onset lupus nephritis with acute kidney injury: A multicenter study.", "title_normalized": "clinicopathological characteristics and renal outcomes of childhood onset lupus nephritis with acute kidney injury a multicenter study" }	[ { "companynumb": "NVSC2019JP070016", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40194", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Systemic lupus erythematosus", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ISHIMORI S,KAITO H,SHIMA Y,KAMIOKA I,HAMAHIRA K,NOZU K ET AL.. CLINICOPATHOLOGICAL CHARACTERISTICS AND RENAL OUTCOMES OF CHILDHOOD-ONSET LUPUS NEPHRITIS WITH ACUTE KIDNEY INJURY: A MULTICENTER STUDY. MODERN RHEUMATOLOGY. 2019?29(6):970-6", "literaturereference_normalized": "clinicopathological characteristics and renal outcomes of childhood onset lupus nephritis with acute kidney injury a multicenter study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20191216", "receivedate": "20191216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17159562, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "JP-MYLANLABS-2019M1123620", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIZORIBINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIZORIBINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ISHIMORI S, KAITO H, SHIMA Y, KAMIOKA I, HAMAHIRA K, NOZU K, ET AL. CLINICOPATHOLOGICAL CHARACTERISTICS AND RENAL OUTCOMES OF CHILDHOOD-ONSET LUPUS NEPHRITIS WITH ACUTE KIDNEY INJURY: A MULTICENTER STUDY. MOD-RHEUMATOL 2019?29(6):970-976.. 2019?29(6):970-976", "literaturereference_normalized": "clinicopathological characteristics and renal outcomes of childhood onset lupus nephritis with acute kidney injury a multicenter study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20191213", "receivedate": "20191213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17151355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "OBJECTIVE\nTo address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea.\n\n\nMETHODS\nFrom May 2005 to May 2007, cases of DILI (alanine transferase > 3 × upper normal limit or total bilirubin > 2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used.\n\n\nRESULTS\nA total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included \"herbal medications\" (102, 27.5%), \"prescription or non-prescription medications\" (101, 27.3%), \"health foods or dietary supplements\" (51, 13.7%), \"medicinal herbs or plants\" (35, 9.4%), \"folk remedies\" (32, 8.6%), \"combined\" (30, 8.2%), \"herbal preparations\" (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hy's law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM.\n\n\nCONCLUSIONS\nDILI appears to be a highly relevant health problem in Korea. \"Herbal medications\" are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.", "affiliations": "Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea.", "authors": "Suk\|Ki Tae\|KT\|;Kim\|Dong Joon\|DJ\|;Kim\|Chang Hoon\|CH\|;Park\|Seung Ha\|SH\|;Yoon\|Jai Hoon\|JH\|;Kim\|Yeon Soo\|YS\|;Baik\|Gwang Ho\|GH\|;Kim\|Jin Bong\|JB\|;Kweon\|Young Oh\|YO\|;Kim\|Byung Ik\|BI\|;Kim\|Seok Hyun\|SH\|;Kim\|In Hee\|IH\|;Kim\|Ju Hyun\|JH\|;Nam\|Soon Woo\|SW\|;Paik\|Yong Han\|YH\|;Suh\|Jeong Ill\|JI\|;Sohn\|Joo Hyun\|JH\|;Ahn\|Byung Min\|BM\|;Um\|Soon Ho\|SH\|;Lee\|Heon Ju\|HJ\|;Cho\|Mong\|M\|;Jang\|Myoung Kuk\|MK\|;Choi\|Sung Kyu\|SK\|;Hwang\|Seong Gyu\|SG\|;Sung\|Ho Taik\|HT\|;Choi\|Jong Young\|JY\|;Han\|Kwang Hyub\|KH\|", "chemical_list": "D004365:Drugs, Chinese Herbal; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1038/ajg.2012.138", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9270", "issue": "107(9)", "journal": "The American journal of gastroenterology", "keywords": null, "medline_ta": "Am J Gastroenterol", "mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000368:Aged; D056486:Chemical and Drug Induced Liver Injury; D004365:Drugs, Chinese Herbal; D005260:Female; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D063487:Prescription Drug Misuse; D015995:Prevalence; D011446:Prospective Studies; D056910:Republic of Korea", "nlm_unique_id": "0421030", "other_id": null, "pages": "1380-7", "pmc": null, "pmid": "22733303", "pubdate": "2012-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A prospective nationwide study of drug-induced liver injury in Korea.", "title_normalized": "a prospective nationwide study of drug induced liver injury in korea" }	[ { "companynumb": "KR-JNJFOC-20120908845", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWN MEDICATION" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "MORE THAN 4 GM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SUK KT, KIM DJ, KIM CH, PARK SH, YOON JH, KIM YS, ET AL. A PROSPECTIVE NATIONWIDE STUDY OF DRUG-INDUCED LIVER INJURY IN KOREA. THE AMERICAN JOURNAL OF GASTROENTEROLOGY SEP-2012;107:1380-1387.", "literaturereference_normalized": "a prospective nationwide study of drug induced liver injury in korea", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20150605", "receivedate": "20120927", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8812007, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "The world is facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although kidney transplant recipients are at increased risk for viral infections, the impact of their chronic immunosuppressed status on the risk for acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown.\nAll cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management, and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mammalian target of rapamycin inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients.\n22 COVID-19 infections were diagnosed in our cohort of 1,200 kidney transplant recipients.\nMost common initial symptoms included fever, cough, or dyspnea. 18 (82%) patients required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Computed tomography of the chest at admission (performed in 15 patients) showed mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. 11 patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non-ICU units, 1 was in the ICU, and 2 patients had died.\nSmall sample size and short follow-up.\nThe clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19 infection.", "affiliations": "Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.", "authors": "Devresse\|Arnaud\|A\|;Belkhir\|Leila\|L\|;Vo\|Bernard\|B\|;Ghaye\|Benoit\|B\|;Scohy\|Anaïs\|A\|;Kabamba\|Benoit\|B\|;Goffin\|Eric\|E\|;De Greef\|Julien\|J\|;Mourad\|Michel\|M\|;De Meyer\|Martine\|M\|;Yombi\|Jean-Cyr\|JC\|;Kanaan\|Nada\|N\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.xkme.2020.06.001", "fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595\nElsevier\n\nS2590-0595(20)30112-6\n10.1016/j.xkme.2020.06.001\nOriginal Research\nCOVID-19 Infection in Kidney Transplant Recipients: A Single-Center Case Series of 22 Cases From Belgium\nDevresse Arnaud 1\nBelkhir Leila 2\nVo Bernard 1\nGhaye Benoit 3\nScohy Anaïs 4\nKabamba Benoit 4\nGoffin Eric 1\nDe Greef Julien 2\nMourad Michel 5\nDe Meyer Martine 5\nYombi Jean-Cyr 4\nKanaan Nada [email protected]\n1∗\n1 Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n2 Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n3 Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n4 Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n5 Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n∗ Address for Correspondence: Nada Kanaan, MD, MSc, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, 1200 Brussels, Belgium. [email protected]\n15 6 2020\nJul-Aug 2020\n15 6 2020\n2 4 459466\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nRationale & Objective\n\nThe world is facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although kidney transplant recipients are at increased risk for viral infections, the impact of their chronic immunosuppressed status on the risk for acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown.\n\nStudy Design\n\nAll cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management, and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mammalian target of rapamycin inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients.\n\nSetting & Participants\n\n22 COVID-19 infections were diagnosed in our cohort of 1,200 kidney transplant recipients.\n\nResults\n\nMost common initial symptoms included fever, cough, or dyspnea. 18 (82%) patients required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Computed tomography of the chest at admission (performed in 15 patients) showed mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. 11 patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non-ICU units, 1 was in the ICU, and 2 patients had died.\n\nLimitations\n\nSmall sample size and short follow-up.\n\nConclusions\n\nThe clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19 infection.\n\nIndex Words\n\nCOVID-19\ncoronavirus disease 2019\nSars-CoV-2 virus\nkidney transplantation\nimmunosuppression\noutcomes\n==== Body\nPlain-Language Summary\n\nSpecific questions arise for kidney transplant recipients who are facing coronavirus disease 2019 (COVID-19) infection. As with other infections, the risk for acquiring COVID-19 might be increased due to the chronic state of immunosuppression. Also, the disease could present with increased severity with eventually poor outcome. Moreover, handling immunosuppression in that context can be challenging. We report our experience with 22 kidney transplant recipients followed up at our academic center in Belgium, in whom we applied a standard strategy of immunosuppression minimization and treatment. Clinical symptoms were similar to those reported in the general population. Among kidney transplant recipients hospitalized with COVID-19 infection, 11% died. Our study expands the knowledge base of COVID-19 infection in kidney transplant recipients.\n\nSince the first case was diagnosed in Wuhan, China, in December 2019, the world has faced a rapidly growing outbreak of a newly discovered contagious infectious disease: coronavirus disease 2019 (COVID-19). COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and primarily manifests as an acute respiratory illness with interstitial and alveolar pneumonia, but can affect multiple organs, such as heart, kidney, digestive tract, blood, and central nervous system.1 As of April 18, 2020, a total of 2,338,335 cases of COVID-19 infection have been confirmed in more than 185 countries and territories and at least 161,030 deaths have been reported to date.2\n\nIn Belgium, the first case of COVID-19 infection in the general population was diagnosed on February 4, 2020. To date, more than 42,000 cases have been reported, including more than 12,000 hospitalizations.3\n\nSpecific questions arise for transplant recipients who are facing COVID-19 infection. As with other infections, could the risk for acquiring COVID-19 be increased due to the chronic state of immunosuppression? Will the infection be more severe than in patients with normal immunity? Moreover, how should immunosuppressive therapy be handled in that context?\n\nCase reports of COVID-19 infection in kidney transplant recipients4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and limited case series14, 15, 16 with a small number of patients have been published to date. In this study, we report 22 COVID-19 disease cases among our cohort that currently includes 1,200 kidney transplant recipients followed up in our academic institution in Belgium.\n\nMethods\n\nPatient Selection\n\nBefore the outbreak onset, about 1,200 kidney transplant recipients who underwent transplantation and were followed up in our hospital in collaboration with peripheral centers were recorded in our database as alive with a functioning graft. Since the first case of COVID-19 infection was diagnosed in Belgium, we have been prospectively monitoring all cases of proven COVID-19 infection in our cohort of kidney transplant recipients followed up in our academic center. Colleagues from peripheral centers with whom we share routine follow-up and managerial decisions of patients were invited by mail to report on all their patients with COVID-19 infection. To date, 22 kidney transplant recipients have been diagnosed with COVID-19 infection (n = 14 in our transplantation center and n = 8 in peripheral centers). Clinical features, management, and outcomes were recorded.\n\nThe study was approved by the local ethics committee (Comité d'Ethique Hospitalo-Facultaire Saint-Luc- Brussels-Belgium; approval number: B 403). The need for informed consent was waived due to deidentified information.\n\nImpact of COVID-19 on Daily Transplantation Activities\n\nSince the onset of the COVID-19 outbreak in Belgium, daily transplantation activities have been severely affected in the whole country. Kidney transplantation is considered only in patients with “high-urgency” status (ie, imminent lack of access for dialysis or psychiatric contraindication to dialysis) or in hypersensitized patients on the waiting list for more than 5 years. In our center, no kidney transplantations have been performed since March 1, 2020. The activity of the outpatient clinic has also been dramatically reduced. Patients were advised very early to stay at home, avoid public transportation and unnecessary contact, and report every symptom before coming to the outpatient clinic. The vast majority of consultations are made by telephone and patients are asked to come in our center only if they underwent transplantation less than 6 months ago or if they have an unstable clinical situation (increase in serum creatinine level, new-onset proteinuria,…), or newly developed symptoms. In case of COVID-19 infection suspicion, patients were sent to a dedicated COVID unit at the emergency department.\n\nDiagnosis\n\nAll kidney transplant recipients presenting symptoms compatible with COVID-19 infection were tested and fully evaluated by a physician (clinical evaluation, chest x-ray, and/or pulmonary computed tomography [CT] and nasopharyngeal swab for reverse-transcriptase polymerase chain reaction [PCR] laboratory test). The laboratory diagnosis of SARS-CoV-2 infection was confirmed by using the Coronavirus COVID-19 genesig Real-Time PCR assay (Primerdesign Ltd) on a nasopharyngeal swab, targeting the RNA-dependent RNA polymerase (RdRp) gene. The amplification was performed on the LightCycler 480 instrument (Roche Diagnostics) according to the manufacturer’s recommendations. A cycle threshold value less than 40 was defined as a positive test.\n\nAssessment of Pulmonary Involvement Using CT\n\nIn patients in whom CT of the chest was performed at admission, the type of lesion and degree of pulmonary parenchyma involvement were reported using the French Society of Radiology classification.17\n\nPulmonary involvement is classified as mild (<10%), moderate (10%-25%), extensive (25%-50%), severe (50%-75%), or critical (>75%). Figure 1 illustrates 3 CT patterns: mild, moderate and severe patterns, respectively.Figure 1 Images are presented in 3-dimensional volume-rendering technique mode to allow an optimal comparison between patients on a single frontal view. (A) Healthy patient. Only the lung contours and walls of bronchi and pulmonary vessels can be depicted. The normal lung parenchyma containing air appears in black. (B) Patient with mild coronavirus disease 2019 (COVID-19) involvement. Ground glass opacities (GGOs) appear in grey (arrowheads) mostly in the central part of the lungs, while consolidations appear in white in the peripheral and basal parts of both lungs (long arrows). (C) Patient with moderate COVID-19 involvement. The GGO is more extensive than in B, while consolidations are prominent in the right upper area. (D) Patient with severe COVID-19 involvement. Both lungs are involved with extensive central and peripheral GGOs. Consolidations are preferentially seen in the peripheral parts of both lungs.\n\nTreatment and Management of Immunosuppression\n\nKidney transplant recipients receive standard immunosuppression in our center, based on a combination of tacrolimus, mycophenolate, and steroids. Daily mycophenolate and steroid doses are 1 g and 4 mg, respectively. Tacrolimus trough levels are 10 to 13 ng/mL during the first month, 7 to 10 ng/mL for the next 2 months, and then 5 to 7 ng/mL. Everolimus is used in case of history of cancer or calcineurin inhibitor nephrotoxicity with a trough level of 5 to 7 ng/mL. Cyclosporine therapy is continued in patients who underwent transplantation before the use of tacrolimus or because of tacrolimus intolerance with trough levels of 50 to 70 ng/mL. Azathioprine is used at a daily dose of 1 mg/kg in case of mycophenolate intolerance or pregnancy desire.\n\nFor COVID-19–infected kidney transplant recipients, we have designed a standard strategy of immunosuppression minimization and treatment, which was sent to our colleagues from peripheral centers at the onset of the outbreak. In all cases, treatment with the antimetabolite drug (mycophenolate or azathioprine) is stopped; the daily dose of tacrolimus, cyclosporine, or everolimus is reduced to reach trough levels at 3 to 5 ng/mL, 30 to 40 ng/mL, and 3 to 5 ng/mL, respectively. The routine steroid dose is unchanged (4 mg/d of methylprednisolone). In case of life-threatening situations (eg, critical admission in the intensive care unit [ICU]), tacrolimus, cyclosporine, or everolimus treatment is stopped. Adjunctive treatment with corticosteroids has been provided to some patients after careful case-by-case evaluation, considering the extent of respiratory involvement and hyperinflammatory status.\n\nIn all kidney transplant recipients requiring hospitalization, following interim Belgian recommendations,18 hydroxychloroquine can be administered in patients with no cardiac contraindication at the discretion of the physician depending on the patient clinical situation for 5 days (400 mg twice daily day 1 and then 200 mg twice daily up to day 5; for estimated glomerular filtration rates < 30 mL/min/1.73 m2, 400 mg twice daily day 1 and then 200 mg/d up to day 5). Hydroxychloroquine treatment is initiated only if the corrected QT interval on the electrocardiogram is > 500 milliseconds.\n\nResults\n\nBaseline Characteristics\n\nFrom March 14, 2020, to April 15, 2020, a total of 22 COVID-19 infections were diagnosed in our cohort. Four patients were mildly ill and were sent back home after their first clinical evaluation. In all 4 patients, the antimetabolite treatment was stopped. They were called by telephone at least twice a week by a transplant physician. Symptoms rapidly improved in all 4 patients.\n\nEighteen patients required hospitalization. Their baseline characteristics are summarized in Table 1. Except for 2 patients, all had comorbid conditions, including treated hypertension, treated diabetes, history of cardiovascular event, obesity, dementia/intellectual disability, and active metastatic malignancy.Table 1 Characteristics of the 18 Hospitalized COVID-19–Infected Kidney Transplant Recipients\n\nCharacteristics\tPopulation (n = 18)\t\nAge, y\t57 (41-73)\t\nWomen\t10 (56%)\t\nRace\t\t\n White\t11 (61%)\t\n North African\t4 (22%)\t\n Asian\t1 (6%)\t\n Black\t2 (11%)\t\nDelay from KT, mo\t89 (1-402)\t\nACE inhibitor/ARB use\t10 (56%)\t\nComorbid conditions\t\t\n Hypertension\t14 (78%)\t\n Diabetes\t4 (22%)\t\n Cardiovascular\t4 (22%)\t\n Obesity\t4 (22%)\t\n Active malignancy\t1 (6%)\t\n Dementia/intellectual disability\t2 (11%)\t\nImmunosuppression\t\t\n Inductiona\t6 (33%)\t\n Tac/MPA/St\t7 (39%)\t\n Tac/Aza/St\t1 (6%)\t\n Tac/St\t2 (11%)\t\n EVL/MPA/St\t3 (16%)\t\n Csa/MPA/St\t2 (11%)\t\n Csa/Aza/St\t2 (11%)\t\n Csa/St\t1 (6%)\t\nClinical presentation\t\t\n Fever\t14 (78%)\t\n Cough\t12 (67%)\t\n Dyspnea\t7 (39%)\t\n Digestive symptoms\t5 (28%)\t\n Neurologic symptoms\t3 (16%)\t\nRadiological presentation on CTb\t\t\n Mild\t3/15 (20%)\t\n Moderate\t8/15 (53%)\t\n Extensive\t1/15 (7%)\t\n Severe\t2/15 (13%)\t\n Critical\t1/15 (7%)\t\nLaboratory parameters at admission\t\t\n Baseline eGFR, mL/min/1.73 m2\t45 (15-95)\t\n C-Reactive protein, mg/Lc\t56 (1.5-314)\t\n Lymphocyte count, /μLd\t730 (50-1440)\t\nNote: Values for categorical variables are given as number (percent); values for continuous variables are given as median (range).\n\nAbbreviations: ACE, angiotensin-converting-enzyme; ARB, angiotensin II receptor blocker; Aza, azathioprine; COVID-19, coronavirus disease 2019; Csa, cyclosporine; CT, computed tomography; eGFR, estimated glomerular filtration rate; EVL, everolimus; KT, kidney transplantation; MPA, mycophenolate; Tac, tacrolimus; St, steroids.\n\na Antithymocyte globulin (n = 4) or basiliximab (n = 2).\n\nb Available for 15 patients.\n\nc Normal value < 5.0 mg/L.\n\nd Normal value of 800 to 5,000/μL.\n\nClinical, Laboratory, and Radiologic Presentation at Diagnosis\n\nThe clinical, laboratory, and radiologic presentation of the 18 hospitalized patients is summarized in Table 1. Interestingly, patient 18 (Table 2), currently in the ICU, showed the highest C-reactive protein (CRP) level. Fifteen underwent CT of the chest at admission. Pulmonary lesions were classified as mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1), respectively.Table 2 Clinical Features of the 18 Hospitalized COVID-19–Infected Kidney Transplant Recipients\n\nPatient\tLength of Stay, d\tAge, y\tSex\tDelay From KT, mo\tIS\tSymptoms\tCT\tIS Management\tOther Treatment\tO2\tAKI\tICU\tOutcome\t\n1\t13\t50s\tM\t191\tTac-MPA-St\tFever+C+Dig\tSevere\tStop MPA\n↘ Tac\tHC\tNC\tNo\tNo\tHome\t\n2\t10\t60s\tM\t102\tEVL-MPA-St\tD+C+N\tND\tStop MPA\n↘ EVL\tHCa\tNC + IV\tNo\tYes, 2 d\tHome\t\n3\t16\t60s\tF\t1\tTac-MPA-St\tFever+D+C\tModerate\tStop MPA\n↘ Tac\tHC\tNo\tNo\tNo\tHome\t\n4\t16\t60s\tF\t250\tTac-St\tN+Dig\tModerate\t↘Tac\tHC\tNo\tNo\tNo\tHome\t\n5\t17\t50s\tM\t2\tTac-MPA-St\tFever+C\tModerate\tStop MPA\n↘ Tac\tHC +\n↗ steroidsb\tNC\tYes\tNo\tHome\t\n6\t17\t60s\tM\t357\tCsa-St\tFever+C\tMild\tNone\tHC\tNC\tNo\tNo\tHome\t\n7\t2\t60s\tF\t260\tCsa-MPA-St\tFever+D+C+N\tND\tNone\tNo\tNo\tNo\tNo\tDeathc\t\n8\t20\t50s\tF\t101\tTac-Aza-St\tC\tModerate\tStop Aza\n↘ Tac\tHC\tNC\tYes\tNo\tDeathc\t\n9\t26\t60s\tF\t36\tTac-MPA-St\tFever+C\tModerate\tStop MPA\n↘ Tac\tHCd\tNC\tYes\tNo\tHome\t\n10\t3\t50s\tF\t402\tCsA-Aza-St\tFever+Dig\tMild\tStop Aza\tNo\tNC\tNo\tNo\tHome\t\n11\t6\t40s\tF\t268\tCsa-MPA-St\tFever+C+D\tModerate\tStop Aza\n↘ Csa\tHC\tNo\tNo\tNo\tHome\t\n12\tOngoing\t40s\tF\t376\tCsa-Aza-St\tFever+C+Dig\tND\tStop Aza\n↘ Csa\tNo\tNo\tNo\tNo\tNon-ICU COVID unit\t\n13\t7\t40s\tF\t3\tEVL-MPA-St\tFever\tExtensive\tStop MPA\n↘ EVL\tHC\tNo\tNo\tNo\tHome\t\n14\t7\t50s\tM\t74\tTac-MPA-St\tFever+C+D\tMild\tStop MMF\n↘ Tac\tHC\tNC\tNo\tNo\tHome\t\n15\t8\t50s\tM\t48\tTac-St\tAsthenia\tSevere\tNonee\tHC\tNC\tYes\tNo\tHome\t\n16\t10\t70s\tM\t10\tTac-MPA-St\tFever\tModerate\tStop MPA\n↘ Tac\tHC\tNo\tNo\tNo\tHome\t\n17\tOngoing\t60s\tF\t5\tTac-MPA-St\tFever+D\tCritical\tStop MPA\n↘ Tac\tHC\tNC\tNo\tNo\tNon-ICU COVID unit\t\n18\tOngoing\t40s\tM\t77\tEVL-MPA-St\tFever+C+D+Dig\tModerate\tStop MPA\nStop EVL\tHC +\n↗steroidsf\tNC +IV\tYes\tYes, ongoing\tICU, critical\t\nAbbreviations: AKI, acute kidney injury; Aza, azathioprine; C, cough; COVID-19, coronavirus disease 2019; Csa, cyclosporine; CT, computed tomography; D, dyspnea; Dig, digestive symptoms; EVL, everolimus; F, female; HC, hydoxychloroquine; ICU, intensive care unit; IS, immunosuppression; IV, invasive ventilation; KT, kidney transplantation; M, male; MMF, mycophenolate mofetil; MPA, mycophenolate; N, neurologic symptoms; NC, nasal cannula; ND, not done; Tac, tacrolimus; St, steroids.\n\na This patient received 5 days of intravenous cefuroxime for suspected concomitant bacterial infection.\n\nb Three-day course of methylprednisolone, 32 mg/d.\n\nc No ICU because of severe comorbid conditions, death in palliative unit.\n\nd This patient received antibiotics for concomitant acute pyelonephritis.\n\ne Tac already reduced for BK virus viremia.\n\nf Methylprednisolone, 16 mg/d, for 2 days and then 1 mg/kg (ongoing).\n\nManagement of Hospitalized Patients\n\nThe management and outcomes of hospitalized patients are described in Table 2. With the exception of 1 patient (patient 7, discussed later), our local protocol of immunosuppression minimization was applied: the antimetabolite treatment was stopped and the tacrolimus/cyclosporine/everolimus dose was reduced to reach trough level targets, as per protocol. Fifteen of the 18 (83%) hospitalized patients were treated with hydroxychloroquine and 2 (11%) had an increase in steroid doses (Table 2). We did not observe cardiac side effects during hydroxychloroquine treatment. However, we observed an increase in tacrolimus trough levels in 5 patients after the initiation of hydroxychloroquine treatment. One patient (patient 2) also received 5 days of intravenous cefuroxime because of suspected additional pulmonary infection.\n\nEleven (61%) patients received supplemental oxygen during hospitalization. Only 2 patients were transferred to the ICU and received invasive ventilation (patients 2 and 18). Both were receiving everolimus because of a history of cancer. Patient 2 was a man in his 60s with a history of osteosarcoma of the thigh and was known for advanced dementia with Lewy bodies. He was admitted for dyspnea and worsening confusion. Chest x-ray findings were compatible with COVID-19 infection that was confirmed by reverse-transcriptase PCR in a nasopharyngeal swab. Oxygen saturation level was normal at admission, but his neurologic status deteriorated within hours, associated with severe hypercapnia. He was admitted to the ICU and rapidly intubated. Nevertheless, the clinical situation improved promptly and invasive ventilation was stopped after 48 hours. He was sent back home 10 days after admission.\n\nPatient 18 was a man in his 40s with a history of Hodgkin cervical lymphoma at age 15 years. He was admitted for fever, dyspnea, dry cough, and diarrhea. Clinical workup showed mild hypoxemia requiring oxygen at 2 L/min using a nasal cannula. CT of the chest showed bilateral pneumonia classified as moderate. Mycophenolate treatment was stopped and hydroxychloroquine treatment was started. However, oxygen needs increased progressively. Five days after admission, the patient showed signs of severe respiratory distress with hypoxemia. He was admitted to the ICU and rapidly intubated. Everolimus treatment was stopped and steroid dosages were increased at 16 mg/d of methylprednisolone for 2 days and then at 1 mg/kg (80 mg) per day because he did not improve. At the time of writing of this report, his condition remains critical, requiring invasive ventilation with a high level of oxygen (fraction of inspired oxygen of 100%).\n\nFive cases of acute kidney injury (defined as plasma creatinine increase > 50% from baseline or plasma creatinine increase ≥ 0.3 mg/dL)19 were observed during hospitalization (28%). However, acute kidney injury rapidly resolved with intravenous hydration, and no patient required dialysis. Overall, kidney function remained stable in the hospitalized patients (Table 2). Baseline estimated glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) before COVID-19 infection was 45 (range, 15-95) mL/min/1.73 m2 versus 38 (range, 15-101) mL/min/1.73 m2 at last follow-up. One patient (patient 9) presented with an acute pyelonephritis associated with bacteremia during hospitalization, but rapidly responded to antibiotic treatment.\n\nOutcomes\n\nAfter a median follow-up of 18 (range, 5-30) days, 13 (72%) of the 18 hospitalized patients recovered and were sent home (no readmissions to date) after a median of 10 (range, 2-26) days. Three (17%) patients are still currently hospitalized in our institution, and 2 (11%) have died. Both patients (patients 7 and 8) who died from COVID-19 infection also presented with very severe comorbid conditions: the first had metastatic uterine carcinoma and was terminally ill, and the second had severe active scleroderma associated with very impaired general health status, which had been deteriorating during the past months. Both patients were considered terminally ill and died in palliative care units. The rate of death of hospitalized COVID-19–infected kidney transplant recipients in our cohort is 11.1% (2/18).\n\nThe severity of pulmonary parenchyma involvement on CT performed at admission did not seem to influence outcome. For example, both patients who showed the most severe involvements on CT (patients 15 and 17) had rapidly favorable clinical evolutions (the first patient was dismissed from the hospital after 8 days and the second patient, though still hospitalized, no longer requires supplemental oxygen). Conversely, patient 18, who is currently intubated in the ICU, needing very high levels of oxygen, had moderate pulmonary involvement on CT at admission.\n\nDiscussion\n\nBecause of their chronic immunosuppressed status, kidney transplant recipients are at increased risk for many viral infections (cytomegalovirus, herpes zoster, norovirus infections…).20,21 Thus, higher rates of infection with COVID-19 and/or increased severity of the disease in our transplant population was feared. However, in past epidemics with Middle East respiratory syndrome (MERS) and SARS-CoV-1, this increased risk was not observed.22\n\nAs in the general population,1 the most common symptoms in our cohort of kidney transplant recipients with COVID-19 infection were fever, dry cough, and dyspnea. As reported,5,23,24 we also observed some atypical presentations with predominant digestive symptoms and acute confusion. Interestingly, the severity of pulmonary involvement on CT of the chest at admission was not associated with worse clinical outcome. Some patients with images of severe pulmonary involvement recovered well, whereas the only patient currently in the ICU had moderate involvement at admission with subsequent dramatic evolution. This suggests that CT of the chest at admission is useful for diagnosis but does not provide prognostic information. However, other factors may affect the severity of the pulmonary involvement on the first CT of the chest, such as the interval between the onset of symptoms and the CT and the presence of underlying chronic pulmonary diseases. Little is known about early markers that may predict the clinical evolution. Tan et al25 recently showed that CRP level increased early in severe COVID-19 infection, before CT findings, suggesting that the initial evolution of CRP levels might provide more prognostic information than early CT. In line with this hypothesis, patient 18 (Table 1) showed a rapid increase in CRP level from 90 mg/L on the day of admission to 304 mg/L on the day of transfer to the ICU (6 days after).\n\nThe current management of COVID-19 disease in kidney transplant recipients still remains ill-defined despite guidelines provided by many scientific societies.26, 27, 28 All these guidelines suggest drastically reducing immunosuppression, especially in clinical situations requiring admittance to the ICU. Of course, no randomized controlled trials have been conducted to assess how immunosuppression should be reduced and how to resume it after remission.\n\nOne important question is the optimal management of kidney transplant recipients who are receiving a mammalian target of rapamycin inhibitor (mTORi)-based regimen. Though mTORis are known to reduce the risk for developing cytomegalovirus or BK virus infections after kidney transplantation,29 their impact on SARS-CoV-2 is currently unknown. mTORis are believed to lead to a proinflammatory status by increasing the production of some cytokines, including interleukin 12 (IL-12), IL-6, IL-1, and IL-23), and tumor necrosis factor α. Thus, the mTORi capacity to boost the deleterious inflammatory response involved in COVID-19 infection is an important yet unresolved question. In this context, some guidelines26,27 have advocated withdrawing mTORis in all COVID-19–infected kidney transplant recipients requiring hospitalization. In our cohort, 3 (16.6%) of the 18 hospitalized kidney transplant recipients had mTORi-based immunosuppression. mTORi treatment was reduced, but maintained, in 2 patients (patients 2 and 13) who finally recovered. By contrast, mTORi treatment was stopped the day patient 18 was admitted to the ICU. He is to date the only patient who has developed such a severe pulmonary illness. Factors associated with worse respiratory outcomes still need to be identified. In patient 18, besides mTORi, comorbid conditions and history of cancer might have put him at risk for untoward evolution. Genetic background such as HLA antigen polymorphisms or angiotensin-converting enzyme polymorphism could also be implicated in the individual response to infection; their precise identification will probably shed some light on how to better handle infection in high-risk populations.30,31\n\nEighty-three percent of our hospitalized kidney transplant recipients received hydroxychloroquine. Early reports suggest a role for hydroxychloroquine in reducing the viral load.32 However, the impact of hydroxychloroquine on the clinical outcome of COVID-19–infected patients is largely unknown and highly debated. Even if hydroxychloroquine was safely used in our cohort, we cannot draw any conclusion regarding its efficacy because of the absence of a control group. The currently recruiting DISCOVERY and SOLIDARITY trials (NCT04315948 and NCT04321616, respectively) will provide some answers regarding treatment efficacy in the general population. The results of these trials will then need to be extrapolated to the kidney transplant recipient population.\n\nNone of our patient received the antivirals currently in the pipeline33 or promising specific anti-inflammatory drugs such as the anti–IL-6 tocilizumab34 because of their unavailability outside of a clinical trial. Interesting data regarding the use of tocilizumab were reported by Alberici et al15 in 6 kidney transplant recipients with severe pneumonia: 3 patients experienced reduction in oxygen requirements and 2 showed improvement in radiologic findings. Two patients eventually died and 1 was discharged from the hospital 9 days after tocilizumab administration.15\n\nIn our cohort, the kidney function outcome was satisfactory. Although 28% of hospitalized patients experienced acute kidney injury, none required hemodialysis. Moreover, kidney function rapidly stabilized after appropriate hydration. To date, we have not observed any acute rejection episodes, but the current follow-up of our patients is short. Because there is a correlation between immunosuppression reduction and increased risk for acute rejection,35 appropriate monitoring of kidney function should be continued and reintroduction of immunosuppressive drugs should be tailored after infection recovery.\n\nAt the time of writing this report, 2 kidney transplant recipients from our cohort died of COVID-19 infection. However, as mentioned, both patients had very severe comorbid conditions and were terminally ill. Italian and Spanish teams have reported higher mortality rates of 27.8% and 25% in the former and latter studies, respectively.14,15 Closer to our findings, a British team reported a 14% mortality rate in their series that included 7 kidney transplant recipients.16\n\nLarger data from US centers have been recently published. Pereira et al36 recently reported a 2-center experience of 90 solid-organ transplant recipients with COVID-19 infection, including 46 kidney transplant recipients. Among the kidney transplant recipients, 12 had severe disease defined as a need for mechanical ventilation, ICU admission, or death. The general management was similar to ours with immunosuppression reduction (88%) and the use of hydroxychloroquine (91%). Sixteen patients from the entire cohort (24%) had died by the end of follow-up. Although this report provides a broad picture of COVID-19 infection in solid-organ transplant recipients, it does not focus on kidney transplant recipients, making it difficult to compare with our population.\n\nAkalin et al37 also published a US case-series including 36 kidney transplant recipients with 28 (78%) requiring hospitalization. Management was not uniform as in our series because immunosuppression reduction and hydroxychloroquine treatment were used in 86%, and patients also received azithromycin (46%), the CCR5 inhibitor leronlimab (21%), and tocilizumab (7%). Interestingly, although kidney transplant recipients from this cohort seem similar to ours regarding comorbid conditions, the outcome appears more severe, with 11 (39%) kidney transplant recipients requiring mechanical ventilation and 6 (21%) requiring kidney replacement therapy. The mortality rate was also higher at the end of follow-up (28% vs 11% in our patients). A possible explanation might be the ethnic origin of the patients in that cohort because 39% and 42% were black and Hispanic, respectively, which differs from our population. These differences in disease severity and outcomes between centers and countries will need to be closely analyzed in larger cohorts with longer follow-up.\n\nIn conclusion, we report our experience of 22 kidney transplant recipients with COVID-19 infection, of whom 18 required hospitalization. Clinical symptoms were similar to those reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with a mortality rate for kidney transplant recipients hospitalized for COVID-19 infection of 11%. Further studies with a higher number of patients and longer follow-up are required to better assess the optimal management and outcomes of kidney transplant recipients with COVID-19 infection.\n\nArticle Information\n\nAuthors’ Full Names and Academic Degrees\n\nArnaud Devresse, MD, Leila Belkhir, MD, PhD, Bernard Vo, MD, Benoit Ghaye, MD, PhD, Anaïs Scohy, PharmD, MSc, Benoit Kabamba, MD, PhD, Eric Goffin, MD, Julien De Greef, MD, Michel Mourad, MD, PhD, Martine De Meyer, MD, Jean-Cyr Yombi, MD, and Nada Kanaan, MD, MSc.\n\nAuthors’ Contributions\n\nResearch idea, study design, data analysis: AD, NK; data acquisition: AD, BV; providing and interpreting CT scans images: BG; performed PCR analysis: AS, BK; patient care: AD, BV, NK, EG, MM, MDM, JCY, JDG, LB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.\n\nSupport\n\nNone.\n\nFinancial Disclosure\n\nThe authors declare that they have no relevant financial interests.\n\nPeer Review\n\nReceived April 27, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form June 3, 2020.\n\nComplete author and article information provided before references.\n==== Refs\nReferences\n\n1 Wang D. Hu B. Hu C. 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Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: a retrospective study Am J Transplant 9 8 2009 1816 1825 19538494\n36 Pereira M.R. Mohan S. Cohen D.J. COVID-19 in solid organ transplant recipients: initial report from the US epicenter Am J Transplant 20 2020 1800 1808 32330343\n37 Akalin E. Azzi Y. Bartash R. Covid-19 and kidney transplantation N Engl J Med 382 2020 2475 2477 32329975\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2590-0595", "issue": "2(4)", "journal": "Kidney medicine", "keywords": "COVID-19; Sars-CoV-2 virus; coronavirus disease 2019; immunosuppression; kidney transplantation; outcomes", "medline_ta": "Kidney Med", "mesh_terms": null, "nlm_unique_id": "101756300", "other_id": null, "pages": "459-466", "pmc": null, "pmid": "32775986", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "32279418;32302078;32181990;25073040;32273181;32031570;32243672;31027892;32354634;32282991;32198834;32330343;32090448;32205204;32292866;32301155;32233067;32354637;32253759;32299017;32281668;32329975;22977217;32220422;32301198;32243690;19538494;32282977", "title": "COVID-19 Infection in Kidney Transplant Recipients: A Single-Center Case Series of 22 Cases From Belgium.", "title_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium" }	[ { "companynumb": "BE-ACCORD-197169", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "211688", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18189817, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197177", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "211688", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197167", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "211688", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197179", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090253", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191749, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197178", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyomavirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191469, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197176", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191272, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197174", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191622, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197170", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197168", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFUROXIME" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191945, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-TEVA-2020-BE-1824880", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" } ], "patientagegroup": "5", "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "COVID-19 pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B, ET AL. COVID-19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE-CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY-MED 2020?2(4):459-466.", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20201020", "receivedate": "20200907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18237395, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" }, { "companynumb": "BE-ACCORD-197173", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191621, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197172", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197181", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18189823, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-TEVA-2020-BE-1824882", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" } ], "patientagegroup": "6", "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurological decompensation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypercapnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B, ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY?MED 2020?2(4):459?466.", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200907", "receivedate": "20200907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18237423, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20201103" } ]
{ "abstract": "We describe the compassionate use of high dose insulin dextrose (HID) for life threatening metformin associated lactic acidosis (MALA) in four patients admitted to intensive care.\nPatients presenting with refractory lactic acidosis believed to be secondary to metformin poisoning were included.High dose insulin dextrose at 0.5units/kg/hour was infused in 50% dextrose. Frequent blood gas analysis allowed titration of therapy. All patients also received continuous veno-venous haemofiltration.\nAll four patients recovered to normal or near normal lactate and pH between 10 and 24 hours of therapy. Two patients had significant separation in time between initiation of HID and haemofiltration to suggest an independent effect of HID on improving pH and lactate.All patients had at least one episode of hypoglycaemia below 4.0 mmol/L with the lowest glucose in any patient during therapy being 3.0 mmol/L. All episodes were corrected with a dextrose infusion without sequelae.\nOur study demonstrates that HID therapy appears to be safe in patients with suspected metformin poisoning. It also appears to work to drive down lactate, improve pH and patients' clinical condition. Further evidence is required to assess the effectiveness of HID therapy in the context of MALA.", "affiliations": "Newham University Hospital, London, United Kingdom.;Newham University Hospital, London, United Kingdom.;Newham University Hospital, London, United Kingdom.;Newham University Hospital, London, United Kingdom.", "authors": "Young\|Theodore\|T\|;Cevallos\|Joaquim\|J\|;Napier\|James\|J\|;Martin-Lazaro\|Juan\|J\|", "chemical_list": null, "country": "Lithuania", "delete": false, "doi": "10.6001/actamedica.v26i1.3958", "fulltext": null, "fulltext_license": null, "issn_linking": "1392-0138", "issue": "26(1)", "journal": "Acta medica Lituanica", "keywords": "acidosis; insulin; lactate; metformin", "medline_ta": "Acta Med Litu", "mesh_terms": null, "nlm_unique_id": "9442465", "other_id": null, "pages": "72-78", "pmc": null, "pmid": "31281219", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "10617608;11602624;1504710;15898827;18945920;19556031;20345411;20577053;21545617;21563902;23549904;24713415;24847880;25283255;25538310;29069937;29291990;29343628;29617642;9205542;9802770", "title": "Metformin poisoning treated with high dose insulin dextrose therapy: a case series.", "title_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series" }	[ { "companynumb": "GB-TEVA-2019-GB-1062045", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?VOL. 26. NO. 1:72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16418517, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-BAUSCH-BL-2019-018048", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190626", "receivedate": "20190626", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16476956, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "GB-INVENTIA-000304", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201991", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MED LITU. 2019?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190720", "receivedate": "20190720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16600306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-035763", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA.. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190626", "receivedate": "20190626", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16477866, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-BAUSCH-BL-2019-017583", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190621", "receivedate": "20190621", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16465349, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "GB-MYLANLABS-2019M1093842", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26 (1):72-8", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191014", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16898609, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-MYLANLABS-2019M1093836", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26 (1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191016", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16898612, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-INDICUS PHARMA-000604", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "079148", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MED LITU. 2019?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190725", "receivedate": "20190725", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16629630, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "GB-BAUSCH-BL-2019-017584", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190621", "receivedate": "20190621", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16465350, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "GB-MYLANLABS-2019M1094655", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191017", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16900190, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-036188", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26 (1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190628", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16489100, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-MYLANLABS-2019M1093831", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191015", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16898615, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-TEVA-2019-GB-1062047", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16418665, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-036181", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA.. 2019?26 (1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190628", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16493435, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-036190", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA.. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190628", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16491911, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-TEVA-2019-GB-1062044", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190611", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16414641, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-TEVA-2019-GB-1062048", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16419371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-BAUSCH-BL-2019-018047", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16474983, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" } ]
{ "abstract": "BACKGROUND\nDabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications - however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function.\n\n\nMETHODS\nTwo patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10 × 150 mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100 × 110 mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half-life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels.\n\n\nCONCLUSIONS\nThere is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding.", "affiliations": "a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia ;;a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia ;;b Intensive Care Unit, Joondalup Hospital , Perth , Australia.;a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia ;", "authors": "Vlad\|Ioana\|I\|;Armstrong\|Jason\|J\|;Ridgley\|James\|J\|;Pascu\|Ovidiu\|O\|", "chemical_list": "D000925:Anticoagulants; D000069604:Dabigatran", "country": "England", "delete": false, "doi": "10.3109/15563650.2015.1126287", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "54(3)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Anticoagulant; coagulation test; dabigatran; overdose", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D000437:Alcoholism; D000925:Anticoagulants; D001780:Blood Coagulation Tests; D003422:Critical Care; D000069604:Dabigatran; D062787:Drug Overdose; D005260:Female; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D008991:Monitoring, Physiologic; D011655:Pulmonary Embolism; D012307:Risk Factors; D055815:Young Adult", "nlm_unique_id": "101241654", "other_id": null, "pages": "286-9", "pmc": null, "pmid": "26735702", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring.", "title_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring" }	[ { "companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2022-00293", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "208040", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 ? 110 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anticoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE MESYLATE" } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Vlad L, Armstrong J, Ridgley J, Pascu O et al. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila). 2016;54(3):286-9", "literaturereference_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20220330", "receivedate": "20220330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20656118, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220423" }, { "companynumb": "AU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-02838BI", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 TABLETS X 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VLAD I,ARMSTRONG J,RIDGLEY J,PASCU O. DABIGATRAN DELIBERATE OVERDOSE: TWO CASES AND SUGGESTIONS FOR LABORATORY MONITORING. JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY 2016?.", "literaturereference_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "AU", "receiptdate": "20160223", "receivedate": "20160223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12105971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2022-00292", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "208040", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 ? 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anticoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE MESYLATE" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Vlad L, Armstrong J, Ridgley J, Pascu O et al. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila). 2016;54(3):286-9", "literaturereference_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20220330", "receivedate": "20220330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20656121, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220423" } ]
{ "abstract": "Vancomycin is used in the treatment of infections caused by gram-positive bacteria resistant to beta-lactam antibiotics. It is also used in the treatment ofenterococci, although this use has been limited due to resistance. The authors report the clinical and pathological presentations of 5 different vancomycin hypersensitivity reactions, including morbilliform eruption, erythroderma, acute generalized exanthematous pustulosis, linear immunoglobulin A bullous dermatosis, and toxic epidermal necrolysis. With the increased prevalence of beta-lactam-resistant bacteria, reliance on vancomycin continues to increase; thus, the recognition of reactions to this drug will be helpful in caring for patients who require this medication in the future.", "affiliations": "Department of Dermatology, Drexel University College of Medicine, 219 North Broad Street, Philadelphia, PA 19107, USA.", "authors": "O'Brien\|Meghan\|M\|;Shah\|Avnee\|A\|;Allen\|Herbert B\|HB\|", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1540-9740", "issue": "9(4)", "journal": "Skinmed", "keywords": null, "medline_ta": "Skinmed", "mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000293:Adolescent; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003873:Dermatitis, Exfoliative; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012872:Skin Diseases, Vesiculobullous; D013262:Stevens-Johnson Syndrome; D014640:Vancomycin; D028761:Withholding Treatment", "nlm_unique_id": "101168327", "other_id": null, "pages": "225-9", "pmc": null, "pmid": "21980707", "pubdate": "2011", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A pentad of vancomycin reactions.", "title_normalized": "a pentad of vancomycin reactions" }	[ { "companynumb": "US-PFIZER INC-2011316213", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "062911", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RESPIRATORY FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HCL" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ALLEN, H.. A PENTAD OF VANCOMYCIN REACTIONS. SKINMED. 2011?9 (4):225?229", "literaturereference_normalized": "a pentad of vancomycin reactions", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200821", "receivedate": "20120105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8322378, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "A 7-year-old girl with an unremarkable medical history presented to a local paediatric emergency department with a 7-day history of fever, sore throat and vomiting, and a 1-day history of rash. She was admitted to the hospital, with presumed Kawasaki disease. A few hours after admission, the patient had sudden onset of two witnessed tonic-clonic seizures and subsequent decreased mental status. She was transferred to the paediatric intensive care unit and started on broad-spectrum antibiotics. On hospital day 2, cerebral spinal fluid cultures and blood cultures grew Streptococcus pyogenes, and repeat physical examination was consistent with acute streptococcal pharyngitis. On hospital day 3, the patient developed left-sided hemiparesis and had another witnessed seizure. A CT scan was obtained and revealed a subdural abscess. She was transferred to a tertiary care centre and underwent craniotomy with evacuation of her subdural abscess. Surgical cultures eventually grew S. pyogenes.", "affiliations": "Department of Family Medicine, University of North Carolina Chapel Hill, Greensboro, North Carolina, USA.;Cone Health Family Medicine Residency, Greensboro, North Carolina, USA.;Cone Health Family Medicine Residency, Greensboro, North Carolina, USA.", "authors": "Walden\|Jeffrey Howard\|JH\|;Hess\|Bryan\|B\|;Rigby\|Michael\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D002648:Child; D013354:Empyema, Subdural; D005260:Female; D006801:Humans; D010291:Paresis; D010612:Pharyngitis; D012640:Seizures; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26385939", "pubdate": "2015-09-18", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11889374;18635385;7442993;24300473;10069590;15173504;15629962", "title": "Streptococcal pharyngitis: an uncommon cause of subdural empyema.", "title_normalized": "streptococcal pharyngitis an uncommon cause of subdural empyema" }	[ { "companynumb": "US-IGSA-GTI003675", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CLINDAMYCIN\\CLINDAMYCIN PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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STREPTOCOCCAL PHARYNGITIS: AN UNCOMMON CAUSE OF SUBDURAL EMPYEMA. BMJ CASE REP. 2015 SEP 18;2015. PII: BCR2015211312. DOI: 10.1136/BCR-2015-211312. PUBMED PMID: 26385939", "literaturereference_normalized": "streptococcal pharyngitis an uncommon cause of subdural empyema", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160729", "receivedate": "20160729", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12607715, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20161109" } ]
{ "abstract": "The prevalence of chronic myeloid leukemia and multiple myeloma has increased in recent years partly because of an improved therapeutic armamentarium for both conditions. Likewise, understanding the complexity inherent in designing combination treatment strategies will become increasingly prescient in the coming years. We describe, to the best of our knowledge, the first reported patient to be treated with second-generation tyrosine kinase inhibitor therapy while on novel therapy for myeloma. The combination was well tolerated and effective for the treatment of chronic myeloid leukemia and concurrent myeloma.", "affiliations": "Departments of aOncology bOncology Pharmacy, Kaiser Permanente, Santa Clara, California cJohn Theurer Cancer Center, Hackensack UMC, Hackensack, New Jersey, USA.", "authors": "Katzel\|Jed A\|JA\|;Lee-Ma\|Annette\|A\|;Vesole\|David H\|DH\|", "chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D001897:Boronic Acids; D011719:Pyrazines; D011743:Pyrimidines; D000069286:Bortezomib; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases", "country": "England", "delete": false, "doi": "10.1097/CAD.0000000000000262", "fulltext": null, "fulltext_license": null, "issn_linking": "0959-4973", "issue": "26(8)", "journal": "Anti-cancer drugs", "keywords": null, "medline_ta": "Anticancer Drugs", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011505:Protein-Tyrosine Kinases; D011719:Pyrazines; D011743:Pyrimidines", "nlm_unique_id": "9100823", "other_id": null, "pages": "907-9", "pmc": null, "pmid": "26111050", "pubdate": "2015-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Safety of a second-generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma.", "title_normalized": "safety of a second generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma" }	[ { "companynumb": "US-FRESENIUS KABI-FK201506010", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "084916", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE INJECTION (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATZEL J,LEE-MA A,VESOLE D. SAFETY OF A SECOND-GENERATION TYROSINE KINASE INHIBITOR AND NOVEL TARGETED THERAPY FOR THE TREATMENT OF A PATIENT WITH CHRONIC MYELOID LEUKEMIA AND MULTIPLE MYELOMA. ANTI-CANCER DRUGS 2015 SEP?26(8):907-909.", "literaturereference_normalized": "safety of a second generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20151120", "receivedate": "20151120", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11760664, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" }, { "companynumb": "PHHY2015US103035", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "NILOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022068", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC MYELOID LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NILOTINIB" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "NILOTINIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022068", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NILOTINIB" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KATZEL JA, LEE-MA A, VESOLE DH. SAFETY OF A SECOND-GENERATION TYROSINE KINASE INHIBITOR AND NOVEL TARGETED THERAPY FOR THE TREATMENT OF A PATIENT WITH CHRONIC MYELOID LEUKEMIA AND MULTIPLE MYELOMA.. ANTI-CANCER DRUGS. 2015;26:907-09", "literaturereference_normalized": "safety of a second generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150827", "receivedate": "20150827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11422701, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20151125" } ]
{ "abstract": "The introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in BRAF-mutant intracranial metastatic melanoma, most tumors will eventually progress. This demonstrates a gap in addressing the best management in such patients. Here, we present a case demonstrating our approach in this patient population.", "affiliations": "Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.", "authors": "Khaddour\|Karam\|K\|https://orcid.org/0000-0001-6697-3516;Johanns\|Tanner M\|TM\|;Ansstas\|George\|G\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.2217/mmt-2020-0022", "fulltext": "\n==== Front\nMelanoma Manag\nMelanoma Manag\nMMT\nMelanoma Management\n2045-0885\n2045-0893\nFuture Medicine Ltd London, UK\n\n10.2217/mmt-2020-0022\nCase Report\nBRAF-MEK inhibitors as steroid-sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma\nhttps://orcid.org/0000-0001-6697-3516\nKhaddour Karam 1\nJohanns Tanner M 1\nAnsstas George 1\n1 Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA\n Author for correspondence: [email protected]\n15 2 2021\n6 2021\n15 2 2021\n8 2 MMT5510 11 2020\n21 1 2021\n15 2 2021\n© 2021 George Ansstas\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License\n\nThe introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in BRAF-mutant intracranial metastatic melanoma, most tumors will eventually progress. This demonstrates a gap in addressing the best management in such patients. Here, we present a case demonstrating our approach in this patient population.\n\nTweetable abstract\n\nManagement of symptomatic BRAF-mutated intracranial melanoma.\n\nKeywords: \n\nBRAF-MEK\nbrain\nimmune checkpoint blockade\nintracranial\nipilimumab\nmetastatic melanoma\nnivolumab\nsteroids\nsymptomatic\ntargeted therapy\n==== Body\nPractice points\n\nStandard of care is lacking regarding the best approach in treating patients with symptomatic intracranial BRAF-mutated melanoma.\n\nSymptomatic patients with intracranial metastatic melanoma are often treated with dexamethasone to control brain edema.\n\nThe use of steroids at baseline can decrease the antitumor efficacy of immune checkpoint blockade (ICB) and lead to poor outcomes.\n\nObjective response to ICB in symptomatic metastatic intracranial melanoma is low and is associated with short duration of response.\n\nObjective response rate to combined BRAF-MEK inhibitors in BRAF-mutated intracranial melanoma is high, albeit short duration of response prior to progression.\n\nPresence of mutations such as CDKN2A is associated with a shorter duration of response to BRAF-MEK inhibitors in patients with BRAF-mutated melanoma.\n\nPreclinical and clinical data suggest the efficacy of ICB might be compromised in patients who receive ICB after progressing during treatment with BRAF-MEK inhibitors.\n\nUsing BRAF-MEK inhibitors (short course) in BRAF-mutated symptomatic intracranial metastatic melanoma might allow the discontinuation of steroids and lead to higher intracranial response. This might optimize the effect of ICB if started prior to progression of the disease.\n\nMelanoma brain metastases represent a unique spectrum of metastatic melanoma due to high associated morbidity and mortality. This is of importance as a high proportion of patients (∼36%) have evidence of intracranial metastases at the time of diagnosis [1]. Survival has improved significantly with the introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors. However, some patients have a high disease burden (defined as ≥3 intracranial lesions), and often demonstrate neurological symptoms. These cases represent a challenge in clinical practice as most clinical trials excluded patients with symptomatic brain metastases. Moreover, the immunosuppressive state caused by baseline use of dexamethasone, which is used to relieve neurological symptoms and brain edema, can attenuate the response to ICB and lead to poorer responses and outcomes [2–5]. Furthermore, despite the high efficacy of targeted treatment with combination BRAF and MEK inhibitors in intracranial metastatic BRAF-mutated melanoma, most tumors will eventually progress due to acquired resistance. Genomic alterations such as the loss of expression of CDKN2A can contribute to acquired resistance leading to a short-lived response to targeted therapy [6,7]. Therefore, the heterogenous molecular nature of melanoma could further compromise the duration of response to targeted therapy. Here, we report the case of a patient successfully treated with planned sequential BRAF-MEK inhibitors followed by ICB after presenting with high-burden, symptomatic intracranial metastatic melanoma requiring high dose dexamethasone. The patient had detectable BRAFV600E and CDKN2A mutations. The treatment course included administration of BRAF-MEK inhibitors for 8 weeks while discontinuing dexamethasone followed by ipilimumab-nivolumab administration. The patient had a near-complete radiological resolution of intracranial disease after initiating ICB with an ongoing durable response at 8 months of follow-up.\n\nCase presentation\n\nA 50-year old female presented with new left arm weakness, headache, slurred speech and vision disturbance. Her past medical history was significant for stage IA melanoma in the left chest wall diagnosed 5 years prior for which she underwent wide local excision. She had another lesion in the left lower extremity 2 years later consistent with malignant melanoma (Stage IB: T1bN0M0), which was treated with wide local excision and sentinel lymph node biopsy. The patient underwent brain magnetic resonance imaging (MRI) due to presence of neurological symptoms which showed numerous scattered lesions (30 lesions) involving the supratentorial and infratentorial compartments bilaterally, consistent with metastatic disease (Figure 1A). The patient was started on dexamethasone (4 mg orally, three-times daily) due to symptomatic vasogenic edema (Figure 2A). Chest computed tomography (CT) revealed a 3 cm right upper lobe pulmonary mass which was biopsied and confirmed malignant melanoma. Next-generation sequencing revealed presence of a BRAFV600E mutation (VAF 41.1%), CDKN2A copy number loss, and tumor mutation burden of 11.1 mutation per megabase (Tempus xT assay). The patient completed whole brain radiation WBRT (total of 30 Gy over 10 fractions) prior to referral to our hospital for further evaluation and management. Repeat brain MRI confirmed persistence of intracranial metastatic lesions. We tapered off dexamethasone within 3-week period after starting treatment with BRAF inhibitor (encorafenib 300 mg once daily orally) and MEK inhibitor (binimetinib 45 mg twice daily orally) as a bridge to control the symptomatic brain lesions prior to initiation of ICB. There were no side effects noted during treatment, and brain MRI after 8 weeks demonstrated partial response in several lesions without new neurological symptoms (Figure 1B). There was also continued resolution of brain edema after starting targeted therapy (Figure 2B). CT showed partial response in pulmonary metastatic lesion. Encorafenib and binimetinib were discontinued 8 weeks after their initiation despite no evidence of progressive disease, and the patient switched to ICB combination therapy including ipilimumab (3 mg/kg intravenously) and nivolumab (1 mg/kg intravenously) every three weeks. Given the risk of rebound disease and flare-up after the discontinuation of targeted therapy, the patient was closely monitored in the clinic but did not demonstrate any concerning signs or symptoms. After the second cycle of ICB, there was near-complete resolution noted on brain MRI. In addition, repeat CT demonstrated complete resolution of the pulmonary metastatic lesion. The patient developed hepatitis (immune related adverse event grade 3) which required holding off ICB and a treatment with 4-week course of high-dose prednisone taper (started 1 mg/kg/day). The patient later started maintenance ICB therapy with nivolumab (480 mg intravenously every 4 weeks). She remains without neurological symptoms and brain MRI continues to show a durable response in intracranial brain metastases after 8 months of initiating treatment (Figure 1C).\n\nFigure 1. Brain MRI demonstrating intracranial metastatic changes during treatment of the patient in the case report.\n\n(A) Axial section of brain MRI in T1 post contrast phase prior to treatment with BRAF-MEK inhibitors which demonstrates 30 scattered enhancing lesions in the supratentorial and infratentorial compartments bilaterally with associated edema. (B) Demonstrates reduction in the size and the number of several lesions 8 weeks after treatment with BRAF-MEK inhibitors and prior to administration of immunotherapy. (C) Marked decrease in the size of bilateral cerebral and cerebellar metastatic lesions with near-complete resolution of several lesions after 6 months of treatment with ICB.\n\nICB: Immune checkpoint blockade.\n\nFigure 2. Brain MRI demonstrating with FLAIR signal demonstrating brain edema.\n\n(A) Axial section of brain MRI with FLAIR signal showing large diffuse signal abnormality throughout the brain prior to treatment with steroids. (B) Significant reduction of the signal abnormality at end of treatment with BRAF-MEK inhibitors.\n\nDiscussion\n\nThe integration of ICB into the treatment paradigm of patients with intracranial metastatic melanoma has substantially improved overall survival compared with the pre-immunotherapy era based on data collected from the national cancer database [1]. Further prospective trials have corroborated the high and durable efficacy of ICB in intracranial metastatic melanoma. One such example is the CheckMate-204 Phase II open-label trial, which prospectively evaluated combination ICB (ipilimumab and nivolumab) followed by maintenance nivolumab in 94 patients with asymptomatic intracranial metastases [8]. This trial demonstrated a high intracranial response rate of 57% (including complete and partial responses) which was similar to the extracranial metastatic response rate. Moreover, the estimated overall survival rate was 81.5% at 1-year which further substantiated the evidence of the intracranial durable response attained through treatment with ICB [8]. Nevertheless, the evidence supporting the use of ICB in patients with high burden symptomatic intracranial metastatic melanoma and those who are treated with a high dose of steroids at baseline is lacking as most clinical trials have excluded patients with the previous characteristics. This stems from the notion that immunosuppression at baseline (including the use of steroids) could reduce the antitumor efficacy of ICB and lead to short-lived response. To this end, another cohort of the CheckMate-204 study addressed this issue by evaluating the efficacy of ipilimumab and nivolumab in 18 patients with symptomatic melanoma brain metastases of which 39% had three or more brain lesions and 61% were on dexamethasone (4 mg or less) [9]. The results demonstrated an objective response rate (ORR) of 22% which was inferior to the response rate observed in patients with asymptomatic brain metastases and those who are not receiving steroids at baseline (ORR = 57%) [9].\n\nInterestingly, BRAF-MEK inhibitors have an advantage over ICB given the high response rates in patients with both asymptomatic and symptomatic intracranial metastatic melanoma whose tumors harbor BRAFV600 mutations (>50 and 59%, respectively) [10]. Nevertheless, the high response rates in intracranial metastases are temporary, as the majority of patients treated with targeted therapy progress eventually, which is likely secondary to acquired resistance mechanisms [10,11]. The presence of CDKN2A copy number loss has been suggested to contribute to resistance to BRAF-MEK inhibitors in melanoma and lead to a shorter duration of response and inferior outcomes [6,7,12]. In addition, the duration of response in intracranial melanoma metastases is shorter compared with extracranial disease [10,13,14]. Of importance, one concern upon discontinuation of BRAF-MEK inhibitors is the rebound effect caused by reactivation of the BRAF kinase which could result in a flare-up and worsening of the metastatic disease [15]. Collectively, the previous evidence supports the high efficacy of BRAF-MEK inhibitors in patients with BRAFV600E melanoma brain metastases, albeit short duration of response with early progression during treatment and the concern of possible flare-up upon discontinuation of targeted therapy.\n\nOur case highlights the challenge often encountered in clinical practice when making a decision to treat patients with BRAF-mutated and symptomatic intracranial metastatic melanoma who are receiving baseline high dose steroids. The use of ICB as a front-line therapy in these patients is expected to be associated with low efficacy and short durable response based on the available evidence. As such, BRAF-MEK inhibitors in these patients can offer an advantage in obtaining high response as their efficacy is not compromised by steroids. However, the obtained response with targeted therapy is sustained for a short period prior to progression. Therefore, we followed an approach using BRAF-MEK inhibitors as a bridge to allow the discontinuation of glucocorticoid and to obtain a response in the intracranial metastatic disease prior to initiating ICB (evidenced by the partial radiological response, decrease in intracranial lesion numbers and control of neurological symptoms). We hypothesized such an approach would allow the resolution of the immunosuppressive effect of steroids and optimize the response to ICB. The presence of CDKN2A copy number loss further supported our rationale to use BRAF-MEK inhibitors temporarily given the short duration of response associated with this genetic alteration [6,7]. It should be noted that whole-brain radiotherapy could have contributed to the response obtained in the intracranial disease, however, we believe that most of the benefit obtained in the intracranial disease in our case was secondary to the use of BRAF-MEK inhibitors given the depth of response.\n\nRecently, there has been an increased interest in evaluating the use of BRAF-MEK inhibitors with ICB in the treatment of metastatic melanoma. These efforts are assessing several approaches in clinical trials including combination targeted and immunotherapy or the sequential use of BRAF-MEK inhibitors followed by ICB and is summarized in Table 1 [16–21]. This is based on the role of BRAF-MAPK pathway in the modulation of the tumor biology in melanoma. Preclinical research supports this notion as BRAFV600E mutant melanoma is associated with immunosuppressive tumor microenvironment leading to diminished antigen presentation and decreased CD8+ T cells [22]. As such, inhibition of the BRAF-MAPK pathway can alter tumor microenvironment favoring an immune permissive effect, which can facilitate the action of ICB [23]. To this end, the concurrent use of BRAF-MEK inhibitors and ICB or the sequenced use could favor a higher response with improved survival and is currently under investigation. Of importance, it has been suggested that when using an approach utilizing targeted therapy followed by ICB, waiting until progression while on BRAF-MEK inhibitors prior to starting immunotherapy could lead to an immunosuppressive environment and downregulation of effector T cells, which could negatively impact the efficacy of ICB [24]. This further supports our approach of switching BRAF-MEK inhibitors to ICB prior to an evidence of progressive disease in our patient.\n\nTable 1. Selected studies of sequenced or combined targeted therapy with immune checkpoint blockade in metastatic melanoma.\n\nStudy (year)\tStudy design\tPatients (n)\tModality of treatment\tPresence of intracranial metastases\tPrimary end point\tSurvival results\tRef.\t\nGutzmer et al. (2020)\tProspective randomized double blinded Phase III\t256\tCombination atezolizumab, vemurafenib and cobimetinib\tYes (5 patients in the study arm)\tPFS\t15.1 vs 10.6 months\t[16]\t\nPuzanov et al. (2020)\tPost hoc Pooled analysis of three clinical trials\t271\tPreviously treated with BRAFi with or without MEKi and later were treated with pembrolizumab\tYes (46 patients in the study arm)\tORR, PFS, OS\tLower ORR, PFS and OS†\t[17]\t\nDummer et al. (2020)\tSingle arm safety run in from Phase III COMBI-I trial\t36\tCombination spartalizumab, dabrafenib, trametinib\tNot included\tDose limiting toxicity\nbiomarker analysis‡\t24 months PFS was 41%\t[18]\t\nBurton et al. (2019)\tSingle arm Phase II\t24\tCombination nivolumab, dabrafenib, trametinib\tIncluded\tSafety and ORR§\tNot provided\t[19]\t\nRibas et al. (2015)\tPhase I\t50\tCombination durvalumab, dabrafenib, trametinib\tNot included\tSafety\tNot provided\t[20]\t\nAmin et al. (2016)\tPhase II\t46\tVemurafenib followed by ipilimumab\tNot included\tSafety\tmPFS was 4.5 months\t[21]\t\n† Baseline characteristics were significantly different in the compared subgroups.\n\n‡ PFS was a secondary end point in the study.\n\n§ ORR was 89% in 19 evaluable patients.\n\nBRAFi: BRAF inhibitor; MEKi: MEK inhibitor; PFS: Progression-free survival; ORR: Objective response rate; OS: Overall survival.\n\nThe preclinical evidence of the compromised outcome with ICB treatment in patients who progressed on BRAF-MEK inhibitors has been echoed by a recent Phase-II trial (ABC trial), which evaluated the efficacy of ICB in 76 patients with melanoma brain metastases [25]. This study included a cohort of 16 patients with symptomatic or leptomeningeal brain metastases of which 75% received ICB treatment after they progressed while on BRAF-MEK inhibitors, and were found to have low response rates (ORR = 6%, progressive disease 81%) [25].\n\nConclusion\n\nThis report describes a patient with BRAF-mutant symptomatic intracranial metastatic melanoma who was successfully treated with BRAF-MEK inhibitors as a bridge to allow discontinuation of steroids prior to ICB therapy. The patient had significant clinical and radiographic response ongoing at 8 months after initiating therapy. Our observation with the previous reported literature suggest: treatment with BRAF-MEK inhibitors may allow the discontinuation of steroids in patients with symptomatic BRAF mutant intracranial metastatic melanoma; bridging temporarily with BRAF-MEK inhibitors prior to evidence of progressive disease may optimize the efficacy of ICB and lead to a durable response; and; integration of tumor molecular characteristics such as CDKN2A copy number loss can aid in planning treatment (favoring a short course with targeted therapy and considering other treatments prior to disease progression). While this case report provides proof-of-concept, further clinical trials are needed to confirm stated conclusions.\n\nFuture perspective\n\nTo date, the management of patients with metastatic intracranial melanoma and symptomatic disease remains challenging with very limited therapeutic options. The use of steroids to relieve symptom associated morbidity might hinder the efficacy of ICB. The role of targeted therapy in such patients with BRAF-mutated melanoma is a possible avenue to circumvent the use of steroids. Research is currently ongoing to investigate the efficacy and safety of and approach combining versus sequencing BRAF-MEK inhibitors and ICB in metastatic melanoma which will offer further insight on the possible role of utilizing short-term targeted therapy prior to ICB in patients with symptomatic intracranial melanoma.\n\nAuthor contributions\n\nThis case report was conceptualized by K Khaddour and G Ansstas. K Khaddour reviewed the literature, wrote the manuscript and created Table 1. K Khaddour, G Ansstas and TM Johanns reviewed the manuscript.\n\nFinancial & competing interests disclosure\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\n\nThe authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.\n\nOpen access\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\n\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1. Iorgulescu JB, Harary M, Zogg CK Improved risk-adjusted survival for melanoma brain metastases in the era of checkpoint blockade immunotherapies: results from a National Cohort. Cancer Immunol. 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Bradley SD, Chen Z, Melendez B BRAFV600E co-opts a conserved MHC Class I internalization pathway to diminish antigen presentation and CD8+ T-cell recognition of melanoma. Cancer Immunol. Res. 3 (6 ), 602–9 (2015). 25795007\n••Study shows that BRAF-mutated melanoma is associated with immunosuppressive tumor microenvironment.\n\n23. Frederick DT, Piris A, Cogdill AP BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19 (5 ), 1225–31 (2013). 23307859\n• Study shows that BRAF inhibition counteract the immunosuppressive effect mediated through BRAF mutation.\n\n24. Dummer R, Ascierto PA, Nathan P Rationale for immune checkpoint inhibitors plus targeted therapy in metastatic melanoma: a review. JAMA Oncol. (Epub ahead of print).\n•• Comprehensive review suggests reduced efficacy of immune checkpoint blockade when administered in melanoma patients after progressing while on BRAF-MEK inhibitors.\n\n25. Long GV, Atkinson V, Lo S Long-term outcomes from the randomized Phase II study of nivolumab (nivo) or nivo + ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets): anti-PD1 brain collaboration (ABC). Ann. Oncol. 30 (Suppl. 5 ), 13110 (2019).\n• Prospective study shows that response rate and survival to immunotherapy are worse in patients with intracranial metastatic melanoma who previously had disease progression while being treated with BRAF-MEK inhibitors.\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2045-0885", "issue": "8(2)", "journal": "Melanoma management", "keywords": "BRAF-MEK; brain; immune checkpoint blockade; intracranial; ipilimumab; metastatic melanoma; nivolumab; steroids; symptomatic; targeted therapy", "medline_ta": "Melanoma Manag", "mesh_terms": null, "nlm_unique_id": "101649842", "other_id": null, "pages": "MMT55", "pmc": null, "pmid": "34084449", "pubdate": "2021-02-15", "publication_types": "D002363:Case Reports", "references": "31936151;25795007;33020648;26037941;32007138;27687304;28592387;32970096;25500362;23290787;25018652;32534646;26433819;30125216;30002157;32120803;32672795;27532019;30134131;23307859", "title": "BRAF-MEK inhibitors as steroid-sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma.", "title_normalized": "braf mek inhibitors as steroid sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-055148", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "125554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM, Q4WK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IPILIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 MILLIGRAM/KILOGRAM, Q3WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT MELANOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IPILIMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "125554", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM/KILOGRAM, Q3WK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT MELANOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NIVOLUMAB" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Immune-mediated hepatitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHADDOUR K, JOHANNS TM, ANSSTAS G. BRAF?MEK INHIBITORS AS STEROID?SPARING BRIDGE PRIOR TO CHECKPOINT BLOCKADE THERAPY IN SYMPTOMATIC INTRACRANIAL MELANOMA. MELANOMA MANAGEMENT. 2021?18(2)", "literaturereference_normalized": "braf mek inhibitors as steroid sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210615", "receivedate": "20210615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19419319, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Respiratory syncytial virus (RSV) infection can cause lower respiratory tract disease and mortality in pediatric hematopoietic stem cell transplant (HSCT) recipients. We report two children who underwent HSCT and developed RSV infection simultaneously at the Bone Marrow Transplant Unit. The treatment with intravenous palivizumab was provided and sequential viral loads were measured in nasopharyngeal (NP) and whole blood samples. To our knowledge, this is the first report where RSV loads were measured in parallel (NP and blood), before and after palivizumab, in correlation with a favorable clinical outcome in both cases.", "affiliations": "Department of Pediatrics, Division of Pediatric Infectious Diseases, Hospital Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago, Chile.;Department of Pediatrics and Pediatric Surgery, Hospital Roberto del Río and Virology Program, Facultad de Medicina, Universidad de Chile, Santiago, Chile.;Transplant Unit, Hospital Luis Calvo Mackenna, Santiago, Chile.;Department of Pediatrics, Division of Pediatric Infectious Diseases, Hospital Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago, Chile.;Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, OH.", "authors": "Torres\|Juan Pablo\|JP\|;Tapia\|Lorena I\|LI\|;Catalán\|Paula\|P\|;De la Maza\|Verónica\|V\|;Mejías\|Asunción\|A\|", "chemical_list": "D000998:Antiviral Agents; D000069455:Palivizumab", "country": "United States", "delete": false, "doi": "10.1002/pbc.26667", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(12)", "journal": "Pediatric blood & cancer", "keywords": "children; hematopoietic stem cell transplant; palivizumab; respiratory syncytial virus", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D000069455:Palivizumab; D018357:Respiratory Syncytial Virus Infections", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "28598593", "pubdate": "2017-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children.", "title_normalized": "intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children" }	[ { "companynumb": "CL-TEVA-2017-CL-831318", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/KG DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "88497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIAL FREQUENCY NOT SPECIFIED", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNE GLOBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADMINISTERED WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower respiratory tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory syncytial virus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytomegalovirus chorioretinitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TORRES JP, TAPIA LI, CATALAN P, DE LA MAZA V, MEJIAS A. INTRAVENOUS PALIVIZUMAB IN RESPIRATORY SYNCYTIAL VIRUS INFECTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN CHILDREN. PEDIATR-BLOOD-CANCER 2017;64:NO. 12.", "literaturereference_normalized": "intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20171208", "receivedate": "20171208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14264648, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "CL-TEVA-2017-CL-831326", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNE GLOBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FROM DAY -1 AT 200-250 NG/ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "16 MG/KG/TOTAL DOSE ON DAYS -6 TO -3", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACICLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUCONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory syncytial virus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Klebsiella test positive", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TORRES JP, TAPIA LI, CATALAN P, DE LA MAZA V, MEJIAS A. INTRAVENOUS PALIVIZUMAB IN RESPIRATORY SYNCYTIAL VIRUS INFECTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN CHILDREN. PEDIATR-BLOOD-CANCER 2017;64:NO. 12.", "literaturereference_normalized": "intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20171211", "receivedate": "20171211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 14272212, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "CL-ORION CORPORATION ORION PHARMA-TREX2017-3837", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORIN A" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, 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"drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2014", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUCONAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTION PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus chorioretinitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Immunodeficiency", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute graft versus host disease in skin", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease in gastrointestinal tract", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia respiratory syncytial viral", "reactionmeddraversionpt": "20.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic graft versus host disease in skin", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201407" } }, "primarysource": { "literaturereference": "TORRES J,TAPIA L. INTRAVENOUS PALIVIZUMAB IN RESPIRATORY SYNCYTIAL VIRUS INFECTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN CHILDREN. PEDIATR BLOOD CANCER. 2017 JUN 09;64(12):.", "literaturereference_normalized": "intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CL", "receiptdate": "20171130", "receivedate": "20171130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14238020, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]
{ "abstract": "Patients with leptomeningeal disease (LMD) from melanoma have very poor outcomes and few treatment options. We present a case of intrathecal (i.t.) administration of autologous tumor-infiltrating lymphocytes (TIL) in a patient with LMD from metastatic melanoma. The patient developed LMD after previous treatments with surgery, high-dose bolus interleukin-2 (HD IL2), and systemic TIL infusion and experienced radiographic progression after intrathecal IL2 (i.t. IL2) therapy. The patient received weekly treatment with increasing numbers of i.t. TIL followed by twice-weekly i.t. IL2. The patient received three i.t. TIL infusions and did not experience any toxicities beyond those expected with i.t. IL2 therapy. Analysis of cerebrospinal fluid demonstrated increased inflammatory cytokines following the i.t.\n\n\nMETHODS\nSubsequent imaging demonstrated disease stabilization, and neurological deficits also remained stable. The patient expired 5 months after the initiation of i.t. TIL therapy with disease progression in the brain, liver, lung, and peritoneal and retroperitoneal lymph nodes, but without LMD progression. These results demonstrate the safety of i.t. administration of TIL in melanoma patients with LMD and support the feasibility of conducting a prospective clinical trial to determine this therapy's clinical benefit among these patients.", "affiliations": "Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. [email protected].;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.", "authors": "Glitza\|Isabella C\|IC\|;Haymaker\|Cara\|C\|;Bernatchez\|Chantale\|C\|;Vence\|Luis\|L\|;Rohlfs\|Michelle\|M\|;Richard\|Jessie\|J\|;Lacey\|Carol\|C\|;Mansaray\|Rahmatu\|R\|;Fulbright\|Orenthial J\|OJ\|;Ramachandran\|Renjith\|R\|;Toth\|Christopher\|C\|;Wardell\|Seth\|S\|;Patel\|Sapna P\|SP\|;Woodman\|Scott E\|SE\|;Hwu\|Wen-Jen\|WJ\|;Radvanyi\|Laszlo G\|LG\|;Davies\|Michael A\|MA\|;Papadopoulos\|Nicholas E\|NE\|;Hwu\|Patrick\|P\|", "chemical_list": "D016207:Cytokines", "country": "United States", "delete": false, "doi": "10.1158/2326-6066.CIR-15-0071", "fulltext": null, "fulltext_license": null, "issn_linking": "2326-6066", "issue": "3(11)", "journal": "Cancer immunology research", "keywords": null, "medline_ta": "Cancer Immunol Res", "mesh_terms": "D016207:Cytokines; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007278:Injections, Spinal; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma; D055756:Meningeal Carcinomatosis; D008875:Middle Aged", "nlm_unique_id": "101614637", "other_id": null, "pages": "1201-6", "pmc": null, "pmid": "26216417", "pubdate": "2015-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "23358426;20960525;23160697;23032743;16939963;12173336;1737371;21498393;9420067;18287337;11300492;22527228;22594466", "title": "Intrathecal Administration of Tumor-Infiltrating Lymphocytes Is Well Tolerated in a Patient with Leptomeningeal Disease from Metastatic Melanoma: A Case Report.", "title_normalized": "intrathecal administration of tumor infiltrating lymphocytes is well tolerated in a patient with leptomeningeal disease from metastatic melanoma a case report" }	[ { "companynumb": "PHHY2016US027865", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ALDESLEUKIN" }, "drugadditional": null, "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERLEUKIN-2" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022137", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALDESLEUKIN" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "20 MIU, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20101120", "drugstartdateformat": "102", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "027", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERLEUKIN-2" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALDESLEUKIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "1 DF, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "032", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERLEUKIN-2" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "52", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to lung", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metastases to meninges", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to spleen", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to muscle", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intracranial pressure increased", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to liver", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metastases to lymph nodes", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to central nervous system", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to peritoneum", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoaesthesia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GLITZA IC, HAYMAKER C, BERNATCHEZ C, VENCE L, ROHLFS M, RICHARD J ET AL.. INTRATHECAL ADMINISTRATION OF TUMOR-INFILTRATING LYMPHOCYTES IS WELL TOLERATED IN A PATIENT WITH LEPTOMENINGEAL DISEASE FROM METASTATIC MELANOMA: A CASE REPORT. CANCER IMMUNOLOGY RESEARCH. 2015?3 (11):1201-6", "literaturereference_normalized": "intrathecal administration of tumor infiltrating lymphocytes is well tolerated in a patient with leptomeningeal disease from metastatic melanoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160308", "receivedate": "20160308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12161399, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "We describe the first case of a FLT-3 mutated AML in a healthy donor, 3years after recombinant human granulocyte colony stimulating factor (rhG-CSF)-mobilized peripheral blood stem cell (PBSC) harvest. The patient had a myeloablative (MA) matched unrelated donor (MUD) stem cell transplant (SCT) for refractory AML. However, he experienced a secondary graft failure. He had a second non myeloablative (NMA) on day +75 from a second MUD. He achieved a complete neutrophil and platelet engraftment. After 4years of follow up, he is alive in complete remission with full second donor chimerism.", "affiliations": "Staten Island University Hospital, Staten Island, NY 10305, USA.;Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.;Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: [email protected].", "authors": "Haddad\|Housam\|H\|;Wungjiranirun\|Manida\|M\|;Gergis\|Usama\|U\|", "chemical_list": "D016179:Granulocyte Colony-Stimulating Factor", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "9(3)", "journal": "Hematology/oncology and stem cell therapy", "keywords": "Filgrastim; Peripheral blood stem cell; Recombinant human granulocyte colony-stimulating factor; Stem cell donor", "medline_ta": "Hematol Oncol Stem Cell Ther", "mesh_terms": "D000328:Adult; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation; D014019:Tissue Donors", "nlm_unique_id": "101468532", "other_id": null, "pages": "123-5", "pmc": null, "pmid": "26173032", "pubdate": "2016-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Acute myeloid leukemia developing in a granulocyte colony-stimulating factor-mobilized stem cell donor: A case report and review of the literature.", "title_normalized": "acute myeloid leukemia developing in a granulocyte colony stimulating factor mobilized stem cell donor a case report and review of the literature" }	[ { "companynumb": "US-SA-2016SA222361", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103869", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", 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"reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HADDAD H, WUNGJIRANIRUN, GERGIS U. ACUTE MYELOID LEUKEMIA DEVELOPING IN A GRANULOCYTE COLONY-STIMULATING FACTOR-MOBILIZED STEM CELL DONOR: A CASE REPORT AND REVIEW OF THE LITERATURE. HEMATOL ONCOL STEM CELL THER (2016)9, 123-25. 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": "5", "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Trisomy 9", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea exertional", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WUNGJIRANIRUN M. ACUTE MYELOID LEUKEMIA DEVELOPING IN A GRANULOCYTE COLONY-STIMULATING FACTOR-MOBILIZED STEM CELL DONOR: A CASE REPORT AND REVIEW OF THE LITERATURE. HEMATOLOGY/ONCOLOGY + STEM CELL THERAPY. 2016;9(3):123-125", "literaturereference_normalized": "acute myeloid leukemia developing in a granulocyte colony stimulating factor mobilized stem cell donor a case report and review of the literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12780941, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-ASPEN PHARMA TRADING LIMITED US-AG-2017-000236", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSULFAN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HADDAD H, WUNGJIRANIRUN M, GERGIS U. ACUTE MYELOID LEUKEMIA DEVELOPING IN A GRANULOCYTE COLONY-STIMULATING FACTOR-MOBILIZED STEM CELL DONOR. A CASE REPORT AND REVIEW OF THE LITERATURE. HEMATOL ONCOL STEM CELL THER. 2016;9:123-125.", "literaturereference_normalized": "acute myeloid leukemia developing in a granulocyte colony stimulating factor mobilized stem cell donor a case report and review of the literature", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170127", "receivedate": "20170127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13157603, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "BACKGROUND\nTransrectal ultrasound-guided prostate biopsies (TRUSBx), in spite of being one of the most frequently performed urological office procedures, are associated with a spectrum of complications, most significantly including infection. The aim of the study is to evaluate the prevalence of fluoroquinolone-resistant bacteria in rectal swabs from our local population prior to TRUSBx and to identify risk factors among a patient population harboring fluoroquinolone-resistant organisms.\n\n\nMETHODS\nWe prospectively included 541 men who were submitted for TRUSBx in our center from March 2011 to June 2015. The indications for TRUSBx were an elevated prostate-specific antigen level and/or abnormal digital rectal exam. All patients were randomly divided into two groups: Group 1 (n = 279 cases) who received standard empirical prophylactic antibiotics and Group 2 who received targeted prophylaxis based on a rectal swab culture and susceptibility result. Differences in risk factors between quinolone-resistant and nonresistant patients were compared. Univariate and multivariate analyses were performed to identify independent potential risk factors associated with fluoroquinolone-resistant rectal flora.\n\n\nRESULTS\nSixteen out of 271 men developed infectious complications after TRUSBx in the group receiving standard empirical prophylaxis (5.7%). No men in the group who received targeted prophylactic antibiotic guided by rectal swab developed infectious complications. Among the 262 patients who underwent prebiopsy rectal swab cultures, 76 men (29%) displayed fluoroquinolone-resistant rectal flora (29%). In the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with an increased risk of fluoroquinolone resistance.\n\n\nCONCLUSIONS\nDetermining the prevalence of fluoroquinolone resistance in rectal flora has important implications in the selection of targeted prophylactic antibiotic regimens. Antimicrobial profiles guided by rectal swabs may prove useful to optimize prophylaxis prior to TRUSBx; this strategy is effective at reducing the rates of infectious complications, including sepsis, especially in men at higher risk of infectious complications.", "affiliations": "Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.", "authors": "Fahmy\|Ahmed\|A\|;Rhashad\|Hazem\|H\|;Mohi\|Mohamed\|M\|;Elabbadie\|Ahmed\|A\|;Kotb\|Ahmed\|A\|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.1016/j.prnil.2016.06.001", "fulltext": "\n==== Front\nProstate IntProstate IntProstate International2287-88822287-903XAsian Pacific Prostate Society S2287-8882(16)30027-710.1016/j.prnil.2016.06.001Original ArticleOptimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound-guided prostate biopsies: A prospective randomized study Fahmy Ahmed [email protected]∗Rhashad Hazem Mohi Mohamed Elabbadie Ahmed Kotb Ahmed Urology Department, Alexandria University, Alexandria, Egypt∗ Corresponding author. Urology Department, Alexandria University, 41 St. Abdelmoneam Sanad, Kamp Sizar, Alexandria, Egypt. [email protected] 7 2016 9 2016 01 7 2016 4 3 113 117 25 5 2016 10 6 2016 14 6 2016 Copyright © 2016 Asian Paciﬁc Prostate Society, Published by Elsevier.2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nTransrectal ultrasound-guided prostate biopsies (TRUSBx), in spite of being one of the most frequently performed urological office procedures, are associated with a spectrum of complications, most significantly including infection. The aim of the study is to evaluate the prevalence of fluoroquinolone-resistant bacteria in rectal swabs from our local population prior to TRUSBx and to identify risk factors among a patient population harboring fluoroquinolone-resistant organisms.\n\nMethods\nWe prospectively included 541 men who were submitted for TRUSBx in our center from March 2011 to June 2015. The indications for TRUSBx were an elevated prostate-specific antigen level and/or abnormal digital rectal exam. All patients were randomly divided into two groups: Group 1 (n = 279 cases) who received standard empirical prophylactic antibiotics and Group 2 who received targeted prophylaxis based on a rectal swab culture and susceptibility result. Differences in risk factors between quinolone-resistant and nonresistant patients were compared. Univariate and multivariate analyses were performed to identify independent potential risk factors associated with fluoroquinolone-resistant rectal flora.\n\nResults\nSixteen out of 271 men developed infectious complications after TRUSBx in the group receiving standard empirical prophylaxis (5.7%). No men in the group who received targeted prophylactic antibiotic guided by rectal swab developed infectious complications. Among the 262 patients who underwent prebiopsy rectal swab cultures, 76 men (29%) displayed fluoroquinolone-resistant rectal flora (29%). In the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with an increased risk of fluoroquinolone resistance.\n\nConclusion\nDetermining the prevalence of fluoroquinolone resistance in rectal flora has important implications in the selection of targeted prophylactic antibiotic regimens. Antimicrobial profiles guided by rectal swabs may prove useful to optimize prophylaxis prior to TRUSBx; this strategy is effective at reducing the rates of infectious complications, including sepsis, especially in men at higher risk of infectious complications.\n\nKeywords\nBiopsyProphylactic antibioticProstate biopsyTransrectal\n==== Body\n1 Introduction\nTransrectal ultrasound-guided prostate biopsies (TRUSBx), in spite of being a frequently performed urological procedure, are associated with a spectrum of complications, most significantly including infection, which affects up to 5% of patients.1 In the most severe cases, infection leads to sepsis, which poses significant morbidity to patients with inpatient hospital stays, intensive care requirements, and even death. Escherichia coli is the pathogen most commonly associated with infections after TRUSBx.2, 3, 4\n\nAntibiotic prophylaxis with fluoroquinolones (FQ) is currently used on a regular routine basis for preventing sepsis after TRUSBx because of its broad spectrum activity against gram-positive and gram-negative organisms and the convenience of using an oral agent with a high sustained concentration in urine and prostate tissue;5, 6, 7 however, there is growing evidence that the infection rate after TRUSBx is on the rise and it continues to be a problem, frequently caused by an increasing prevalence of FQ-resistant organisms.8, 9, 10, 11, 12\n\nIn an attempt to reduce the rate of infectious complications, there are an increasing number of publications citing different prophylaxis regimens.13, 14, 15 The aim of this study is to evaluate the prevalence of FQ-resistant bacteria in rectal swabs from men presented to the outpatient department at Alexandria University Hospital, Egypt, prior to TRUSBx and to identify the risk factors among a patient population harboring FQ-resistant organisms.\n\n2 Materials and methods\nWe prospectively included 541 men who were submitted for TRUSBx in our center from March 2011 to June 2015. All patients were randomly divided into two groups: Group 1 (n = 279 cases) who received standard empirical prophylactic antibiotic with oral ciprofloxacin 500 mg and metronidazole 500 mg at least 1 hour before biopsy and continued this twice daily for 3 days (a total of 6 doses of each antibiotic) and Group 2 who received targeted prophylaxis based on a rectal swab culture and susceptibility results performed 1 week before TRUSBx provided in a 3-day regimen on the day before the biopsy, the day of the biopsy, and the day after the biopsy (Fig. 1).\n\nSealed opaque envelopes were used as the method of randomization which were placed into a box and mixed. Allocation concealment was achieved using an independent person (“biopsy nurse”) who selected one of the sealed opaque envelopes blindly. Thus patients were randomly allocated to Group 1 or Group 2 before the procedure. The study was approved through the Institutional Review Board.\n\nDemographic data were obtained for all patients, as well as diabetic status, recurrent urinary tract infections (UTI), presence of a urinary catheter, prior FQ exposure within 6 months before the biopsy, and past TRUS biopsies (Table 1). The results of rectal swabs and infectious complications within 30 days of the biopsy were also recorded. The definition of post-TRUSBx infection was distinct clinical presentations, including fever > 38.5°C, UTI, pyelonephritis, bacteremia, prostatitis, systemic inflammatory response syndrome, and sepsis. The indications for TRUS biopsies were an elevated prostate-specific antigen level (PSA) and/or abnormal digital rectal exam. All TRUSBx were performed at our institution in an office-based setting.\n\n2.1 TRUSBx technique\nAll patients provided informed consent before the biopsy after they had been instructed by the physician regarding all possible complications. Patients were strictly advised not to take nonsteroidal anti-inflammatories and anticoagulant medications for a week before the application.\n\nA standard prebiopsy preparation was applied for all patients. No enema was used. Patients only fasted the night before. The biopsy procedure was carried out under local periprostatic anesthesia. TRUS-guided biopsies were achieved through transrectal ultrasonography using a 7-MHz probe attached. Biopsies were carried out with the patient in the left decubital position using an automated biopsy gun with a disposable 18-G biopsy needle.\n\nAll biopsies were carried out through a systematic approach (a standard 12-core biopsy taken from the base, mid gland, and the apex of the right and left sides of the lateral and far-lateral peripheral zone). Two transitional zone biopsies were added in cases of a previous history of negative biopsies.\n\nPatients were advised to present to the emergency department if they developed symptoms of sepsis within 30 days of the biopsy.\n\nAll patients with sepsis, as defined as fever > 38°C in the presence of constitutional symptoms, were admitted for inpatient management. Empiric treatment with meropenem 1 g [intravenous (i.v.)] twice daily was commenced after collecting blood and urine for culture.\n\nThe main outcome criterion was the incidence of bacteriuria (defined as ≥ 103colony-forming units/mL) within 30 days of biopsy. Secondary endpoints included the incidence of clinical symptoms of fever, flushing, chills, or any weakness on physical examination and UTI, defined as the association of leukocyturia (>5 cells/high-power field) and bacteriuria, or any significant change in the biological results suggesting an infection including a blood cell count and C-reactive protein.\n\n2.2 Statistical analysis\nDifferences in risk factors between quinolone-resistant and nonresistant patients were compared using a Fisher exact test with statistical significance ascribed at P < 0.05. Univariate and multivariate analyses were performed to identify independent potential risk factors associated with FQ-resistant rectal flora. Statistical analyses were performed with SPSS version 21.0 (SPSS Inc., Chicago, IL, USA) statistical software package.\n\n3 Results\nThe mean age of patients was 63.6 years and 65.2 years in Group 1 and Group 2, respectively (P = 0.4).There was no difference in mean PSA value (P = 0.62) or age-adjusted Charlson comorbidity score (P = 0.25) between the two groups.\n\nSixteen men out of 279 men developed infectious complications after TRUSBx in the group receiving standard empirical prophylaxis (5.7%) in the form of fever and pyelonephritis including two cases of sepsis. None of the two men admitted for sepsis required intensive care treatment and all were successfully managed with i.v. fluids and i.v. meropenem (1 g twice daily). No men in the group who received targeted prophylactic antibiotic guided by rectal swab developed infectious complications. This result was statistically significant (P = 0.003). Culture and susceptibility results for the two men with sepsis demonstrated FQ resistant extended-spectrum β-lactamase-producing Escherichia coli.\n\nAmong the 262 patients who underwent prebiopsy rectal swab cultures, 76 men (29%) displayed FQ-resistant rectal flora (29%). Of the 76 bacterial isolates, 84.2% were E. coli and 10.5% were Klebsiella pneumonia. Antimicrobial susceptibility testing to FQ-resistant strains obtained by rectal swab showed the highest resistance notably to cotrimoxazole (85%), followed by cefotaxime (63%), and the highest sensitivity shown to carbapenems (92.1%), fosomycin (85.5%), amikacin (79%), followed by nitrofurantoin (63%), and sulbactam/cefoperazone (42.1%; Fig. 2).\n\nAge, diabetic status, presence of a urinary catheter, and a history of prior prostate biopsy were not associated with FQ resistance. Prior UTI and antibiotic exposure before prostate biopsy was associated with quinolone resistance (P = 0.041 and 0.001, respectively; Table 2).\n\nIn the univariate analysis, prior UTI and history of exposure to antibiotics increased the risk of FQ resistance [odds ratio (OR), 4.45; 95% confidence interval (CI), 1.36–10.52; P = 0.02, and OR, 34.2 CI, 3.16–178.52; P = 0.001, respectively] (Table 3).\n\nIn the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with increased risk of FQ resistance (OR, 41.2; 95% CI, 3.16–328.46; P = 0.008; Table 4).\n\n4 Discussion\nThe use of prophylactic antibiotics prior to TRUSBx reaches a consensus; however, data to guide the optimal choice of prophylactic antibiotic are currently lacking. No standard regimen for antibiotic prophylaxis has been formulated despite the need to optimize prophylaxis against infectious complications post-TRUSBx being recognized a long time ago.16\n\nMultiple strategies aimed at improving the safety and acceptability of prostate biopsies are the subject of ongoing research studies. Different prophylactic regimens depending on local microbiological profiles, and alternate approaches to prostate biopsies, such as the transperineal approach, are considered depending on availability.17 Rectal disinfection and washing the biopsy needle with povidone–iodine are other approaches used with the aim of reducing infection complications post-TRUSBx in some centers.18, 19\n\nThe European Association of Urology guideline recommends the use of a FQ as a first-line agent for the prevention of infection from transrectal prostate biopsy, with ciprofloxacin being superior to ofloxacin.20 Our current clinical practice usually includes an empirical oral FQ antibiotic usage of 3 days starting the day before the procedure owing to their excellent prostatic penetration;7 these agents also provide good coverage against the key pathogens implicated in post-TRUSBx infectious complications.21 However, FQ resistance has emerged as a growing problem resulting in a significant increase in infectious complications in men undergoing TRUS biopsies.\n\nMany reports have shown that the prevalence of FQ-resistant E. coli in Western countries is on the rise.9, 11 In the USA, FQ-resistant bacteria were identified in 22% of samples from rectal swab cultures before TRUSBx.22 Furthermore, in American men who developed acute prostatitis after TRUSBx, the FQ-resistant rate was reported to be 57.1%.23 Batura et al24 obtained rectal swabs from 445 men undergoing TRUSBx and found a 13.3% incidence of FQ-resistant coliforms. The present study looks at the local susceptibility for FQ in our patient population, with an incidence of FQ resistance as high as 29% which is relatively high and may be due to an increase in antibiotic prescriptions in the past few years. In light of the worldwide emergence of FQ resistance and its increasing implication in post-TRUSBx infectious complications including sepsis, the current recommendations for antimicrobial prophylaxis need to be reevaluated.\n\nOur results showed that targeted antibiotic prophylaxis guided by a pre-TRUSBx rectal swab was dramatically effective in lowering postbiopsy infectious complications. No men in the group who received targeted prophylactic antibiotics guided by a rectal swab developed an infectious complication. In contrast, men treated with empirical prophylactic antibiotic regimen had a 5.7% rate of infectious complications despite receiving ciprofloxacin and metronidazole for 3 days. This rate matches the worldwide reported incidence for infectious complication post-TRUSBx of around 2–6%.17 Two cases of sepsis had cultures of ciprofloxacin-resistant E. coli, suggesting that ciprofloxacin resistance is a significant contributor to the failure of standard prophylaxis. This may be attributed to the frequent unsupervised use of these antibiotics or inadequate dosing with subsequent development of resistance in the rectal flora, creating potentially worse problems in cases of post-TRUS biopsy sepsis, where these drugs would have reduced efficacy as empirical treatment.\n\nSeveral reports in literature have suggested that rectal swab cultures before a biopsy may allow for an individualized and targeted approach to providing prophylactic antibiotics and decreased overall cost of care. Duplessis et al22 showed that rectal cultures obtained before TRUSBx with the use of selective media to identify FQ-resistant Enterobacteriaceae facilitate targeted antibiotic prophylaxis and appear to be highly efficacious in reducing postprostatic biopsy infection rates. Taylor et al23 reported no infectious complications in 112 men who received targeted antimicrobial prophylaxis and this was associated with a reduced cost of care. Our data show similar results, with no cases of infectious complications in the group that received targeted antibiotic prophylaxis guided by rectal swab culture, whereas 16 cases among 279 patients receiving empirical FQ prophylaxis developed infectious complications including two cases of sepsis (P = 0.003).\n\nConcerns regarding the practical implementation of rectal swab collection need considering. Optimal timing of swab collection, duration of targeted antibiotic regimen, target population, and cost effectiveness has to be clearly established. The feasibility, and cost effectiveness of routine rectal swabs for every patient undergoing TRUSBx must be considered, as it represents a significant burden for clinical microbiology laboratories, and would incur several additional costs (culture media, targeted antibiotics, etc.).\n\nIn a previous study comparing cost-effectiveness of targeted versus empirical prophylaxis per 100 men undergoing TRUSBx, Taylor et al23 showed that the total cost of managing infectious complications in patients in the empirical group was US $13,219 including hospital admission, outpatient and emergency room visits, prolonged antibiotic treatment, diagnostic imaging procedures, laboratory tests, and professional fees. Cost-effectiveness analysis revealed that targeted prophylaxis yielded a cost savings of US $4,499 per post-TRUSBx infectious complication averted. Currently, there is no conclusive evidence of the overall benefit of routine adoption of targeted prophylaxis and the burden of the additional costs limits the widespread replacement of such an approach.\n\nA more practical and feasible approach to optimize the use of antimicrobial prophylaxis for TRUSBx is to consider the selective application of rectal swabs before prostate biopsy in patients with high risk factors and to use the standard protocol for low-risk patients. However, men at high risk for developing post-TRUSBx infections are not yet well defined. A number of recent studies tried to look at these risk factors for infection post-TRUSBx.\n\nLiss et al11 obtained rectal swabs from 136 men before TRUSBx over a 3-month period. In 22% of patients, rectal cultures showed quinolone-resistant E. coli, and patients with diabetes, Asian ethnicity, and a prior history of TRUSBx were determined to be at a higher risk for colonization with resistant organisms, although these differences did not reach statistical significance. In this series, five patients (3.6%) developed post-TRUSBx fever, among which only one had a positive rectal culture. Kanafani et al25 and Lautenbach et al26 pointed out in their studies that previous use of FQ was an independent risk factor for acquiring infections with extended-spectrum β-lactamase-producing E. coli-producing organisms. Similar to those observations, prior UTI and history of exposure to antibiotics increased the risk of FQ resistance by univariate analysis in the present study. In the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with increased risk of FQ resistance (P = 0.008).\n\nAs an alternative to FQ standard prophylaxis, changing to broad-spectrum antimicrobials with extremely low resistance rates in rectal flora, eliminating the need for rectal culture has also been suggested.12, 14 However, the high cost and frequent use of these antibiotics again may lead to the subsequent development of resistance in rectal microbiota, potentially limiting its use in prophylaxis prior to TRUSBx. Our patients' antimicrobial susceptibility testing showed the highest sensitivity to cabapenems, fosomycin, and amikacin.\n\nThe present study raises awareness of local susceptibility for FQ in our patient population and highlights the utility of a rectal swab as an approach to optimize antibiotic prophylaxis prior to TRUSBx in high-risk patients. Thus a benefit of screening prior to TRUSBx and targeted prophylaxis should be considered as a thoughtful, predictable alternative to routine empirical prophylaxis. Using a risk stratification approach seems to be effective at identifying those men at higher risk of infectious complications. Future studies will need to evaluate the cost effectiveness and clinical utility of a prebiopsy rectal culture in targeting antibiotic prophylaxis.\n\nWe acknowledge several limitations of the present study. Firstly, there might be a recall bias, relying on patient recall for past histories of UTI and antibiotic use. Similarly, the frequency of exposure to FQ and the duration preceding TRUSBx could not be ascertained, therefore it is possible that some patients might have forgotten these past events which may have led to an underestimation of the total number of patients with a history of antibiotic use. Secondly, a true cost-benefit analysis between routine empirical antibiotic prophylaxis and targeted antibiotic prophylaxis has not been formally undertaken in our study. Finally, lack of culture standardization in microbiological laboratories may represent a limiting factor.\n\nIn conclusion, determining the prevalence of FQ resistance in rectal flora has important implications in the selection of targeted prophylactic antibiotic regimens. Antimicrobial profiles guided by rectal swabs may prove useful to optimize prophylaxis prior to TRUSBx; this strategy is effective at reducing the rates of infectious complications, including sepsis, especially in men at higher risk for infectious complications.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Study cases. FQ, fluroquinolones; TRUSBx, transrectal ultrasound-guided prostate biopsies.\n\nFig. 2 Antimicrobial susceptibility testing to fluoroquinolone-resistant strains.\n\nTable 1 Patients' demographics.\n\nVariables\tGroup 1 (n = 279)\tGroup 2 (n = 262)\tP\t\nMean age (y)\t63.6\t65.2\t0.461\t\nMean PSA (ng/mL)\t18\t22\t0.624\t\nMean prostate volume (mL)\t64\t59\t0.187\t\nNo. of diabetes patients\t73 (26.2)\t80 (30.5)\t0.422\t\nAAC (mean)\t\t\t0.252\t\n• 0–1\n\n\t175\t156\t\n• 2–3\n\n\t65\t57\t\n• 2–5\n\n\t32\t38\t\n• ≥ 6\n\n\t7\t11\t\nPrior UTI\t136 (48.7)\t116 (44.3)\t0.582\t\nPresence of urinary catheter\t35 (12.5)\t26 (9.9)\t0.182\t\nPrior antibiotic exposure within 6 mo\t90 (32.2)\t87 (33.2)\t0.922\t\nPrior prostate biopsy\t52 (18.6)\t54 (20.6)\t0.863\t\nData are presented as n (%).\n\nACC, age-adjusted Charlson comorbidity score; PSA, prostate-specific antigen; UTI, urinary tract infection.\n\nTable 2 Risk factors and quinolone resistance status.\n\nVariables\tFQ resistant (n = 76)\tFQ sensitive (n = 186)\tP\t\nAge ≥ 65 (y)\t12 (15.7)\t30 (16.1)\t0.18\t\nDiabetes\t28 (36.8)\t52 (27.9)\t0.62\t\nPrior UTI\t39 (51.3)\t77 (41.33)\t0.041a)\t\nPresence of urinary catheter\t9 (11.8)\t17 (9.1)\t0.52\t\nPrior antibiotic exposure within 6 mo\t45 (59.2)\t42 (22.5)\t0.001a)\t\nPrior prostate biopsy\t18 (23.6)\t36 (19.3)\t0.24\t\nData are presented as n (%).\n\nFQ, fluoroquinolone; UTI, urinary tract infection.\n\na) Statistically significant.\n\nTable 3 Univariate logistic regression analysis of factors influencing quinolone resistance.\n\nFQ resistance\tOR (95% CI)\tP\t\nAge ≥ 65 y\t1.28 (0.42–4.35)\t0.453\t\nDiabetes\t3.47 (0.1–6.32)\t0.520\t\nPrior UTI\t4.45 (1.36–10.52)\t0.02a)\t\nPresence of urinary catheter\t1.08 (0.22–6.43)\t0.38\t\nPrior antibiotic exposure within 6 mo\t34.2 (3.16–178.52)\t0.001a)\t\nPrior prostate biopsy\t3.02 (0.82–6.88)\t0.24\t\nCI, confidence interval; FQ, fluoroquinolone; OR, odds ratio; URI, urinary tract infection.\n\na) Statistically significant.\n\nTable 4 Multivariate logistic regression analysis of factors influencing quinolone resistance.\n\nFQ resistance\tOR (95% CI)\tP\t\nPrior UTI\t1.62 (0.85–11.08)\t0.659\t\nPrior antibiotic exposure within 6 mo\t41.2 (3.16–328.46)\t0.008a)\t\nCI, confidence interval; FQ, fluoroquinolone; OR, odds ratio; URI, urinary tract infection.\n\na) Statistically significant.\n==== Refs\nReferences\n1 Challacombe B. 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Nakama-Peeples A. Peterson E.M. Osann K. Prevalence and significance of fluoroquinolone resistant Escherichia coli in patients undergoing transrectal ultrasound guided prostate needle biopsy J Urol 185 2011 1283 1288 21334021 \n12 Kehinde E.O. Al-Maghrebi M. Sheikh M. Anim J.T. Combined ciprofloxacin and amikacin prophylaxis in the prevention of septicemia after transrectal ultrasound guided biopsy of the prostate J Urol 189 2013 911 915 23009873 \n13 Adibi M. Hornberger B. Bhat D. Raj G. Roehrborn C.G. Lotan Y. Reduction in hospital admission rates due to post-prostate biopsy infections after augmenting standard antibiotic prophylaxis J Urol 189 2013 535 540 22982426 \n14 Batura D. Rao G.G. Nielson P.B. Charlett A. Adding amikacin to fluoroquinolone-based antimicrobial prophylaxis reduces prostate biopsy infection rates BJU Int 107 2011 760 764 21029317 \n15 Simsir A. Kismali E. Mammadov R. Gunaydin G. Cal C. 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Does washing the biopsy needle with povidone-iodine have an effect on infection rates after transrectal prostate needle biopsy? Urol Int 85 2010 147 151 20453481 \n20 Heidenreich A. Bastian P.J. Bellmunt J. Bolla M. Joniau S. Mason M.D. Guidelines on prostate cancer [Internet] 2013 European Association of Urology Arnhem (NL) [cited 2013 May 10]. Available from: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf \n21 Campeggi A. Ouzaid I. Xylinas E. Lesprit P. Hoznek A. Vordos D. Acute bacterial prostatitis after transrectal ultrasound-guided prostate biopsy: Epidemiological, bacteria and treatment patterns from a 4-year prospective study Int J Urol 21 2014 152 155 23906113 \n22 Duplessis C.A. Bavaro M. Simons M.P. Marguet C. Santomauro M. Auge B. Rectal cultures before transrectal ultrasound-guided prostate biopsy reduce post-prostatic biopsy infection rates Urology 79 2012 556 561 22386395 \n23 Taylor A.K. Zembower T.R. Nadler R.B. Scheetz M.H. Cashy J.P. Bowen D. Targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care J Urol 187 2012 1275 1279 22341272 \n24 Batura D. Rao G.G. Nielsen P.B. Prevalence of antimicrobial resistance in intestinal flora of patients undergoing prostatic biopsy: implications for prophylaxis and treatment of infections after biopsy BJU Int 106 2010 1017 1020 20346055 \n25 Kanafani Z.A. Mehio-Sibai A. Araj G.F. Kanaan M. Kanj S.S. Epidemiology and risk factors for extended-spectrum beta-lactamase-producing organisms: a case control study at a tertiary care center in Lebanon Am J Infect Control 33 2005 326 332 16061138 \n26 Lautenbach E. Patel J.B. Bilker W.B. Edelstein P.H. Fishman N.O. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae : Risk factors for infection and impact of resistance on outcomes Clin Infect Dis 32 2001 1162 1171 11283805\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2287-8882", "issue": "4(3)", "journal": "Prostate international", "keywords": "Biopsy; Prophylactic antibiotic; Prostate biopsy; Transrectal", "medline_ta": "Prostate Int", "mesh_terms": null, "nlm_unique_id": "101605566", "other_id": null, "pages": "113-7", "pmc": null, "pmid": "27689069", "pubdate": "2016-09", "publication_types": "D016428:Journal Article", "references": "21334021;16391904;9763070;20224265;21771239;21958223;20346055;21705048;22341272;23906113;23009873;16061138;8705220;20453481;21420152;22244150;10759665;21029317;22982426;20089283;21944136;23532481;23041343;11283805;22386395", "title": "Optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound-guided prostate biopsies: A prospective randomized study.", "title_normalized": "optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound guided prostate biopsies a prospective randomized study" }	[ { "companynumb": "EG-BAUSCH-BL-2016-027255", "fulfillexpeditecriteria": "1", "occurcountry": "EG", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "020743", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FAHMY A, RHASHAD H, MOHI M, ELABBADIE A, KOTB A. OPTIMIZING PROPHYLACTIC ANTIBIOTIC REGIMEN IN PATIENTS ADMITTED FOR TRANSRECTAL ULTRASOUND-GUIDED PROSTATE BIOPSIES: A PROSPECTIVE RANDOMIZED STUDY.. PROSTATE INT. 2016;4:113-117.", "literaturereference_normalized": "optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound guided prostate biopsies a prospective randomized study", "qualification": "3", "reportercountry": "EG" }, "primarysourcecountry": "EG", "receiptdate": "20161111", "receivedate": "20161111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12934744, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "EG-BAUSCH-BL-2016-027148", "fulfillexpeditecriteria": "1", "occurcountry": "EG", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "020743", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FAHMY A, RHASHAD H, MOHI M, ELABBADIE A, KOTB A. OPTIMIZING PROPHYLACTIC ANTIBIOTIC REGIMEN IN PATIENTS ADMITTED FOR TRANSRECTAL ULTRASOUND-GUIDED PROSTATE BIOPSIES: A PROSPECTIVE RANDOMIZED STUDY. PROSTATE INT. 2016;113-117.", "literaturereference_normalized": "optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound guided prostate biopsies a prospective randomized study", "qualification": "3", "reportercountry": "EG" }, "primarysourcecountry": "EG", "receiptdate": "20161106", "receivedate": "20161106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12914916, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]
{ "abstract": "Roux-en-y-gastric bypass (RYGB) is the most commonly performed bariatric procedure worldwide which is taking the lead in resolving of comorbid conditions. Short- and long-term complications of RYGB procedure have been recognized, including osteopenia, osteomalacia and more rarely neurological disorders. Oxalate nephropathy is a complication of RYGB that has been described earlier in the literature and may end with renal failure and dialysis if not recognized and treated early. The etiology of this phenomenon is still unclear, but the length of common limb remains the theory that mostly contributed to its development. We believe that this limb should be more than 100 cm to prevent severe malabsorption. Here, we report a reversible case of oxalate nephropathy 3 months after RYGB in a 51-year-old patient.", "affiliations": "Gastroenterology Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.;General Surgery Division, Central Military Hospital, Beirut, Lebanon.;General Surgery Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.;Gastroenterology Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.;General Surgery Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.", "authors": "Farhat\|Said\|S\|;Houssam\|Abtar\|A\|;Ghassaoui\|Ali\|A\|;Khaled\|El Ajami\|EA\|;El Khoury\|Mansour\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/omcr/omw054", "fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omw054omw054Case ReportA case of reversible hyperoxaluria nephropathy early after roux-en-y-gastric\nbypass induced by vitamin C intake Farhat Said 1Houssam Abtar 2Ghassaoui Ali 3Khaled El Ajami 1El Khoury Mansour 3\n1 Gastroenterology Division, Saint Georges\nHospital University Medical Center, University of Balamand,\nBeirut, Lebanon\n2 \nGeneral Surgery Division, Central Military Hospital, Beirut, Lebanon\n\n3 \nGeneral Surgery Division, Saint Georges Hospital University Medical Center,\nUniversity of Balamand, Beirut, Lebanon\n Corresponding address. Saint Georges Hospital\nUniversity Medical Center, University of Balamand, P.O. Box 166 378, Achrafieh, Beirut 11\n00 2807, Lebanon. Tel: +961-1-441-000 or +961-1-575-700; Fax:\n+961-1-582-560; E-mail:\[email protected] 2016 29 8 2016 29 8 2016 2016 8 omw05425 11 2015 24 5 2016 31 5 2016 © The Author 2016. Published by Oxford University\nPress.2016This is an Open Access article distributed under the terms of the Creative Commons\nAttribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits\nnon-commercial re-use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited. For commercial re-use, please contact\[email protected] bypass (RYGB) is the most commonly performed bariatric procedure\nworldwide which is taking the lead in resolving of comorbid conditions. Short- and\nlong-term complications of RYGB procedure have been recognized, including osteopenia,\nosteomalacia and more rarely neurological disorders. Oxalate nephropathy is a complication\nof RYGB that has been described earlier in the literature and may end with renal failure\nand dialysis if not recognized and treated early. The etiology of this phenomenon is still\nunclear, but the length of common limb remains the theory that mostly contributed to its\ndevelopment. We believe that this limb should be more than 100 cm to prevent severe\nmalabsorption. Here, we report a reversible case of oxalate nephropathy 3 months after\nRYGB in a 51-year-old patient.\n==== Body\nINTRODUCTION\nNearly 35% of adults aged 20 years and over were overweight in 2008, and 11%\nwere obese according to the World Health Organization (WHO); this percentage will continue\nto increase with time. Roux-en-y-gastric bypass (RYGB) is the most common procedure done and\nleads to improvements in weight, sugar levels, insulin resistance, cardiovascular risk\nfactors and sleep apnea. Although both short- and long-term complications of RYGB procedure\nhave been recognized, including osteopenia, osteomalacia, and more rarely neurological\ndisorders, the procedure has been deemed relatively safe and effective [1].\n\nRecent data suggest that modern bariatric procedures, such as RYGB, may also impart a\n2-fold increased risk of nephrolithiasis, whereas 20–75% of patients may have\nhyperoxaluria, including 20% with very high urine oxalate levels, also putting them\nat considerable risk of oxalate nephropathy [2].\n\nCASE REPORT\nWe report a case of RYGB that leads to oxalate nephropathy 3 months after the procedure: a\n51-year-old male patient with type 2 diabetes mellitus and a body mass index (BMI) of 42\nkg/m2 (Table 1). A\nstandard RYGB procedure was performed, and a 30–50 ml gastric pouch was created; the\nlength of the Roux segment was 150 cm, and the length of the jejunum from the ligament of\nTreitz to the jejuno-jejunal anastomosis was 40 cm. Table 1. Patient's demographics and biochemical results\n\nCharacteristics\t\nSex\tMale\t\nAge (year)\t51\t\nBMI (kg/m2)\t42\t\nRenal function\tNormal\t\nDiabetes mellitus\tYes\t\nHypertension\tNo\t\nHyperlipidemia\tNo\t\nChronic obstructive pulmonary disease\tNo\t\nSmoker\tYes\t\nBiochemical results on admission\t\nSerum creatinine (mg/dl)\t8.42\t\n24 h Urine oxalate level (mg)\t80\t\n\n\nThree months after the procedure, the patient started complaining of productive cough,\nchills and bilateral flank pain over a period of 2 days associated with decreased fluid\nintake and low urine output. He was found to have elevated creatinine on laboratory workup\n(8.42 mg/dl). He was admitted for further investigation and was started on the appropriate\nantibiotics for the diagnosis of pneumonia. During history taking, the patient was found to\nbe on non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen) and high-dose vitamin C, 1\ng/day which is much higher than the normal dose (75 mg for women and 90 mg for men) on his\nown. His creatinine continued to increase during his stay at the hospital reaching 9.5 mg/dl\nand was oliguric. Twenty-four-hour urine oxalate level was 80 mg (normal range =\n4–31 mg/24 h), and CT scan was done to rule out obstructive nephropathy. Kidney\nbiopsy specimen was obtained, and it showed deposition of calcium oxalate crystals in the\nlumen of few tubules compatible with oxalate nephropathy (Fig. 1). He was started on intravenous (IV) hydration, high oral calcium\nsupplementation (1500 mg/day), low oxalate diet and steroid therapy (20 mg/day) as treatment\nfor acute interstitial nephritis (AIN). After this regimen, the urine volume increased and\nhis creatinine level decreased. Progressively creatinine decreased to reach 1.9 mg/dl 10\ndays after (Fig. 2). During a period of 3\nmonths, the patient got readmitted twice: once for gastroenteritis and once for bilateral\nlower limbs edema, and investigations revealed low total protein, albumin levels and\ngeneralized fatigue. For this reason, decision was taken to reverse the RYGB. Figure 1. Histopathology showed deposition of calcium oxalate crystals in the lumen of\nfew tubules (black arrow). (A) Polarized light 50×. (B) Hematoxylin and eosin\n50×.\n\n\nFigure 2. Serum creatinine level changes during hospital stay.\n\n\n\nDISCUSSION\nOxalate nephropathy is a complication of RYGB that has been described earlier in the\nliterature and will be encountered more frequently clinically, in our opinion, as the number\nof bariatric operations is increasing, especially RYGB. In the study done by Nasr et\nal. [3], 11 patients presented with\nacute kidney injury (AKI) 6 months after RYGB and were diagnosed with oxalate nephropathy.\nIn another study done by Sinha et al. [1], 31 patients had oxalate nephropathy 2.2 years post RYGB. Oxalate nephropathy\nwas seen also in kidney transplant recipient patients 27 and 7 years, respectively, after\nRYGB as described by Troxell et al. [2]. Matlaga et al. [4] showed that nephrolithiasis incidence after RYGB is 7.65% (in a study with\n4639 RYGB patients) when compared with 4.63% in the same number of patients that did\nnot undergo bariatric operation. Our patient presented with AKI (creatinine = 8.42\nmg/dl) 3 months after the operation, which has never been reported before.\n\nWe think that the etiology of this early formation of oxalate deposits was multifactorial\nincluding: RYGB by itself as a malabsorptive factor, high dose of vitamin C intake, NSAIDs\nthat the patient was taking to relieve the flank pain, high oxalate diet (coffee,\nchocolates, cocoa) and low fluid intake by the patient over 24 h that led to low urinary\nvolumes.\n\nAccording to several studies, the use of traditional NSAIDs is well established to be\nassociated with AKI with relative risks compared with non-user ranging from 1.6 to 2.2.\nIndomethacin users account for the highest risk ratio of developing AKI. NSAIDs can cause\nAKI by two different mechanisms: hemodynamically mediated [decrease in prostaglandin (PG)\nsynthesis due to inhibition of cyclooxygenase (COX-1) enzymes in combination with renal\nvasoconstriction] and AIN [5].\n\nVitamin C is believed to result in a hyperoxaluric state. The recommended daily intake of\nvitamin C is between 75 and 90 mg/day. Several cases of oxalate nephropathy have been\nreported with vitamin C intake <2 g/day [6]. The mechanism of oxalate deposit formation is contributed by the increased fat\nmalabsorption which leads to increased colonic fat that binds to free calcium, increasing\nunbound oxalate that is able to cross the colonic mucosa. In malabsorptive states (like\nafter RYGB), the percentage of oxalate absorbed from the gut and excreted in urine can be\nmarkedly increased and hyperoxaluria often correlates with steatorrhea [7].\n\nThe pathogenesis of hyperoxaluria after RYGB is not completely understood, but the length\nof the common channel is one of the most important factors leading to significant fat\nmalabsorption in some, causing enteric hyperoxaluria. Although RYGB operation with a Roux\nlimb of <150 cm in length is generally believed not to cause fat malabsorption, data\nsuggest that hyperoxaluria may indeed occur, and represent a risk for calcium oxalate\nnephrolithiasis [1].\n\nSome earlier studies of patients with inflammatory bowel disease correlate the degree of\nhyperoxaluria with the degree of steatorrhea; this pathogenesis might explain why patients\nwho have had distal RYGB (through creation of a longer Roux limb and subsequently shorter\ncommon channel for nutrient absorption) can be at higher risk for developing calcium oxalate\nkidney stones compared with standard RYGB patients [8].\n\nThe goal of management is to reach normal creatinine levels and normal diuresis. Many\ntreatments can be applied starting with oxalate-free diet, limit fat intake, appropriate\nhydration to maintain urine output of at least 2 l, oral calcium supplementation and\nreversal of the surgery [9]. This strategy, if\napplied early, can reverse the nephropathy and can prevent irreversible tubular damage\nleading to dialysis. More recent treatments like supplementation of Oxalobacter\nformigenes bacteria, a normal commensurate part of the human gut\nmicroflora which metabolizes oxalate as an energy source have been applied and showed\npromising results by reducing the urinary oxalate levels [1].\n\nIn conclusion, surgeons should be aware of this complication and be aggressive in their\ntreatment strategies in order not to reach dialysis. We suggest counting accurately the\nlength of the common channel during each gastric bypass as well as maintaining oxalate-free\nand fat-free diet with oral calcium supplementation postoperatively.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nThere were no sources of funding.\n\nETHICAL APPROVAL\nNo ethical approval is required.\n\nCONSENT\nWritten informed consent was obtained from the patient for the publication of this case\nreport.\n\nGUARANTORS\nF.S. and H.A. are guarantors of this study.\n==== Refs\nREFERENCES\n1 Sinha MK Collazo-Clavell ML Rule A Milliner DS Nelson W Sarr MG \nHyperoxaluric nephrolithiasis is a complication of roux-en-y gastric bypass\nsurgery . Kidney Int \n2007 ;72 :100 –7 .17377509 \n2 Troxell ML Houghton DC Hawkey M Batiuk TD Bennett WM \nEnteric oxalate nephropathy in the renal allograft: an underrecognized\ncomplication of bariatric surgery . Am J Transplant \n2013 ;13 :501 –9 .23311979 \n3 Nasr SH D'Agati VD Said SM Stokes MB Largoza MV Radhakrishnan J \nOxalate nephropathy complicating roux-en-y gastric bypass: an\nunderrecognized cause of irreversible cause of irreversible renal\nfailure . Clin J Am Soc Nephrol \n2008 ;3 :1676 –83 .18701613 \n4 Matlaga BR Shore AD Magnuson T Clark JM Johns R Makary MA \nEffect of gastric bypass surgery on kidney stone disease .\nJ Urol \n2009 ;181 :2573 –7 .19375090 \n5 Ungprasert P Cheungpasitporn W Crowson CS Matteson EL \nIndividual non-steroidal anti-inflammatory drugs and risk of acute kidney\ninjury: a systematic review and meta-analysis of observational studies .\nEur J Intern Med \n2015 ;26 :285 –91 .25862494 \n6 Sunkara V Pelkowski TD Dreyfus D Satoskar A \nAcute kidney disease due to excessive vitamin C ingestion and remote\nroux-en-y gastric bypass surgery superimposed on CKD . Am J\nKidney Dis \n2015 ;66 :721 –4 .26271145 \n7 Kumar R Lieske JC Collazo-Clavell ML Sarr MG Olson ER Vrtiska TJ \net al. Fat malabsorption and increased intestinal absorption are common\nafter roux-en-y gastric bypass surgery . Surgery \n2011 ;149 :654 –61 .21295813 \n8 Duffey BG Pedro RN Makhlouf A Kriedberg C Stessman M Hinck B \nRoux-en-y gastric bypass is associated with early increased risk factors\nfor development of calcium oxalate nephrolithiasis . J Am Coll\nSurg \n2008 ;206 :1145 –53 .18501812 \n9 Whitson J Stackhouse G Stoller M \nHyperoxaluria after modern bariatric surgery: case series and literature\nreview . Int Urol Nephrol. \n2010 ;42 :369 –74 .19572208\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2053-8855", "issue": "2016(8)", "journal": "Oxford medical case reports", "keywords": null, "medline_ta": "Oxf Med Case Reports", "mesh_terms": null, "nlm_unique_id": "101642070", "other_id": null, "pages": "omw054", "pmc": null, "pmid": "29497551", "pubdate": "2016-08", "publication_types": "D002363:Case Reports", "references": "25862494;26271145;23311979;19375090;18701613;18501812;17377509;19572208;21295813", "title": "A case of reversible hyperoxaluria nephropathy early after roux-en-y-gastric bypass induced by vitamin C intake.", "title_normalized": "a case of reversible hyperoxaluria nephropathy early after roux en y gastric bypass induced by vitamin c intake" }	[ { "companynumb": "LB-PFIZER INC-2017542603", "fulfillexpeditecriteria": "1", "occurcountry": "LB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "018989", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FLANK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASCORBIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, 1X/DAY, HIGH DOSE OF VITAMIN C", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASCORBIC ACID." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperoxaluria", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Nephropathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FARHAT, S.. A CASE OF REVERSIBLE HYPEROXALURIA NEPHROPATHY EARLY AFTER ROUX?EN?Y?GASTRIC BYPASS INDUCED BY VITAMIN C INTAKE. OXFORD MEDICAL CASE REPORTS. 2017?2016 (8):205?207", "literaturereference_normalized": "a case of reversible hyperoxaluria nephropathy early after roux en y gastric bypass induced by vitamin c intake", "qualification": "1", "reportercountry": "LB" }, "primarysourcecountry": "LB", "receiptdate": "20180925", "receivedate": "20171222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14319329, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "LB-MYLANLABS-2017M1080610", "fulfillexpeditecriteria": "1", "occurcountry": "LB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASCORBIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSE ASCORBIC-ACID AT 1 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASCORBIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FLANK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oliguria", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Crystal nephropathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FARHAT S, HOUSSAM A, GHASSAOUI A, KHALED EA, EL KHOURY M. A CASE OF REVERSIBLE HYPEROXALURIA NEPHROPATHY EARLY AFTER ROUX-EN-Y-GASTRIC BYPASS INDUCED BY VITAMIN C INTAKE. OXF-MED-CASE-REPORTS 2017?2016(8):205-207.", "literaturereference_normalized": "a case of reversible hyperoxaluria nephropathy early after roux en y gastric bypass induced by vitamin c intake", "qualification": "3", "reportercountry": "LB" }, "primarysourcecountry": "LB", "receiptdate": "20180103", "receivedate": "20180103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14347995, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.", "affiliations": "Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.;Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden.;Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.", "authors": "Ringdén\|Olle\|O\|;Gustafsson\|Britt\|B\|;Sadeghi\|Behnam\|B\|", "chemical_list": "D015415:Biomarkers", "country": "Switzerland", "delete": false, "doi": "10.3389/fimmu.2020.567210", "fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.567210\nImmunology\nPerspective\nMesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease\nRingdén Olle 1* Gustafsson Britt 2 Sadeghi Behnam 1 1Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden\n2Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden\nEdited by: Robert James Hayashi, Washington University School of Medicine in St. Louis, United States\n\nReviewed by: Astrid Gertrude Suzanne Van Halteren, Leiden University Medical Center, Netherlands; Frederic Baron, University of Liège, Belgium\n\n*Correspondence: Olle Ringdén [email protected] article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology\n\n\n19 10 2020 \n2020 \n11 56721029 5 2020 02 9 2020 Copyright © 2020 Ringdén, Gustafsson and Sadeghi.2020Ringdén, Gustafsson and SadeghiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.\n\ngraft-versus-host disease (GVHD)mesenchymal stromal cell (MSC)pediatric haematopoietic stem cell transplantationcell theraphydecidua stromal cells (DSCs)\n==== Body\nIntroduction\nHematopoietic cell transplantation (HCT) is an established treatment for children with both malignant and non-malignant hematopoietic diseases and inborn errors of metabolism (1–4). The main obstacles to success are relapse of the disease, infections, graft failure, toxicity of various organs, hemorrhagic cystitis, and graft-versus-host disease (GVHD). To prevent GVHD, patients are treated with immunosuppressive drugs, most commonly, calcineurin inhibitor combined with Methotrexate (5). Despite this, a majority of the patients developed acute GVHD, with a considerable mortality, even if this was significantly lower in children compared to adults (6). To confirm the gastrointestinal GVHD histopathological biopsies is recommended, since e.g., viruses could cause gastrointestinal symptoms (7–9). Cortisone is first-line therapy for acute GVHD (10) and almost all immunosuppressive therapies are used as a secondary treatment with varying degrees of success (11). Friedenstein et al. were the first to describe MSCs (12). We introduced mesenchymal stromal cells (MSCs) as a new therapy for acute GVHD (13, 14). MSCs are rare in all tissues in the body and can differentiate into several cells of mesenchymal cell lineages, such as bone, cartilage, tendon, cardiomyocytes, muscles, and fat (15, 16). There is no specific CD marker for MSCs. However, they stain positive for CD29, CD73, CD90, CD105, and CD166. They are negative for hematopoietic markers, CD34, CD45, and CD14. They are not true stem cells because they cannot regenerate and maintain a whole tissue compartment. MSCs express HLA class I molecules and contain intracellular HLA class II that is expressed on the cell surface after interferon-γ stimulation (17). After injection, MSCs do not appear to be long lived and have been demonstrated in the circulation only shortly after infusion into patients who underwent autologous HCT for breast cancer (18).\n\nImmunosuppression\nMSCs have potent immunomodulatory effects and inhibit phytohemagglutinin induced T cell proliferation and alloreactivity in mixed lymphocyte cultures (MLC) (17, 19, 20). MSCs' inhibition of alloreactivity in vitro is independent of the major histocompatibility system (21). Furthermore, after differentiation into osteocytes, chondrocytes and adipocytes, immunosuppression was still induced (17). MSCs also prolonged skin allograft survival in baboons (19). Several factors and mechanisms are involved in MSC-mediated immune modulation.\n\nBone marrow MSCs (BM-MSCs) are susceptible to complement activation after contact with human blood (22). This results in cell dysfunction or cell death (23). When in contact with blood, BM-MSCs also elicit activation of clotting factors (24).\n\nMSC immunosuppression has been studied extensively (25–28). Stromal cells from various organs such as BM, Wharton's jelly, placenta tissues and cord blood have varying immunosuppressive effects in the MLC (17, 19–21, 29, 30). The MLC is also inhibited by skin fibroblasts (31). Immunosuppressive factors produced by MSCs include prostaglandin E2 (32), HLA-G5 (33), and galectins (34). MSCs also produce indoleamine-2,3, dioxygenase (IDO), which inhibits T cells by converting of tryptophan to kynurenine [(35), Figure 1]. IDO is involved in the induction of regulatory T cells and the inhibition of Th17 differentiation (36). IDO produced by MSCs also promotes differentiation of macrophages toward M2 phenotypes (37). MSCs also induce contact-dependent immunosuppression. Among these are activation of the PD-1 pathway (38), by activation of VCAM-1 and ICAM-1 (39), purification of CD39 and increased adenosine production (40), and Fas-mediated T-cell apoptosis (41). There are differences in various species and, in mice, several models failed to reduce alloreactivity and GVHD (42). To inhibit GVHD in mice, MSCs need to be licensed by IFN-γ, nitric oxide, or transduced with IL10 to prevent GVHD. In a colitis model in mice, it was shown that prevention of colitis by MSCs requires CD11b+ macrophages (43). In a murine model of GVHD, it was demonstrated that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic T-cells, and that this process is essential to initiate MSC-induced immunosuppression (44). After IV infusion, recipient phagocytes engulf apoptotic MSCs and produce IDO, which is necessary for immune suppression. MSCs produce exosomes and microparticles, some of which are small complexed entities that contain both immunomodulatory proteins, micro RNA and mediators for homing abilities (45). Exosomes were also used to reverse acute GVHD (46).\n\nFigure 1 The multiple effects of MSCs on immune cells. (A) MSCs increase the proportion of CD4+CD25+ cells and IL-10 production. (B) MSCs decrease markers for activated T cells, CD25, CD69, and CD38. MSCs delayed maturation of APC and decreased expression of HLA-DR. (C) Dendritic cell type 1 when stimulated had decreased TNF-α and IL-12, when co-cultured with MSCs. (D) MSCs increased IL-10 secretion by LPS-stimulated dendritic cells type 2, CD4+ cell had decreased IL5-secretion. (E) T-helper cell type 1 IFN-γ production was significantly decreased by MSCs. (F) T-helper cell type 2 increased IL-4 secretion in the presence of MSCs. (G) MSCs inhibit mixed lymphocyte cultures and subsequent development of cytotoxic T cells by a soluble factor. (H) Several soluble factors are produced by MSCs, amongst them are IL-6, IL-8, stem-cell derived factor 1 (SDF1), vascular endothelial growth factor (VEGF). Soluble factors that have been suggested to inhibit T-cell activation are prostaglandin E2, which induces regulatory T-cells, indoleamine 2,3-dioxygenase (IDO), which is induced by IFN-γ which catalyzes the conversion from tryptophan to kynurenine and inhibits T-cell responses. Other soluble factors that have been suggested to inhibit T-cell responses are TGFβ1, hepatocyte growth factor and IL-2. (I) MSC induce macrophage differentiation from M1 to M2. (References are mentioned in the text).\n\nMesenchymal Stromal Cells For Treatment of Acute GVHD\nWe introduced MSCs, as a therapy for acute GVHD, by treating a 9-year-old boy with life-threatening grade IV acute GVHD, as well as a phase-I study in GVHD patients whom were resistant to several immunosuppressive therapies (13, 14). We also performed a multi-center phase II study, including 55 patients with severe steroid resistant GVHD (47). Complete responders had lower transplantation-related mortality 1 year after infusion than patients with partial or no response (11 [37%] of 30 vs. 18 [72%] of 25; p = 0.002). Patients with complete response to MSCs had a 2-year survival of 53% as opposed to 16% in partial and non-responders. Children had a trend for better response (64%) as opposed to adults (47%). Subsequently, several single-center studies were performed with varying results using various sources of stromal cells, for instance, adipose tissue (48). Lucchini et al. gave platelet lysate expanded MSCs to children with severe steroid refractory acute or chronic GVHD with varying responses (49). Commercial MSCs (prochymal) were given to 12 children with therapy-resistant grade III and IV acute GVHD (50). A complete response was seen in seven children (58%), a partial response in two (17%), and mixed responses were recorded in three (25%) of the children. The 100-day survival was 58%. Osiris performed a double-blind placebo controlled phase 2/3 study using prochymal for severe acute GVHD (51). The children were given 8 × 106 MSCs/kg twice a week or placebo. Among 260 patients, including children and adults, who were randomized in this trial, a complete response at 28 days was 74% in the MSCs group and 30% in the placebo group (52). However, the 180-day durable response of liver GVHD was 29% in the MSC group compared to 5% in the placebo group (p = 0.047%). Among patients with acute GVHD grades III–IV, Remestemcell-L demonstrated significantly higher overall response, 65%, as opposed to 23% in the placebo arm (p = 0.05). Children had a better outcome of treatment with MSCs for acute GVHD as compared to adults. These pediatric patients were also reported separately (53). Ball and coworkers reported on 37 children treated with MSCs for steroid-refractory grade III–IV acute GVHD (54). A response was observed in 65% of the children. The 3-year survival was 37%. Kurtzberg et al. reported on 241 children with steroid refractory acute GVHD who were treated for 4 weeks with infusion of 2 × 106 MSCs/kg (Remestemcel-L) twice weekly (55). The overall response rate at day +28 was 65%. Survival at 100 days was 82% among the responders and 39% among the non-responders (p ≤ 0.001). In a Brazilian multicenter study, involving 16 children and 30 adults with steroid refractory GVHD, half of the patients responded and 1-year survival was 20% (56). A study using platelet-lysate-expanded MSC for steroid refractory acute GVHD included eight children and 22 adults. The overall response rate at day +28 was 50% in the adults and 88% in the children (p = 0.099). The survival was 88% in the children as opposed to 25% in the adults (p = 0.003) (57).\n\nA study used BM-MSCs pooled from multiple third-party donors (58). The study included 92 adult and pediatric patients with steroid refractory acute GVHD. The patients received a median of three doses of pooled MSCs without toxicity. The overall response was 82% and 6-month survival was 64%. In a previous separate analysis of children, the overall response at day 28 was 77% and the 2-year survival was 77% (59). At our unit, long-term follow up of patients treated with BM-MSCs with steroid refractory GVHD included nine children and 22 adults (60). Two-year survival was only 26%. Patients receiving MSCs from passage 1–2 had significantly better survival than those receiving MSCs from passage 3–4 (p < 0.01). A meta-analysis reported that children had a better response to MSCs therapy for steroid refractory acute GVHD, with an overall response rate of 82%, as opposed to 70% in adults (p = 0.04) (61). A more recent meta-analysis included children and adults given MSCs for prophylaxis (n = 651) and for treatment of acute GVHD (n = 149) and chronic GVHD (n = 76) (62).\n\nMesenchymal Stromal Cells For Treatment of Chronic Graft-Versus-Host Disease\nChronic GVHD is a great burden for many patients after HCT (63, 64). It seems logical to use MSCs to treat chronic GVHD, which resembles auto-immune disorders. MSCs were reported to be successful in many models of autoimmune diseases (65, 66). There are only a few reports on MSCs for chronic GVHD and most are about adults (14, 67, 68). Lucchini et al. used platelets-lysate expanded MSCs in four children with chronic GVHD (49). Transient benefits were noted. One child had a complete response that subsequently re-flared.\n\nDSCs appear to have a stronger immunosuppressive effect than MSCs from bone marrow (30, 69). Thus, we used DSCs to treat chronic GVHD in three pediatric patients with severe grade 3 chronic GVHD (Based on National Institute of Health, NIH) (70). The three pediatric patients were affected in several organs such as the skin, mouth, eyes, gastrointestinal tract, liver, lungs and joints, fascia. Two patients received two doses of DSC and one patient received one dose. Two patients had a partial response in the liver, normalization of elevated liver enzymes and, in one patient, esophageal varices disappeared. However, the overall grading of chronic GVHD remained very severe (3) according to NIH grading (71). A meta-analysis of 76 children and adults with chronic GVHD suggested improved survival using MSCs (62).\n\nPrevention of GVHD and Graft Failure\nIn mice, MSCs were shown to prevent the development of lethal GVHD (72). Lazarus et al. performed co-transplantation of HLA-identical sibling bone marrow and donor MSCs in 46 patients (73). No patient had graft failure and grades III–IV acute GVHD were seen in 15% of the patients. We performed co-transplantation of HCT and MSCs to enhance engraftment (74). All patients had engraftment and full donor chimerism. A prospective randomized study of HCT and with co-infusion of MSCs or placebo reported decreased risk of acute GVHD and increased likelihood of relapse (75). Engraftment of neutrophils and platelets was similar in the two groups. Most studies of co-transplantation of HCT and MSCs are performed in adult patients or in a combination of pediatric and adult patients (76, 77). In a pediatric study, parental haplo-identical MSCs were used to promote engraftment in unrelated donor umbilical cord blood transplantation (78). In another pediatric study, MSCs were given to recipients of haplo-identical grafts (79). No patient had graft failure as opposed to 10% of the retrospective controls. A meta-analysis, which included 651 children and adults, showed improved survival in patients treated with MSCs as prophylaxis (62). MSCs may also be used to treat graft failure (80, 81).\n\nMSCs For Metabolic Disorders\nHurler's disease is deficiency of the enzyme alfa-L-iduronidase. HCT may partially prevent disease progression if performed before the patient is 2 years of age (82, 83). HCT patients with Hurler's disease and metachromatic leukodystrophy were given MSCs to enhance enzyme production after HCT (84). The rationale for using MSCs was because these cells express high levels of alpha-L-iduromidase and arylsulphatase-A. Four out of five patients with metachromatic leukodystrophy had improved nerve conduction velocity. Five patients with osteogenesis imperfecta who underwent HCT had donor osteoblast engraftment, new dense bone, increased total bone mineral content and improved growth velocity (85). The frequency of bone fractures decreased. Gene-marked MSCs were given to six HCT patients with MSC engraftment in bone and accelerated growth velocity. In a fetus with bilateral femur fractures due to severe osteogenesis imperfecta, in utero transplantation of MSCs showed 7% engraftment and the patient had fewer fractures than expected after birth (86).\n\nMSCs For Hemorrhages and Side-Effects\nWe used MSCs for hemorrhagic cystitis, colon perforation, and pneumomediastinum after HCT (87). Adult patients are more vulnerable and had more toxicity after HCT as opposed to pediatric patients. However, toxicity also occurs in children with advanced hematological malignancies treated with multiple rounds of chemotherapy prior to transplantation. Stromal cells induce clotting and may stop or prevent bleeding. This effect appears to be stronger for DSCs than BM-MSCs (88). Yim et al. reported on two patients with pneumomediastinum/pneumothorax with resolution after MSCs treatment (89).\n\nMaterials and Methods\nPatients\nSix children diagnosed with grade II–IV acute gastrointestinal GVHD, with or without skin involvement, were treated with DSCs (Table 1). The patients comprised five boys and one girl aged from 10 months to l6 years. Informed consent was obtained from the legal guardians of the patients. Diagnoses were pre-B-ALL in two children, Langerhans cell histiocytosis (LCH), sickle cell anemia, osteopetrosis, and severe combined immunodeficiency (SCID). The conditioning therapy was total body irradiation and etoposide in the two patients with leukemia. The four children with other disorders were given fludarabine together with treosulfan in three patients and with the addition of thiotepa in one patient with sickle cell anemia. A boy with osteopetrosis was given a low dose of busulfan, in addition to fludarabine. Donors were matched unrelated in three patients, cord blood in two children, and bone marrow from an HLA-identical sibling donor in one patient. Post-transplant immunosuppression consisted of tacrolimus together with sirolimus in four patients (Table 1). Three patients were given antithymocyte globulin (90).\n\nTable 1 Characteristics of pediatric patients treated with DSCs for acute GVHD.\n\nNo\tUPN\tSex/age\tDiagnosis\tConditioning\tDonor\tGraft\tImmuno-suppression\tAcute GVHD grade\tOrgans involved\tDay of acute GVHD\tDay of DSC\t\n1\t1555\tM/1\tLangerhans cell, histiocytosis\tFlu treo\tUD\tCB\tPrograf rapamune\tIII SR\tGI skin\t+ 20\t+23, +43\t\n2\t1625\tF/16\tHigh risk pre B-ALL\tTBI+VP16\tMUD\tBM\tPrograf rapamune ATG\tII SR\tGI skin\t+ 18\t+30\t\n3\t1687\tM/9\tIntermediate risk pre B-ALL\tTBI+VP16\tHLA id sister\tBM\tPrograf rapamune\tIII SR\tGI skin\t+ 9\t+31, +38, +45, +55, +284, +298\t\n4\t1692\tM/14\tSickle cell anemia\tFlu treo TT\tMUD\tBM\tPrograf rapamune ATG\tII SR\tGI\t+ 182\t+200\t\n5\t1707\tM/1\tOsteopetrosis\tFlu Bu2\tMUD\tPB\tPrograf methotrexate ATG\tII SR\tGI\t+ 17\t+ 21, +70, +78, + 86, +93\t\n6\tUAH\tM/1\tSCID\tFlu treo\tUD\tCB\tCyclosporine MMF\tIV SR\tGI skin\t+ 33\t+ 57, +64, +71, +78, +92, +113\t\nM, male; F, female; Flu, Fludarabine; Treo, Treosulphan; UD, unrelated donor; CB, cord blood; GI, gastro-intestinal tract; TBI, total body irradiation; VP16, vepesid; BM, bone marrow; ATG, anti-thymocyte globulin; TT, Thiotepa; Bu, short course busulphan; SR, steroid refractory; MUD, matched unrelated donor; HLA id, human leukocyte antigen identical; UAH, Uppsala Academic Hospital; SCID, severe combined immunodeficiency; MMF, murophenolate mofetil.\n\nAcute GVHD was graded according to Seattle criteria (91). The diagnosis of gastrointestinal GVHD was based on biopsies from endoscopies (7–9). Skin biopsies were not performed. Donor recipient chimerism was followed by PCR and patients with acute GVHD were full-donor chimeras (9, 92). Cytomegalovirus (CMV) was followed weekly by PCR and reactivation was treated with ganciclovir (93). Epstein-Barr virus (EBV) PCR was only regularly followed in patients with an EBV-mismatched donor (94). Adenovirus was not monitored routinely (95), and only when an infection was suspected.\n\nEthics\nWe received ethical approval from the regional ethic committee to harvest DSCs from Caesarian section placentas and use them for treatment of GVHD and toxicity after HCT (2009/418-31-34 and 2010/2061-32, 2010/452-31/4, and 2014-2132-32). The procedure for using DSCs was also later approved by the Central Ethical Review Board in Sweden (Dnr 011-2016). The method for clinical culture of DSCs was also approved by the Swedish Product Agency (Dnr 6.1.3-42994/2013).\n\nDecidua Stromal Cell Culture\nThe method to culture and expand DSCs was previously published in detail (96). DSCs express CD166, CD105, CD73, CD44, and CD29. They did not express hematopoietic markers CD34, CD14, and CD45. DSCs were negative for bacteria, mycoplasma, and fungi before infusion. The DSCs were cultured and expanded in a good manufacturing process laboratory. DSCs were stored in liquid nitrogen, thawed, and resuspended in CliniMACS PBS/EDTA buffer, supplemented with 10% AB plasma or 5% albumin (69). The cells were washed three times and resuspended in NaCl and 10% AB serum or 5% albumin. The infusion solution was filtered through a 70 μM cell strainer (BD Bioscience, Franklin Lakes, NI) before being transferred to a heparinized syringe (Leo Pharma, Ballerup, Denmark) at 2 × 106 cells/ml. The DSC was infused intravenously using a central venous line. The central venous line was flushed with 2–5 mL of NaCl with 25 IE heparin/ml in children weighing over 15 kg and 12.5 IE heparin/ml in children weighing under 15 kg.\n\nResults\nPatient 1 (UPN, unique patient number, 1555). A male baby boy was presented with disseminated LCH disease including bone marrow involvement and was pretreated with steroids and chemotherapy, followed by a HCT. The boy received an unrelated cord blood transplant. We previously reported that LCH can be cured by HCT (97, 98). Due to poor engraftment he was treated with granulocytes colony-stimulating factor (G-CSF) from day +20 after HCT. He reached absolute neutrophil counts (ANC) >0.5 × 109/L on day +27. On day +20 after HCT, he started vomiting and had watery diarrhea 10 times/day. His diarrhea deteriorated and he developed a skin rash on the back of his body. He was given high- dose prednisolone (2 mg/kg). Due to unresponsiveness he was treated with DSCs 3 days later and one additional dose was administered 3 weeks after the steroids had been introduced (Table 1). DSC doses were above 2 × 106/kg and viability was 78 and 95% in the two infusions, respectively (Table 2). At day 28 after DSC infusion, he had a partial response (PR). At day 56 and at the 6-month follow-up he showed no signs of acute GVHD (Table 2). He was diagnosed with a CMV reactivation on day +61 treated with ganciclovir. He is currently alive and well more than 8 years after HCT and from last follow up he showed Lansky score of 100%.\n\nTable 2 Decidua stromal cells (DSCs) for therapy of acute GVHD characteristics, cell dose and outcome.\n\nPatient\tUPN\tDSC dose no\tDSC viability %\tCell dose × 106/kg\tPassage\tDay 28 response\tDay 56 response\t6 months response\tChronic GVHD grade\tOutcome\t\n1\t1555\t1\t78\t2.7\t2\tPR\tCR\tCR\t0\tAlive and well, Lansky score 100%\t\n\t\t2\t95\t2.4\t2\t\t\t\t\t\t\n2\t1625\t1\t91\t1.7\t3\tCR\tCR\tCR\t0\tDied from leukemic relapse 2 years post HCT\t\n3\t1687\t1\t97\t1.2\t4\tCR\tPR\tPR\t2\tModerate chronic GVHD obstructive bronchiolitis. Presently Lansky score 100%\t\n\t\t2\t69\t1.1\t3\t\t\t\t\t\t\n\t\t3\t96\t1.1\t4\t\t\t\t\t\t\n\t\t4\t96\t1.1\t4\t\t\t\t\t\t\n\t\t5\t96\t1.2\t4\t\t\t\t\t\t\n\t\t6\t94\t1.5\t3\t\t\t\t\t\t\n4\t1692\t1\t96\t0.9\t4\tPR\tPR\tPR\t2\tDied from cerebral hemorrhage\t\n5\t1707\t1\t89\t1.9\t4\tCR\tPR\tCR\t0\tAlive and well. Lansky score 100%\t\n\t\t2\t100\t1.7\t4\t\t\t\t\t\t\n\t\t3\t91\t1.5\t4\t\t\t\t\t\t\n\t\t4\t95\t1.6\t4\t\t\t\t\t\t\n\t\t5\t82\t1.5\t3\t\t\t\t\t\t\n6\tUAH\t1–6\t69–100\t1.0\t3–4\tPR\tCR\tCR\t0\tAlive and well, Lansky score 100%\t\nPR, partial response; CR, complete response; UAH, Uppsala Akademic Hospital.\n\nPatient 2 (UPN 1625). A 16-year-old female with high risk B-ALL in 2nd complete remission (CR) received bone marrow from an unrelated donor. The patient was treated pre-HCT according to the NOPHO (Nordic Pediatric Hematology Oncology) ALL protocol 2008 and was in complete remission pre HCT, including MRD <0.01% (99). She experienced CMV reactivation on day +19, treated with ganciclovir. ANC reached >0.5 × 109/L on day +23. Eighteen days post-transplant, she developed steroid refractory grade II acute GVHD of the gastro-intestinal tract and a skin rash. She was treated with a high dose of steroids from day +20, but did not respond. Due to steroid resistance, she was treated with one dose of DSCs 30 days after HCT (Table 1). The DSC dose was 1.7 × 106/kg with 91% viability (Table 2). Her symptoms of acute GVHD disappeared and she was considered to be in a complete response at day 28 and remained so. However, the patient died from leukemic relapse 2 years after HCT.\n\nPatient 3 (UPN 1687). A 9-year-old boy with an intermediate risk of B-ALL in CR2 received a bone marrow graft from his HLA-identical sister. He was previously treated according to the NOPHO ALL protocol 2008 (99). Both donor and recipient were CMV seropositive. He had no CMV reactivation. On day +10 he had hemorrhagic cystitis grade II that resolved. Already on day 9 after HCT he developed acute GVHD of the gastrointestinal tract and erythema of the skin. He did not respond to high doses of steroids and was considered steroid refractory. On day +30 he also developed a varicella-zoster reactivation. One month after HCT he was given 1.2 × 106 DSC/ × 106/kg with a viability of 97% (Table 2). At day 28 after DSC treatment was initiated, he had complete resolution of all signs of acute GVHD but received another three additional weekly doses (Tables 1, 2). However, at 6 months, it was evident that he had developed signs of chronic GVHD as sicca and lichenoid changes of the skin, treated with extracorporeal psoralene and ultraviolet light (PUVA). After another 2 months he developed signs of a more generalized GVHD, with symptoms from both the skin, the liver, and the gastrointestinal tract. The biopsy from the GI-tract revealed GVHD, grade II (8) and he was given two more doses of DSC (Tables 1, 2). The symptoms of acute GI-GVHD disappeared but one and a half year after transplant he was still having symptoms of moderate chronic GVHD, mainly symptoms of bronchiolitis obliterans. 6.5 years after HCT he is suffering from NIH grade 2 chronic GVHD and is now treated with a JAK2 inhibitor, but from his last follow up he scored Lansky 100%.\n\nPatient 4 (UPN 1692). A 14-year-old boy arrived in Sweden, from an African country with an untreated severe sickle cell disease. He had a history of multiple sickle cell crises, as severe pain, osteonecrosis, cerebral infarctions, and bleedings and was therefore planned for a HCT. Before HCT he was treated with Hydrea capsules, but the treatment showed very moderate effect. He was finally transplanted and received bone marrow (0.25 × 106 CD34+ cells/kg) from an unrelated donor (12/12 match). He reached ANC >0.5 × 109/kg on day +19. On day +28 he was treated with acyclovir for a herpes simplex virus infection. Immunosuppression was tacrolimus combined with sirolimus. During discontinuation of immunosuppression on day 182 after HCT he developed diarrhea diagnosed as gastrointestinal GVHD. Steroids were administered, but the diarrhea continued. One week later he was given 0.9 × 106 DSC/ × 106/kg (Table 2). He had a partial response at 28 days and at follow-up at 6 months. Seven months after HCT he had CMV reactivation treated with ganciclovir. One year after the transplant he developed chronic GVHD, NIH overall score 2 (Table 2). However, the patient died from severe cerebral hemorrhage 1 year and 9 months after HCT, where previous cerebral damage pre HCT probably contributed to cerebral hemorrhage post HCT.\n\nPatient 5 (UPN 1707). A 1-year-old boy with osteopetrosis rejected the first graft and was re-transplanted 2 months later. He received a peripheral blood graft from an unrelated donor (Table 1). HLA-match was 10/12 with one antigen-HLA-C and –DP-mismatches. CD34+ cell dose was 34 × 106/kg. He had CMV reactivation on day +11, treated with ganciclovir. On day 17 after HCT he developed diarrhea grade II that did not respond to steroids. He was subsequently given five doses of DSC in doses ranging from 1.5 to 1.9 × 106/kg per kg (Table 2). The viability of the cells ranged from 82 to 100%. At day 28 after initiation of DSC therapy, he had a complete response. At day 56 he had some abdominal pain and a loose stool. At the 6-month follow-up the stool was normal. He did not develop any chronic GVHD and is currently alive and well 6 years after transplantation, with a Lanskys score of 100%.\n\nPatient 6 The boy, born at term, non-consanguineous parents, was admitted to the hospital at the age of 9 months, with symptoms of severe respiratory infections, failure to thrive, and low lymphocytes. He was investigated for suspected severe combined immunodeficiency (SCID). Genetic analysis revealed a JAK-3 gene mutation (two heterozygous variants, leading to a frame shift and premature stop codon; p.Ser 449LysfsX71). At 12 months of age the boy was transplanted, with cord blood as a stem cell source. Pre-HCT the boy was colonized with rhinovirus, which also was observed after transplantation. On day 29, PCR-chimerism analysis revealed 60% donor cells. Subsequently, during immunosuppressive tapering, he developed a skin rash and, a few days later, also massive diarrhea due to gastrointestinal GVHD. This was diagnosed on a colon biopsy showing crypt destruction with several apoptotic bodies and regenerated features of grade IV gastrointestinal GVHD (8). He did not respond to steroids or mycophenolate mofetil therapy (Tables 1, 2). From day 57 after HCT, he was treated with weekly doses of DSCs. He had a partial response at day 28 and continued to need albumin transfusions. He received a total of six doses of DSCs before the resolution of gastrointestinal GVHD. At day 56 and 6 months after transplant he had a complete response and was doing well. Apart from rhinovirus, no viral, or fungal infections were diagnosed post-HCT. He is currently alive and well, 5 years after transplantation. He doesn't need any medications goes to school and shows Lanskys score of 100%.\n\nOverall Follow Up\nThe outcome among these six children treated for severe gastrointestinal and sometimes also acute skin GVHD at the 28-day follow-up was a complete response in three patients and a partial response in three patients (Table 2). At 6 months, a complete response was seen in four patients and a partial response in two patients. Two patients developed moderate chronic GVHD. One patient with high risk pre-B-ALL died of leukemic relapse 2 years after transplantation. A boy with sickle cell anemia died of cerebral hemorrhage 1 year and 1 month after HCT, although he had a history of multiple severe sickle cell crises before HCT. Three patients are alive and well and one patient is suffering from moderate chronic GVHD with obstructive bronchiolitis but responded to Jak-2 inhibition. Now he scores Lansky 100%. Overall, there is a 5-year survival of 67%.\n\nDiscussion\nAlthough this is only a small series of pediatric patients treated for acute GVHD, it still holds some promise. None of the children died from GVHD and 6-year survival was four out of six (67%). This is similar to what was achieved with DCSs with 21 patients, most of them older adults with a 4-year survival of 57% (100). The two deaths were due to relapse in the patient with high-risk ALL and cerebral hemorrhage in the patient with sickle cell disease. These are unfortunate yet expected complications after HCT. Patients who survived acute GVHD have an reduced risk of leukemic relapse (101). The graft-versus-leukemia (GVL) effect did not prevent relapse in this girl with high risk B-ALL. She did not develop chronic GVHD. The study from the International Registry suggested that acute GVHD had a profound GVL effect in ALL patients (102). A European study in ALL patients found that chronic GVHD was more important to decrease relapse probability (103). There were only two patients who developed moderate chronic GVHD. Children have a relatively low risk of chronic GVHD (104, 105). However, there is an increased risk of chronic GVHD in patients who survive acute GVHD (101). Children have a better outcome than adults after HCT and this is striking in patients with severe acute GVHD (6). In a prospective randomized study performed by Osiris, it was reported that children treated for severe acute GVHD, as opposed to adults, had a better outcome (51). The first multicenter study using MSCs for acute GVHD also showed a better outcome in children than adults (47). However, this was not supported by a meta-analysis, which showed that survival following MSC therapy for acute GVHD did not differ in children and adults (106).\n\nAn advantage of using MSCs as opposed to other drugs to treat acute GVHD is safety, with few, if any side-effects (107, 108). There were no side-effects caused by the stromal cells in any of the six children treated with DSCs.\n\nThe ideal source of stromal cell for treatment of acute GVHD, MSC from bone marrow, adipose tissue, Wharton's jelly, umbilical cord, placenta tissue or DSCs, may be discussed. In a humanized mouse model, it was shown that MSCs from BM, umbilical cord, and adipose tissue had different properties (109). In Table 3 is listed the different properties of MSCs from bone marrow compared to DSCs. Bone marrow aspiration is quite a painful procedure. Thus, alternative sources such as adipose tissue, cord, placenta tissue, or fetal membrane, stromal cells are more easily accessible. We found that DSCs had a stronger immunosuppression of alloreactivity in vitro in mixed lymphocyte cultures compared to MSCs from other sources. We therefore selected DSCs for further investigation (30). DSCs also appeared to be more effective for treating acute GVHD compared to BM-MSCs (69). However, it is unlikely that different sources of stromal cells will be compared in prospective randomized studies for the treatment of acute GVHD. Currently, there are several promising drugs for treating acute GVHD, such as Ruxolitinib, Vedolizumab and Etanercept (110–112). However, it seems that an advantage of using MSCs is the toxicity profile.\n\nTable 3 Differences between bone marrow-derived mesenchymal stromal cells and placenta-derived decidual stromal cells.\n\nCharacteristic\tMSC\tDSC\t\nExpansion potential\t++\t++++\t\nDifferentiation to fat and cartilage\t+++\t+/–\t\nSize, volume\t4600 fl\t2400 fl\t\nExpress PDL-1, PDL-2\t+\t++\t\nExpress CD49d, homing to inflammatory tissue (integrin)\t+\t++\t\nVascular cell adhesion molecule 1 (VCAM-1) expression\t+\t–\t\nExpress HLA class II after IFNγ stimulation\t+\t–\t\nPro-coagulant tissue factor\t6%\t39%\t\nCD55 complement regulatory activity\t62%\t98%\t\nReduction in clotting time\t55%\t70%\t\nPrevent alloreactivity in vitro (MLC)\t++\t+++\t\nNeeds direct contact for immunosuppression\t–\t+\t\nOverall response in steroid refractory acute GVHD\t75%\t100%\t\nMLC, mixed lymphocyte culture.\n\nThe first child (UPN1555) was treated with G-CSF for poor engraftment. G-CSF was reported to be associated with severe acute GVHD because it can trigger alloreactive T-cells (113, 114). G-CSF may have potentiated acute GVHD in this child.\n\nSeveral large studies have been using MSCs, as shown from a single report on children from Kurtzberg et al. who recently reported on 241 children with grade II–IV steroid refractory acute GVHD (115). The 28-day overall response rate was 65% with a 14% complete response. The 100-day survival was 67%. These results were achieved with the commercially available MSCs Remestemcel-L. The randomized study by Osiris, which did not show an overall improvement in the placebo-controlled trial, showed that pediatric patients had a significantly better outcome using MSCs compared to the placebo group (53). Bonig et al. used MSCs pooled from multiple donors to treat acute GVHD (58). They reported an overall response rate of 82% following a median of three doses of pooled MSCs. Overall, 6-month survival was 64%.\n\nMSCs have mainly been used for treatment of acute GVHD in pediatric patients. They have not been used much for chronic GVHD. This is because stromal cells have a strong anti-inflammatory effect, which may be more effective for acute inflammatory processes such as acute GVHD and less effective in chronic fibrotic processes (116). Another indication for MSCs, mainly used in adults, is hemorrhagic cystitis (117, 118). MSCs have also been used for the treatment of acute respiratory distress syndrome (ARDS). There is a wealth of experimental data suggesting the potential of MSCs for sepsis and ARDS (119–121). We treated a young boy who developed ARDS after HCT with MSCs (122). He died from massive Aspergillus infection. DSCs were shown to dramatically reverse ARDS in a male patient early after HCT (123). There is limited clinical experience (124). The lack of data on pediatric patients for these more novel indications could be because they are under development. If effective in the adult studies, MSCs will also be used for hemorrhagic cystitis, ARDS, and other indications that are more experimental today.\n\nIn addition to acute GVHD, MSCs have also been used to prevent and reverse graft failure, enhance engraftment, or as prophylaxis to reduce GVHD (74, 79–81). These studies include pediatric patients and adults.\n\nAs discussed above, the immunosuppressive effects of MSCs are induced by direct contact, as well as via several soluble factors. Exosomes and microvesicles derived from MSCs were shown to protect from acute kidney injury (125), myocardial ischemia (126), and pulmonary hypotension (127) in animal models. Exosomes for MSCs were also demonstrated to reverse severe acute GVHD (46). Since exosomes will only transfer soluble effect by MSCs and not a direct immunosuppressive effect, it is less likely that exosomes will replace MSCs in the near future.\n\nTo conclude, MSCs from various sources are mainly used in pediatric patients to treat severe acute GVHD and have shown encouraging response rates and survival efficacy. Thus, commercially available MSCs are registered as a drug in Canada, Japan and New Zeeland (128). Furthermore, MSCs also have the potential to cure other acute inflammatory and toxic disorders seen in pediatric patients, such as hemorrhages, ARDS, poor engraftment, and possibly also neuroinflammatory disorders (129).\n\nData Availability Statement\nThe datasets presented in this article are not readily available because There is no restriction for the authors of this article to use this datasets. However it is not publicly available. The reviewers are of course welcome to request any data they feel are of importance for evaluating the study properly. Requests to access the datasets should be directed to [email protected]; [email protected].\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Ethical committee of Karolinska Institutet, Stockholm, Sweden. Approval to collect placentas and isolate decidual stromal cells (DSC), Dnr 20019/413-31/4 and 2010/2061-32. To use DSCs for treatment of acute GVHD and toxicity after hematopoietic cell transplantation (Dnr 2010/452-31/4 and 2014/2132-32). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\nOR, BG, and BS: concept and design, collection and assembly of data, manuscript writing, and final approval of manuscript. OR and BG: financial support. OR and BS: administrative support. 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(2020 ) 111 :591 –4\n. 10.1007/s12185-019-02804-w 31853810\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-3224", "issue": "11()", "journal": "Frontiers in immunology", "keywords": "cell theraphy; decidua stromal cells (DSCs); graft-versus-host disease (GVHD); mesenchymal stromal cell (MSC); pediatric haematopoietic stem cell transplantation", "medline_ta": "Front Immunol", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003656:Decidua; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D010865:Pilot Projects; D011379:Prognosis; D012720:Severity of Illness Index; D017154:Stromal Cells; D016896:Treatment Outcome", "nlm_unique_id": "101560960", "other_id": null, "pages": "567210", "pmc": null, "pmid": "33193339", "pubdate": "2020", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "21934657;32044400;31817480;5654088;30471340;22966167;26228813;11233907;21042238;26765648;15615264;3547128;17541394;25162829;17709496;31989101;20130212;21396594;23114789;19309241;38500;17664353;16338616;1316137;20644118;10637244;18185520;24904175;27941780;20138817;8932846;7004534;22288598;29395680;24452962;15846293;31505228;11986244;32070420;24445866;22542159;15846285;17611560;6116868;6340576;22510383;19308773;21393326;9846518;22704511;18955980;15121408;2653461;31231381;6437023;29027756;17638847;32018062;18468541;25529339;27777142;20955701;3892795;22277374;28819280;23992039;15827960;20818445;19330008;11823036;10102814;21843360;20350611;7760610;20109568;21076475;21820393;29533533;22431999;31853810;16732175;15494428;19489103;26192403;28287644;28306336;16885046;21307841;30455077;9040587;10560915;19905962;19498381;3910558;23307526;19424010;32248590;18420833;21546330;31173898;12589164;14550804;10086387;27175026;33085820;2996920;22781662;15940052;29141887;2297567;15257050;15001472;17910665;14691124;14751;14972;23133515;31001253;29045348;21747949;20457269;25478942;12542793", "title": "Mesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease.", "title_normalized": "mesenchymal stromal cells in pediatric hematopoietic cell transplantation a review and a pilot study in children treated with decidua stromal cells for acute graft versus host disease" }	[ { "companynumb": "SE-TEVA-2021-SE-1933568", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MMF" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." } ], "patientagegroup": "2", "patientonsetage": "1", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft versus host disease in gastrointestinal tract", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft versus host disease in skin", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RINGDEN O, GUSTAFSSON B, SADEGHI B. MESENCHYMAL STROMAL CELLS IN PEDIATRIC HEMATOPOIETIC CELL TRANSPLANTATION A REVIEW AND A PILOT STUDY IN CHILDREN TREATED WITH DECIDUA STROMAL CELLS FOR ACUTE GRAFT?VERSUS?HOST DISEASE. FRONT?IMMUNOL 2020?11:567210.", "literaturereference_normalized": "mesenchymal stromal cells in pediatric hematopoietic cell transplantation a review and a pilot study in children treated with decidua stromal cells for acute graft versus host disease", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210721", "receivedate": "20210721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19591368, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "SE-TEVA-2021-SE-1933569", "fulfillexpeditecriteria": "1", "occurcountry": "SE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "THYMOCYTE IMMUNE GLOBULIN NOS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ANTITHYMOCYTE?GLOBULIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROGRAF" } ], "patientagegroup": "2", "patientonsetage": "1", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft versus host disease in gastrointestinal tract", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RINGDEN O, GUSTAFSSON B, SADEGHI B. MESENCHYMAL STROMAL CELLS IN PEDIATRIC HEMATOPOIETIC CELL TRANSPLANTATION A REVIEW AND A PILOT STUDY IN CHILDREN TREATED WITH DECIDUA STROMAL CELLS FOR ACUTE GRAFT?VERSUS?HOST DISEASE. FRONT?IMMUNOL 2020?11:567210.", "literaturereference_normalized": "mesenchymal stromal cells in pediatric hematopoietic cell transplantation a review and a pilot study in children treated with decidua stromal cells for acute graft versus host disease", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210721", "receivedate": "20210721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19591372, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]
{ "abstract": "Pediatric patients with non-Hodgkin lymphoma (NHL) in developing countries (DCs) present with greater tumor load even at lower stages and with comorbidities that impact therapy delivery. This causes toxic mortality with \"standard\" intensive protocols or recurrences with \"gentler\" treatment.\n\n\n\nWe developed and evaluated a risk stratification schema that guides intensity of therapy.\n\n\n\nSixty-nine patients were prospectively assigned to five risk groups (A-E; n = 6, 15, 16, 15, and 17) following staging and treated with protocols of risk-stratified intensity. Risk stratification utilized St. Jude stage, disease bulk, and sites involved.\n\n\n\nBetween 2006 and 2011, 69 patients with B-cell NHL were enrolled. Among these, 72.5% were boys with mean age of 6.9 years (±3.33 [SD]; range 2.4-14.2 years). Eighty-seven percent had Burkitt lymphoma, 82.6% had advanced stage (25 [36.2%] stage III; 32 [46.4%] stage IV), and 24.6% were central nervous system positive. Mean lactate dehydrogenase increased progressively across the risk strata. Among these, 0/6, 1/15, 3/16, 2/15, and 7/17 patients relapsed/progressed within each risk stratum. Fifteen patients died; three from treatment-related toxicity. At a median follow-up of 6.2 years, the overall and event-free survival (EFS) for all patients was 78.1 and 75.4%, respectively; EFS was related to risk assignment. The frequency of documented infectious and noninfectious toxicities increased with higher risk group assignment causing prolongation of admissions and potential treatment delays.\n\n\n\nReduction in treatment intensity for an identified subset of patients with NHL is feasible, while high-intensity therapy is required for high-risk groups. This risk stratification system may be a first step toward improving the outcomes in some DCs.", "affiliations": "Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Division of Nursing, King Fahd National Center for Children's Cancer, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.", "authors": "Belgaumi\|Asim F\|AF\|;Anas\|Mohammed\|M\|;Siddiqui\|Khawar S\|KS\|;Akhter\|Mohammed F\|MF\|;Al-Kofide\|Amani\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.26335", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(6)", "journal": "Pediatric blood & cancer", "keywords": "developing countries; lymphoma; pediatrics; risk stratification; toxicity", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000359:Aftercare; D002051:Burkitt Lymphoma; D002648:Child; D002675:Child, Preschool; D019049:Developed Countries; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011446:Prospective Studies; D018570:Risk Assessment; D015996:Survival Rate", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "27878966", "pubdate": "2017-06", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Risk-adapted stratification for optimally intensive treatment assignment of pediatric patients with non-Hodgkin lymphoma is an effective strategy in developing countries.", "title_normalized": "risk adapted stratification for optimally intensive treatment assignment of pediatric patients with non hodgkin lymphoma is an effective strategy in developing countries" }	[ { "companynumb": "SA-JNJFOC-20170512561", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DOSE- 1000 MG/ M2/DAY (PROTOCOL A, B, C, D)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "UNSPECIFIED DOSE IN PROTOCOL B??DOSE-15 MG/ M2 ONCE 6 HOUR (PROTOCOL E)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEUCOVORIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DOSE-750 MG/M2 (PROTOCOL A, B) 300MG/M2. DOSE/ ONCE 12 H FOR 6 DOSES (PROTOCOL C AND D)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DOSE-2MG/ KG/ DAY (PROTOCOL A, B, C, D)??DOSE-60MG/ M2/ DAY (PROTOCOL E)", "drugenddate": null, "drugenddateformat": null, 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{ "abstract": "BACKGROUND\nBing-Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy.\nA 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye.\nBrain imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration. Flow cytometry of the cerebrospinal fluid (CSF) revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for immunoglobulin M and kappa light chain. Thus, the diagnosis of BNS was established.\n\n\nMETHODS\nThe patient was initially treated with intrathecal methotrexate and systemic chemotherapy. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start maintenance treatment with IV rituximab and per os ibrutinib.\n\n\nRESULTS\nFollowing 1 year posttreatment initiation, visual problems have resolved completely and the patient remains on hematologic and imaging complete response.\n\n\nCONCLUSIONS\nWe propose a novel sequential chemoimmunotherapy approach for BNS treatment aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity.", "affiliations": "Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;First Department of Radiology, National and Kapodistrian University of Athens, School of Medicine, Areteion Hospital.;\"Athens Vision\" Ophthalmology Clinic, Athens, Greece.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;First Department of Radiology, National and Kapodistrian University of Athens, School of Medicine, Areteion Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.", "authors": "Gavriatopoulou\|Maria\|M\|;Ntanasis-Stathopoulos\|Ioannis\|I\|;Moulopoulos\|Lia-Angela\|LA\|;Manaios\|Alexandros\|A\|;Fotiou\|Despina\|D\|;Eleutherakis-Papaiakovou\|Evangelos\|E\|;Migkou\|Magdalini\|M\|;Bourgioti\|Charis\|C\|;Terpos\|Evangelos\|E\|;Kastritis\|Efstathios\|E\|;Dimopoulos\|Meletios-Athanasios\|MA\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000017794", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31689856MD-D-19-0139210.1097/MD.0000000000017794177944800Research ArticleClinical Case ReportTreatment of Bing–Neel syndrome with first line sequential chemoimmunotherapy A case reportGavriatopoulou Maria MD, PhDa∗Ntanasis-Stathopoulos Ioannis MDaMoulopoulos Lia-Angela MD, PhDbManaios Alexandros MDcFotiou Despina MDaEleutherakis-Papaiakovou Evangelos MD, PhDaMigkou Magdalini MD, PhDaBourgioti Charis MDbTerpos Evangelos MD, PhDaKastritis Efstathios MD, PhDaDimopoulos Meletios-Athanasios MD, PhDaNA. a Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospitalb First Department of Radiology, National and Kapodistrian University of Athens, School of Medicine, Areteion Hospitalc “Athens Vision” Ophthalmology Clinic, Athens, Greece.∗ Correspondence: Maria Gavriatopoulou, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece (e-mails: [email protected], [email protected]).11 2019 01 11 2019 98 44 e1779421 2 2019 04 9 2019 03 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nBing–Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy.\n\nPatient concerns:\nA 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye.\n\nDiagnoses:\nBrain imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration. Flow cytometry of the cerebrospinal fluid (CSF) revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for immunoglobulin M and kappa light chain. Thus, the diagnosis of BNS was established.\n\nInterventions:\nThe patient was initially treated with intrathecal methotrexate and systemic chemotherapy. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start maintenance treatment with IV rituximab and per os ibrutinib.\n\nOutcomes:\nFollowing 1 year posttreatment initiation, visual problems have resolved completely and the patient remains on hematologic and imaging complete response.\n\nLessons:\nWe propose a novel sequential chemoimmunotherapy approach for BNS treatment aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity.\n\nKeywords\nBing–NeelibrutinibmethotrexaterituximabWaldenström macroglobulinemiaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nBing–Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Although the recent years there has been a significant effort in formulating clinical practice guidelines, still diagnosis and management remains challenging.[1] BNS is characterized by the malignant invasion of lymphoplasmacytic cells in the central nervous system (CNS), including brain parenchyma, spinal cord, meninges, and cerebrospinal fluid (CSF). It may present as a disease relapse among previously treated patients with WM or as the initial manifestation of symptomatic disease even in the absence of other criteria for symptomatic WM, as in our case.[1,2] From its initial description by Bing and von Neel in 1936,[3] the literature reports of the disease are scarce, whereas the 4 largest multicenter case-series encompass 24 to 44 patients.[2,4–6] Although the incidence of BNS is difficult to be determined precisely, a retrospective cohort including more than 1500 patients with WM suggested a prevalence of <1%.[7] Clinical presentation varies significantly among BNS cases ranging from locomotor and sensory deficits to neuropsychiatric disorders, and it depends on the affected CNS compartment.[1,6] Hyperviscosity syndrome, immunoglobulin M (IgM)-related neuropathies, WM transformation to high-grade lymphoma or de novo lymphomas evading CNS may have overlapping clinical signs and symptoms with BNS and, thus, they should be ruled out during the diagnostic workup.[1] Magnetic resonance imaging (MRI) is recommended and may be highly suggestive of CNS invasion; interestingly, optic nerve involvement has been rarely reported.[5] Although biopsy is considered the gold standard for definitive diagnosis, CSF analysis supporting the presence of lymphoplasmacytic lymphoma is also acceptable.[1] Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy. In our case, CSF flow cytometry and immunofixation showing monoclonal B-cells and IgM paraprotein with the same kappa-light chain restriction as in the serum and the bone marrow established BNS diagnosis. In compliance with the CARE guidelines, patient informed consent has been obtained and all reported clinical and imaging data have been de-identified.\n\n2 Case description\nA 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye. Clinical examination was otherwise unremarkable. The patient reported no weight loss or B-symptoms. At the time of initial WM diagnosis, the bone marrow biopsy showed 15% infiltration of M(κ)-clonal lymphoplasmacytic cells and the serum immunofixation was positive for monocloncal IgM, while serum IgM levels were 147 mg/dL. Laboratory examinations were within normal ranges with no signs of anemia or thrombocytopenia, whereas clinical and imaging assessment did not reveal any sites of lymphadenopathy or hepatosplenomegaly. Therefore, the patient was defined as asymptomatic and had been under follow-up every 4 months. Two years postinitial diagnosis a new diagnostic bone marrow biopsy revealed an increase in clonal infiltration up to 40% and genetic tests performed both in the bone marrow and in the serum cell-free DNA did not detect any MYD88 or CXCR4 mutations. The presence of mutations in the aforementioned genes was evaluated by allele-specific polymerase chain reaction and direct sequencing, as previously described.[8] Serum IgM levels had been gradually increasing as well with no other concurrent symptomatology and reached at 723 mg/dL at the time of presentation with visual loss (serum M-peak = 0.61 g/dL) (Fig. 1A). Her medical history was also remarkable of right eye cataract surgery, thyroidectomy, and T4 hormone replacement therapy, but she had no history of migraine. She was also current smoker with mild hypercholesterolemia. Due to the presence of risk factors for cardiovascular disease, we performed initially an extensive workup including electrocardiogram, cardiac ultrasound, sonography of the carotid, and vertebral arteries that revealed no clinically significant abnormalities. Coagulation studies were within normal limits. No serum autoantibodies were detected. Apart from an erythrocyte sedimentation rate of 140 mm at 1st hour, there were no other clinical signs of giant cell arteritis. Although the IgM was relatively low, we evaluated serum viscosity, which was 2.0 cp and, thus, we ruled out hyperviscosity syndrome. MRI of brain revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration (Fig. 2A). MRI of the spine indicated no abnormalities. Subsequently, we performed a lumbar puncture; flow cytometry of the CSF revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes accounting for the 86% of CD45 positive cells along with CD3(+)CD4(+) and CD3(+)CD8(+) T-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for IgM and kappa light chain (Fig. 1B). MYD88 status was indeterminate. Thus, the diagnosis of BNS was established. Patient was initially treated with intrathecal methotrexate 15 mg twice weekly and systemic chemotherapy with HyperCVAD. However, after the course 1 of the 1st cycle she experienced grade 3 neutropenic fever that eventually resolved with granulocyte colony-stimulating factor and intravenous antibiotics. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start treatment with IV rituximab 375 mg/m2 every 4 weeks and per os ibrutinib 420 mg daily. Six months posttreatment initiation the patient has great visual improvement with resolution of papilledema and bilateral optic nerve swelling (Fig. 2B), whereas IgM levels have been reduced to 25.6 mg/dL, the serum protein electrophoresis (Fig. 1C) and immunofixation are negative for monoclonal component and bone marrow biopsy shows no evidence of disease infiltration. Therefore, the patient has achieved clinical, hematologic, and radiologic complete response. No adverse events have been reported except for transient diarrhea grade 1 probably related to ibrutinib. After completing 1 year treatment with rituximab, the patient discontinued rituximab and remains on ibrutinib monotherapy in complete response and with no major adverse events.\n\nFigure 1 (A) Serum electrophoresis before treatment initiation demonstrating a monoclonal M-paraprotein of 0.61 g/dL. (B) Cerebrospinal fluid (CSF) electrophoresis showing a monoclonal component in the gamma region; immunofixation revealed immunoglobulin M and kappa light-chain monoclonal bands. (C) Serum electrophoresis after 6 months of treatment initiation showing disappearance of the monoclonal band, whereas serum immunofixation was negative.\n\nFigure 2 (A) At presentation brain magnetic resonance imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. T1-weighted image in the axial plane shows diffuse enlargement of both optic nerves (arrows). (B) Corresponding T1-weighted image in the axial plane of the same patient 3 months after treatment demonstrates decrease in the size of both nerves.\n\n3 Discussion\nThe principal aim of BNS therapeutics is patients’ clinical improvement and progression-free survival (PFS) prolongation irrespectively of the possible persistence of the lymphoplasmacytic clone or MRI findings.[1] Due to the rarity of the disease, no universal treatment guidelines have been formulated yet; thus, the therapeutic strategy is personalized and depends on patient characteristics and comorbidities, prior lines of therapy, the involved CNS compartment and the availability of treatment regimens. It may include systemic and/or intrathecal chemotherapy, radiotherapy, and targeted therapies.[1] The reported response rates among patients receiving traditional chemotherapy regimens with or without rituximab reach at 70%, whereas a response rate of 85% has been recently reported with ibrutinib monotherapy.[2,4,6] Interestingly, exposure to rituximab was associated with improved overall survival in 1 retrospective study.[4] Ibrutinib has been shown to penetrate the blood–brain barrier[9] and has shown significant clinical efficacy as monotherapy among 28 BNS cases in a multicenter case series study[6] and 9 case reports.[9–15] In our case, we initially chose to administrate high-dose intrathecal methotrexate along with systemic chemotherapy that resulted in rapid improvement in symptoms and disappearance of malignant clonal cells in the CSF. Subsequently, based on the reported efficacy results of both rituximab and ibrutinib we decided to switch therapy to a less toxic chemofree regimen. Taking into consideration the benefit mentioned earlier from rituximab and ibrutinib administration for patients with BNS, along with the improved PFS of patients with WM receiving ibrutinib-rituximab in the phase 3 iNNOVATE trial,[16] we opted for administrating ibrutinib and rituximab combination and our patient has achieved complete remission according to the Task Force criteria from the 8th International Workshop for WM.[1]\n\nIn conclusion, we report an infrequent presentation of the extremely rare BNS and we propose a novel sequential chemoimmunotherapy approach aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity. In the absence of randomized clinical trials, multidisciplinary and inter-institutional collaboration is considered essential to improve diagnosis and treatment outcomes for patients with BNS.\n\nAuthor contributions\nConceptualization: Maria Gavriatopoulou, Meletios-Athanasios Dimopoulos.\n\nInvestigation: Maria Gavriatopoulou.\n\nMethodology: Maria Gavriatopoulou.\n\nWriting – original draft: Maria Gavriatopoulou.\n\nWriting – review & editing: Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, Lia-Angela Moulopoulos, Alexandros Manaios, Despoina Fotiou, Evangelos Eleutherakis-Papaiakovou, Charis Bourgioti, Evangelos Terpos, Efstathios Kastritis, Meletios-Athanasios Dimopoulos.\n\nAbbreviations: BNS = Bing–Neel syndrome, CSF = cerebrospinal fluid, MRI = magnetic resonance imaging, PFS = progression-free survival, WM = Waldenström macroglobulinemia.\n\nHow to cite this article: Gavriatopoulou M, Ntanasis-Stathopoulos I, Moulopoulos LA, Manaios A, Fotiou D, Eleutherakis-Papaiakovou E, Migkou M, Bourgioti C, Terpos E, Kastritis E, Dimopoulos MA. Treatment of Bing–Neel syndrome with first line sequential chemoimmunotherapy. Medicine. 2019;98:44(e17794).\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Minnema MC Kimby E D'Sa S \nGuideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome . Haematologica \n2017 ;102 :43 –51 .27758817 \n[2] Simon L Fitsiori A Lemal R \nBing-Neel syndrome, a rare complication of Waldenstrom macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO) . Haematologica \n2015 ;100 :1587 –94 .26385211 \n[3] Bing J Neel A \nTwo cases of hyperglobulinemia with affection of the central nervous system on a toxi-infectious basis . Acta Med Scand \n1936 ;88 :492 –506 .\n[4] Castillo JJ D'Sa S Lunn MP \nCentral nervous system involvement by Waldenstrom macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study . Br J Haematol \n2016 ;172 :709 –15 .26686858 \n[5] Fitsiori A Fornecker LM Simon L \nImaging spectrum of Bing-Neel syndrome: how can a radiologist recognise this rare neurological complication of Waldenstrom's macroglobulinemia? \nEur Radiol \n2019 ;29 :102 –14 .29922935 \n[6] Castillo JJ Itchaki G Paludo J \nIbrutinib for the treatment of Bing-Neel syndrome: a multicenter study . Blood \n2019 ;133 :299 –305 .30523119 \n[7] Kulkarni T Treon SP Manning R \nClinical characteristics and treatment outcome of CNS involvement (Bing-Neel syndrome) in Waldenstrom's macroglobulinemia . Blood \n2013 ;122 :5090 .\n[8] Bagratuni T Ntanasis-Stathopoulos I Gavriatopoulou M \nDetection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies . Leukemia \n2018 ;32 :2617 –25 .30026568 \n[9] Mason C Savona S Rini JN \nIbrutinib penetrates the blood brain barrier and shows efficacy in the therapy of Bing Neel syndrome . Br J Haematol \n2017 ;179 :339 –41 .27409073 \n[10] Cabannes-Hamy A Lemal R Goldwirt L \nEfficacy of ibrutinib in the treatment of Bing-Neel syndrome . Am J Hematol \n2016 ;91 :E17 –9 .26689870 \n[11] Varettoni M Defrancesco I Diamanti L \nBing-Neel syndrome: illustrative cases and comprehensive review of the literature . Mediterr J Hematol Infect Dis \n2017 ;9 :e2017061 .29181138 \n[12] Boudin L Patient M Romeo E \nEfficacy of ibrutinib as first-line treatment of tumoral Bing-Neel syndrome . Leuk Lymphoma \n2018 ;59 :2746 –8 .29569974 \n[13] O’Neil DS Francescone MA Khan K \nA case of Bing-Neel syndrome successfully treated with ibrutinib . Case Rep Hematol \n2018 ;2018 :8573105 .30228918 \n[14] Plander M Szendrei T Vadvari A \nStandard dose of ibrutinib is effective in the treatment of Bing-Neel syndrome . Pathol Oncol Res \n2018 .\n[15] Tallant A Selig D Wanko SO \nFirst-line ibrutinib for Bing-Neel syndrome . BMJ Case Rep \n2018 ;2018 .\n[16] Dimopoulos MA Tedeschi A Trotman J \nPhase 3 trial of ibrutinib plus rituximab in Waldenstrom's macroglobulinemia . N Engl J Med \n2018 ;378 :2399 –410 .29856685\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "98(44)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000368:Aged; D001927:Brain Diseases; D005260:Female; D006801:Humans; D007167:Immunotherapy; D060828:Induction Chemotherapy; D009902:Optic Neuritis; D013577:Syndrome; D008258:Waldenstrom Macroglobulinemia", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e17794", "pmc": null, "pmid": "31689856", "pubdate": "2019-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of Bing-Neel syndrome with first line sequential chemoimmunotherapy: A case report.", "title_normalized": "treatment of bing neel syndrome with first line sequential chemoimmunotherapy a case report" }	[ { "companynumb": "GR-PFIZER INC-2020029419", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { 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TREATMENT OF BING-NEEL SYNDROME WITH FIRST LINE SEQUENTIAL CHEMOIMMUNOTHERAPY: A CASE REPORT.. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IBRUTINIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBRUTINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAVRIATOPOULOU M. TREATMENT OF BING-NEEL SYNDROME WITH FIRST LINE SEQUENTIAL CHEMOIMMUNOTHERAPY: A CASE REPORT. 2019?98(44):E17794.", "literaturereference_normalized": "treatment of bing neel syndrome with first line sequential chemoimmunotherapy a case report", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17207819, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GR-TEVA-2019-GR-1156732", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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"1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "375 MG/M2 EVERY 4 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75493", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRIAMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "037", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAVRIATOPOULOU M, NTANASIS-STATHOPOULOS I, MOULOPOULOS LA, MANAIOS A, FOTIOU D, ELEUTHERAKIS-PAPAIAKOVOU E, ET AL. TREATMENT OF BING-NEEL SYNDROME WITH FIRST LINE SEQUENTIAL CHEMOIMMUNOTHERAPY: A CASE REPORT. MEDICINE 2019?98(44):E17794.", "literaturereference_normalized": "treatment of bing neel syndrome with first line sequential chemoimmunotherapy a case report", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200104", "receivedate": "20191224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17194442, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "To review the experience of a dedicated paediatric multidisciplinary lipid clinic in the management of familial hypercholesterolaemia (FH) by studying the demographics, clinical presentations as well as statin therapy and outcomes.\n\n\n\nRetrospective database review of all patients under 18 years old seen in the lipid clinic at an Australian tertiary paediatric hospital between April 1999 and August 2017. Outcome measures collected included patient demographics, family history, lipid profile, age at treatment commencement, treatment outcomes and complications.\n\n\n\nOne hundred and eight patients (53 males) were seen in the lipid clinic. Eighty-five had low-density lipoprotein cholesterol (LDL-C) levels at or above the 75th percentile for sex prior to treatment. Of these, 75 had a first-degree relative with hypercholesterolaemia and/or early cardiac death. Four patients had clinical manifestations. Thirty-two patients (14 males) were started on statin therapy for likely FH. LDL-C levels reduced by 2.4 mmol/L (1.4 to 2.7) in boys and 1.9 mmol/L (0.8 to 2.8) in girls at 12 month follow-up. Five patients reported side effects requiring adjustment in therapy. Main reasons for not starting statin therapy in eligible patients were parental refusal and/or lost to follow up (77%).\n\n\n\nA dedicated multidisciplinary lipid clinic is helpful for streamlining and monitoring management of paediatric FH. Clinical manifestations of FH are rare in children and may represent more severe form of FH or other lipid disorder. Statin therapy is efficacious and well tolerated but current recommended targets of treatment are difficult to attain. Greater awareness and coordinated services are required to overcome poor family engagement.", "affiliations": "Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.;Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.;Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.;Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.", "authors": "Yeung\|Jeffrey\|J\|0000-0002-6385-667X;Chisholm\|Kerryn\|K\|;Spinks\|Catherine\|C\|;Srinivasan\|Shubha\|S\|", "chemical_list": "D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors", "country": "Australia", "delete": false, "doi": "10.1111/jpc.15426", "fulltext": null, "fulltext_license": null, "issn_linking": "1034-4810", "issue": "57(8)", "journal": "Journal of paediatrics and child health", "keywords": "dedicated lipid clinic; paediatric familial hypercholesterolaemia; statin; treatment refusal", "medline_ta": "J Paediatr Child Health", "mesh_terms": "D000293:Adolescent; D001315:Australia; D002648:Child; D008078:Cholesterol, LDL; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006938:Hyperlipoproteinemia Type II; D008297:Male; D012189:Retrospective Studies", "nlm_unique_id": "9005421", "other_id": null, "pages": "1201-1207", "pmc": null, "pmid": "33830584", "pubdate": "2021-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic.", "title_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic" }	[ { "companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-24733", "fulfillexpeditecriteria": "2", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PRAVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "077917", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type IIa hyperlipidaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRAVASTATIN" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yeung J, Chisholm K, Spinks C, Srinivasan S. Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. Journal of Paediatrics and Child Health. 2021;57(8):1201-1207", "literaturereference_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20201614, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" }, { "companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-24734", "fulfillexpeditecriteria": "2", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205587", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type IIa hyperlipidaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN" } ], "patientagegroup": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yeung J, Chisholm K, Spinks C, Srinivasan S. Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. Journal of Paediatrics and Child Health. 2021;57(8):1201-1207", "literaturereference_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20200976, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-24732", "fulfillexpeditecriteria": "2", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "205587", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type IIa hyperlipidaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Yeung J, Chisholm K, Spinks C, Srinivasan S. Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. Journal of Paediatrics and Child Health. 2021;57(8):1201-1207", "literaturereference_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20200936, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-24731", "fulfillexpeditecriteria": "2", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "205587", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type IIa hyperlipidaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood creatine phosphokinase increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Yeung J, Chisholm K, Spinks C, Srinivasan S. Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. Journal of Paediatrics and Child Health. 2021;57(8):1201-1207", "literaturereference_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211216", "receivedate": "20211216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20194369, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" }, { "companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2021-24735", "fulfillexpeditecriteria": "2", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ROSUVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205587", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type IIa hyperlipidaemia", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ROSUVASTATIN" } ], "patientagegroup": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myalgia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yeung J, Chisholm K, Spinks C, Srinivasan S.. Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. Journal of Paediatrics and Child Health. 2021;57(8):1201-1207", "literaturereference_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20200975, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]
{ "abstract": "OBJECTIVE\nThere is a paucity of the studies of adolescents with acute lymphoblastic leukemia (ALL). This is more noticeable in low- and middle-income countries. The international 5-year event-free survival (EFS) and overall survival (OS) for this age group is around 80%, with pediatric-inspired protocols offering better results.\n\n\nMETHODS\nA retrospective analysis of adolescents aged 16-20 diagnosed with ALL during the period 2004-2015 treated with a high-risk pediatric protocol at an academic center from a middle-income country was performed. Five-year OS and EFS were estimated by the Kaplan-Meier analysis. Hazard ratios of relapse and death were estimated by the Cox regression model.\n\n\nRESULTS\nFive-year EFS and OS for 57 adolescents were 23.3% and 48.9%, respectively. From the 41 patients who achieved complete remission, 24 (58.5%) relapsed. Bone marrow and central nervous system were the most frequent sites of relapse. Hazard ratio of treatment failure and death for patients with organomegaly at diagnosis was 2.026 and 2.970, respectively. Treatment-related toxicity developed in 31 (54.4%) patients and febrile neutropenia was the most frequent in 14 (24.6%) cases. Twelve patients (21.1%) had poor adherence to treatment.\n\n\nCONCLUSIONS\nHigh relapse rate and low 5-year EFS compared with international standards, was documented. Use of intensified pediatric regimens, adherence to proven effective medications, improved supportive care, and prevention of abandonment are necessary to improve survival rates in these patients.", "affiliations": "Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.", "authors": "Jaime-Pérez\|José C\|JC\|;Jiménez-Castillo\|Raúl A\|RA\|;Pinzón-Uresti\|Mónica A\|MA\|;Cantú-Rodríguez\|Olga G\|OG\|;Herrera-Garza\|José L\|JL\|;Marfil-Rivera\|Luis J\|LJ\|;Gómez-Almaguer\|David\|D\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.26396", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(7)", "journal": "Pediatric blood & cancer", "keywords": "acute lymphoblastic leukemia; adherence; adolescence; compliance; survival rates", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D003906:Developing Countries; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007843:Latin America; D008137:Longitudinal Studies; D008297:Male; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016016:Proportional Hazards Models; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "27957789", "pubdate": "2017-07", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Real-world outcomes of treatment for acute lymphoblastic leukemia during adolescence in a financially restricted environment: Results at a single center in Latin America.", "title_normalized": "real world outcomes of treatment for acute lymphoblastic leukemia during adolescence in a financially restricted environment results at a single center in latin america" }	[ { "companynumb": "MX-FRESENIUS KABI-FK201706461", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL?WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA. 2017; 64 (7) :E26396. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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{ "abstract": "Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors.\n\n\n\nPatients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value.\n\n\n\nAmong 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality.\n\n\n\nIn this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.", "affiliations": "Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.", "authors": "Koks\|Marije S\|MS\|0000-0002-0559-6881;Ocak\|Gurbey\|G\|;Suelmann\|Britt B M\|BBM\|;Hulsbergen-Veelken\|Cornelia A R\|CAR\|;Haitjema\|Saskia\|S\|;Vianen\|Marieke E\|ME\|;Verhaar\|Marianne C\|MC\|;Kaasjager\|Karin A H\|KAH\|;Khairoun\|Meriem\|M\|", "chemical_list": "D000082082:Immune Checkpoint Inhibitors", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0252978", "fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0252978\nPONE-D-21-05652\nResearch Article\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nCancer Risk Factors\nMedicine and Health Sciences\nOncology\nCancer Risk Factors\nBiology and Life Sciences\nBiochemistry\nBiomarkers\nCreatinine\nBiology and Life Sciences\nPopulation Biology\nPopulation Metrics\nDeath Rates\nBiology and Life Sciences\nAnatomy\nRenal System\nKidneys\nMedicine and Health Sciences\nAnatomy\nRenal System\nKidneys\nMedicine and Health Sciences\nPharmacology\nDrugs\nDiuretics\nMedicine and health sciences\nPharmacology\nDrugs\nAnalgesics\nNSAIDs\nMedicine and health sciences\nPain management\nAnalgesics\nNSAIDs\nMedicine and Health Sciences\nWomen's Health\nObstetrics and Gynecology\nGynecologic Cancers\nMedicine and Health Sciences\nOncology\nCancers and Neoplasms\nLung and Intrathoracic Tumors\nNon-Small Cell Lung Cancer\nImmune checkpoint inhibitor-associated acute kidney injury and mortality: An observational study\nImmune checkpoint inhibitor-associated acute kidney injury and mortality\nhttps://orcid.org/0000-0002-0559-6881\nKoks Marije S. Data curation Formal analysis Investigation Methodology Validation Writing – original draft Writing – review & editing 1\nOcak Gurbey Conceptualization Data curation Formal analysis Investigation Methodology Supervision Validation Writing – original draft Writing – review & editing 123\nSuelmann Britt B. M. Methodology Supervision Writing – review & editing 4\nHulsbergen-Veelken Cornelia A. R. Data curation Investigation Writing – review & editing 5\nHaitjema Saskia Data curation Investigation Writing – review & editing 5\nVianen Marieke E. Data curation Investigation Writing – review & editing 6\nVerhaar Marianne C. Methodology Supervision Writing – review & editing 1\nKaasjager Karin A. H. Conceptualization Methodology Supervision Writing – review & editing 6\nKhairoun Meriem Conceptualization Data curation Formal analysis Investigation Methodology Supervision Validation Writing – original draft Writing – review & editing 1\n1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\n2 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands\n3 Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands\n4 Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\n5 Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\n6 Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\nStepkowski Stanislaw Editor\nUniversity of Toledo, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\n E-mail: [email protected]\n8 6 2021\n2021\n16 6 e025297819 2 2021\n26 5 2021\n© 2021 Koks et al\n2021\nKoks et al\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nBackground\n\nImmune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors.\n\nMethods\n\nPatients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value.\n\nResults\n\nAmong 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality.\n\nConclusions\n\nIn this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.\n\nThe author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript.\nData Availability\n\nAll relevant data are within the manuscript.\n==== Body\nIntroduction\n\nIn the last decade, immune checkpoint inhibition has become an important treatment for patients with a broad range of malignancies, including melanoma, non-small-cell lung carcinoma, urinary tract cancer, and Hodgkin lymphoma [1–5]. Immune checkpoint inhibitors (ICPi) are humanized monoclonal antibodies that increase antitumor immune responses by blocking inhibitory pathways in T lymphocytes [6,7]. The first ICPi, targeting cytotoxic T lymphocyte–associated antigen 4, earned FDA approval in 2011 [8]. ICPi blocking programmed cell death protein 1 and programmed death ligand 1 have followed since, and novel agents are currently entering clinical trials [9].\n\nAlongside their beneficial effects in patients with cancer, ICPi are known to cause a unique spectrum of autoimmune-related side effects through unrestrained T cell activation. These immune-related adverse events (irAE) may affect multiple organ systems, typically involving the skin, gastrointestinal tract, liver, and endocrine system [10,11]. Renal dysfunction, presenting as acute kidney injury (AKI), is increasingly recognized as an irAE of ICPi [12]. Diagnosing ICPi-associated AKI (ICPi-AKI) can be challenging as patients with advanced malignancies may have various other reasons for developing AKI, including fluid depletion, infection, exposure to nephrotoxic agents, cardiac failure, hypercalcemia, or urinary tract obstruction due to tumor progression [13]. The majority of kidney biopsies in patients with suspected ICPi-AKI show acute tubulointerstitial nephritis as the dominant histopathological lesion, although glomerular diseases are also reported [14–17].\n\nRecently, two observational studies showed that AKI is common in patients receiving ICPi, both reporting an incidence of 17% [18,19]. These studies also aimed to identify risk factors for development of AKI in ICPi users. The first and largest cohort study reported proton pump inhibitor use at baseline to be associated with increased risk of AKI, while the most recent cohort study found previous diagnosis of hypertension and development of non-kidney irAE to increase AKI risk. As the reported risk factors for AKI are inconsistent, further research on this topic is necessary. Other issues that require further investigation is whether development of ICPi-AKI is associated with long-term renal dysfunction and increased mortality. Insights regarding long-term renal function and mortality might affect decision-making on continuation of ICPi treatment in patients who develop ICPi-AKI and hence affect cancer outcomes.\n\nThe aim of this study was to describe the incidence, risk factors, and mortality of AKI in patients receiving ICPi. Furthermore, we sought to investigate renal outcomes after development of AKI in ICPi users.\n\nMaterials and methods\n\nStudy population\n\nWe performed a retrospective observational cohort study of patients aged ≥18 years who received ICPi between January 1, 2013, and May 31, 2020, at the University Medical Center Utrecht, an academic hospital in the Netherlands. Patients who received nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab, or tremelimumab were included. When patients were consecutively treated with more than one ICPi, i.e. 9.5% of all patients, only the first ICPi was recorded. We excluded patients on renal replacement therapy, without serum creatinine measurement in the 12 months prior to first ICPi administration, or without any serum creatinine measurement after first ICPi administration. This study was performed in accordance with the Declaration of Helsinki. The Medical Research Ethics Committee Utrecht decided that institutional review board approval was not required, as no patients were subjected to interventions nor were any rules of conduct imposed upon them. Patient IDs were visible to the researchers in order to access electronic patient files, required to determine presumptive AKI etiologies. All data were anonymized before analysis. Follow-up started at first ICPi administration and ended with either death or the end of follow-up (July 31, 2020), whichever occurred first.\n\nData collection\n\nPatients receiving ICPi were identified through the Utrecht Patient Oriented Database (UPOD). In brief, UPOD is an infrastructure of relational databases based on the hospital-wide electronic patient record systems, comprising characteristics of all patients treated at the University Medical Center Utrecht since 2004. The structure and content of UPOD have been described in more detail elsewhere [20]. Through UPOD, data on patient age, sex, malignancy type, comorbid conditions, date of death, serum creatinine measurements, and baseline use of antihypertensive- and nephrotoxic medication were collected. Treatment with potentially nephrotoxic chemotherapy or targeted therapy during the six months prior to first ICPi administration was recorded (Table 1). Patients were defined as having hypertension if they were using antihypertensive medication at baseline. The Charlson Comorbidity Index was used to quantify the extent of comorbidities, including diabetes, chronic kidney disease, and cardiovascular diseases [21]. As ICPi-associated myositis has been reported and would be accompanied with serum creatinine elevation not due to kidney dysfunction, episodes of myositis were recorded [22]. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [23].\n\n10.1371/journal.pone.0252978.t001 Table 1 Baseline characteristics.\n\n\tAll patients N = 676\tNo AKI N = 580\tAKI N = 96\t\nAge, median (IQR)\t64\t(53–71)\t64\t(54–71)\t64\t(53–73)\t\nFemale (%)\t256\t(37.9)\t215\t(37.1)\t41\t(42.7)\t\neGFR (mL/min/1.73 m2), median (IQR)\t90\t(75–101)\t90\t(75–101)\t92\t(73–103)\t\neGFR group\t\t\t\t\t\t\t\n <60 mL/min/1.73 m2 (%)\t68\t(10.1)\t57\t(9.8)\t11\t(11.5)\t\n 60–90 mL/min/1.73 m2 (%)\t263\t(38.9)\t229\t(39.5)\t34\t(35.4)\t\n ≥90 mL/min/1.73 m2 (%)\t345\t(51.0)\t294\t(50.7)\t51\t(53.1)\t\nMalignancy type\t\t\t\t\t\t\t\n Melanoma (%)\t319\t(47.2)\t273\t(47.1)\t46\t(47.9)\t\n NSCLC (%)\t163\t(24.1)\t143\t(24.7)\t20\t(20.8)\t\n Gynecologic cancer (%)\t19\t(2.8)\t12\t(2.1)\t7\t(7.3)\t\n Urinary tract cancer (%)\t81\t(12.0)\t72\t(12.4)\t9\t(9.4)\t\n Other (%)\t94\t(13.9)\t80\t(13.8)\t14\t(14.6)\t\nCharlson Comorbidity Index, median (IQR)\t8\t(7–9)\t8\t(7–9)\t8\t(7–9)\t\nDiabetes (%)\t63\t(9.3)\t51\t(8.8)\t12\t(12.5)\t\nHypertension (%)\t234\t(34.6)\t196\t(33.8)\t38\t(39.6)\t\nMedication\t\t\t\t\t\t\t\n ACEi or ARB, diuretic, PPI, or NSAID (%)\t344\t(50.9)\t284\t(49.0)\t60\t(62.5)\t\n ACEi or ARB (%)\t147\t(21.7)\t119\t(20.5)\t28\t(29.2)\t\n Diuretic (%)\t96\t(14.2)\t76\t(13.1)\t20\t(20.8)\t\n PPI (%)\t243\t(35.9)\t200\t(34.5)\t43\t(44.8)\t\n NSAID (%)\t64\t(9.5)\t53\t(9.1)\t11\t(11.5)\t\nPrior chemotherapy or targeted therapya (%)\t193\t(28.6)\t162\t(27.9)\t31\t(32.3)\t\nCheckpoint inhibitor type\t\t\t\t\t\t\t\n Nivolumab (%)\t202\t(29.9)\t176\t(30.3)\t26\t(27.1)\t\n Ipilimumab (%)\t45\t(6.7)\t35\t(6.0)\t10\t(10.4)\t\n Pembrolizumab (%)\t236\t(34.9)\t200\t(34.5)\t36\t(37.5)\t\n Combined therapyb (%)\t132\t(19.5)\t113\t(19.5)\t19\t(19.8)\t\n Other (%)\t61\t(9.0)\t56\t(9.7)\t5\t(5.2)\t\nACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin-receptor blocker; eGFR, estimated glomerular filtration rate; NSAID, non-steroidal anti-inflammatory drug; NSCLC, non-small-cell lung carcinoma; PPI, proton pump inhibitor.\n\naChemotherapy or targeted therapy included carboplatin, cisplatin, oxaliplatin, gemcitabine, capecitabine, cyclophosphamide, methotrexate, pemetrexed, mitomycin, topotecan, ifosfamide, irinotecan, axitinib, imatinib, pazopanib, bortezomib, bevacizumab, sorafenib, sunitinib, bortezomib, carfilzomib, everolimus, temsirolimus, imatinib, dasatinib, vemurafenib, dabrafenib, cetuximab, panitumumab, venetoclax, lenalidomide, crizotinib, and ibrutinib.\n\nbCombined therapy consisted of nivolumab and ipilimumab.\n\nOutcomes\n\nThe primary outcome was development of AKI, defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria [24]. Baseline creatinine was defined as the most recent creatinine measurement before the date of first ICPi administration (median of 1 (IQR 0 to 4) day, maximum of 37 days). The highest creatinine value within three months of AKI onset was used to define AKI as KDIGO stage 1, stage 2, and stage 3, referring to an increase of 1.5 to 1.9, 2.0 to 2.9, and ≥3.0 times the baseline creatinine value, respectively. We analyzed predetermined baseline variables as potential risk factors for AKI. Furthermore, we evaluated renal outcome (persistent renal dysfunction) and mortality in patients who had developed AKI and ICPi-AKI. Persistent renal dysfunction was diagnosed in AKI patients with a final creatinine measurement (at the end of follow-up) of >1.3 times the baseline value. This definition was based on results of a study comparing different definitions of renal recovery after cardiac surgery-associated AKI [25].\n\nICPi-AKI versus non-ICPi-AKI\n\nAKI etiology was determined by retrospective chart review performed by three researchers. A novel definition and classification system for ICPi-AKI, proposed by Gupta et al., was applied to distinguish ICPi-AKI from other AKI etiologies (non-ICPi-AKI) [26]. This classification acknowledges several gradations of diagnostic uncertainty in the absence of kidney biopsy by identifying definite, probable, and possible ICPi-AKI. Definite ICPi-AKI was confirmed when kidney biopsy showed a histopathological lesion compatible with nephrotoxicity caused by ICPi. Probable ICPi-AKI was allocated to patients meeting three criteria: 1) creatinine elevation of ≥1.5 times the baseline value on at least two consecutive values or need for renal replacement therapy; 2) absence of an alternative plausible cause; 3) at least one of three additional criteria: sterile pyuria, eosinophilia, or recent or concomitant non-kidney irAE. An AKI episode was labeled as possible ICPi-AKI when an alternative etiology was not readily attributable, i.e. there was no prior or simultaneous episode of dehydration, hypotension, sepsis, hypercalcemia, acute cardiac event, excessive bleeding, myeloma cast nephropathy, hydronephrosis, or bladder outlet obstruction. AKI was considered non-ICPi-related in patients with hemodynamic or pre-renal causes (including acute tubular necrosis), post-renal obstruction, or other causes.\n\nStatistical analysis\n\nWe present continuous variables with medians and interquartile ranges (IQRs) and categorical variables with counts and percentages. The association between baseline characteristics and AKI was evaluated using Cox proportional hazard regression analysis. Persistent renal dysfunction rates in patients with ICPi-AKI versus non-ICPi-AKI were compared using a Pearson’s chi-squared test. To evaluate the association between AKI and subsequent mortality, a time-dependent Cox proportional hazard regression model was used [27]. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. HRs were adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to a diuretic, angiotensin-converting enzyme inhibitor (ACE-inhibitor) or angiotensin-receptor blocker (ARB), proton pump inhibitor, or non-steroidal anti-inflammatory drug (NSAID), chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index. All analyses were performed using IBM SPSS Statistics version 25.0.\n\nResults\n\nOf the 678 patients who received ICPi between January 1, 2013, and May 31, 2020, one patient had previously objected to use of personal data for research, and one patient had no baseline creatinine measurement, resulting in inclusion of 676 patients in the cohort. Baseline characteristics of the 676 patients are shown in Table 1. The median age was 64 (IQR 53 to 71) years, 256 (37.9%) patients were female, and the median baseline eGFR was 90 (IQR 75 to 101) mL/min/1.73 m2. Melanoma (47.2%) was the most frequent malignancy type, followed by non-small-cell lung carcinoma (24.1%). Nivolumab was the most commonly prescribed ICPi when considering both monotherapy and combined therapy, used by 334 (49.4%) patients.\n\nIncidence and causes of AKI\n\nA total of 96 (14.2%) patients developed AKI following ICPi therapy, during a total follow-up time of 856 person-years (Table 2). Stage 1 AKI occurred in 73 (76.0%), stage 2 in 16 (16.7%), and stage 3 in seven (7.3%) patients. None of the patients required renal replacement therapy. The rate of AKI was 112 per 1000 person-years. Median time from first ICPi administration to AKI was 15 (IQR 5 to 37) weeks. A nephrologist was consulted in 12 (12.5%) patients with AKI, and urinalysis was performed in 54 (56.3%) patients with AKI. Urinalysis showed leucocyturia in 20 patients (37.0% of all AKI patients with urinalysis) and microscopic hematuria in 18 patients (33.3% of all AKI patients with urinalysis). Among all patients meeting AKI criteria based on serum creatinine elevation (N = 96), one patient was diagnosed with myositis, however, this diagnosis was established more than six months after the initial serum creatinine elevation.\n\n10.1371/journal.pone.0252978.t002 Table 2 Stage, etiology, and renal outcome of patients with AKI and ICPi-AKI.\n\nPatients with AKI\t96\t(14.2% of all patients)\t\nAKI stage\t\t\t\n Stage 1 (%)\t73\t(76.0)\t\n Stage 2 (%)\t16\t(16.7)\t\n Stage 3 (%)\t7\t(7.3)\t\nRenal outcome after AKI\t\t\t\n Persisting renal dysfunction (%)\t34\t(35.4)\t\n Renal recovery (%)\t62\t(64.6)\t\nEtiology among patients with AKI\t\t\t\n Definite ICPi-AKI (%)\t1\t(1.0)\t\n Probable ICPi-AKI (%)\t8\t(8.3)\t\n Possible ICPi-AKI (%)\t23\t(24.0)\t\n Hemodynamic or pre-renal cause (%)\t53\t(55.2)\t\n Post-renal cause (%)\t7\t(7.3)\t\n Other cause (%)\t4\t(4.2)\t\nPatients with ICPi-AKI\t32\t(4.7% of all patients)\t\nICPi-AKI stage\t\t\t\n Stage 1 (%)\t26\t(81.3)\t\n Stage 2 (%)\t6\t(18.8)\t\n Stage 3 (%)\t0\t\t\nRenal outcome after ICPi-AKI\t\t\t\n Persisting renal dysfunction (%)\t13\t(40.6)\t\n Renal recovery (%)\t19\t(59.4)\t\nAKI, acute kidney injury; ICPi-AKI, immune checkpoint inhibitor-associated acute kidney injury.\n\nChart review regarding causes of AKI in all 96 patients revealed that 32 patients (33.3% of all AKI patients) had ICPi-AKI, which was subdivided into three levels of diagnostic certainty. One (1.0%) patient was diagnosed with definite ICPi-AKI as confirmed by kidney biopsy, which showed acute tubulointerstitial nephritis. Eight (8.3%) patients met the criteria of probable ICPi-AKI, and 23 (24.0%) patients had possible ICPi-AKI. In 53 (55.2%) patients, AKI was likely related to a hemodynamic or pre-renal cause, and in seven (7.3%) patients, AKI was attributed to post-renal obstruction. Four (4.2%) patients had AKI due to other causes, including urinary tract infection and myeloma cast nephropathy.\n\nRegarding the 32 patients with definite, probable, and possible ICPi-AKI, 81.3% had stage 1 AKI and 18.8% had stage 2 AKI. There were no cases of stage 3 AKI among patients with ICPi-AKI. Median time from first ICPi administration to ICPi-AKI was 15 (IQR 5 to 31) weeks. A nephrologist was consulted in six (18.8%) ICPi-AKI patients, and urinalysis was performed in 14 (43.8%) ICPi-AKI patients. Urinalysis showed leucocyturia in six patients (42.9% of all ICPi-AKI patients with urinalysis) and microscopic hematuria in three patients (21.4% of all ICPi-AKI patients with urinalysis). Corticosteroid treatment was started in 11 (34.4%) patients with ICPi-AKI and ICPi treatment was interrupted in 14 (43.8%) patients with ICPi-AKI. Three patients with ICPi-AKI were re-challenged with ICPi, whereupon one patient once more developed AKI. This AKI episode was attributed to a combination of ICPi nephrotoxicity and a hemodynamic cause.\n\nRisk factors for AKI\n\nAnalysis of the relationship between baseline variables and development of AKI showed that, after adjustment for potential confounders, a gynecologic malignancy was associated with a 3.91-fold (95% CI 1.55 to 9.85) increased risk of AKI, and monotherapy with ipilimumab was associated with a 2.31-fold (95% CI 1.03 to 5.20) increased risk of AKI. The risk of developing AKI was increased 2.61-fold (95% CI 1.21 to 5.60) with the use of a diuretic, 2.49-fold (95% CI 1.10 to 5.60) with the use of an ACE-inhibitor or ARB, and 1.69-fold (95% CI 1.04 to 2.75) with the use of a proton pump inhibitor (Table 3). Diabetes was not associated with AKI (crude HR 1.44, 95% CI 0.79 to 2.64; adjusted HR 1.06, 95% CI 0.55 to 2.05).\n\n10.1371/journal.pone.0252978.t003 Table 3 Risk factors for AKI.\n\n\tHazard ratio (95% CI)\t\nCrude\tAdjusted\t\nAge (years)\t<65\t1\t(reference)\t1\t(reference)\t\n≥65\t0.97\t(0.65–1.45)\t0.86\t(0.51–1.45)\t\nSex†\tMale\t1\t(reference)\t1\t(reference)\t\nFemale\t1.21\t(0.80–1.81)\t1.24\t(0.82–1.88)\t\nBaseline eGFR group‡ (mL/min/1.73 m2)\t≥90\t1\t(reference)\t1\t(reference)\t\n60–90\t0.85\t(0.55–1.31)\t0.78\t(0.48–1.27)\t\n<60\t1.10\t(0.57–2.11)\t0.82\t(0.40–1.68)\t\nMalignancy type§\tMelanoma\t1\t(reference)\t1\t(reference)\t\nNSCLC\t0.91\t(0.54–1.54)\t0.67\t(0.38–1.19)\t\nGynecologic cancer\t3.38\t(1.52–7.51)\t3.91\t(1.55–9.85)\t\nUrinary tract cancer\t0.93\t(0.46–1.91)\t0.93\t(0.44–2.00)\t\nOther\t1.09\t(0.60–1.98)\t1.28\t(0.67–2.44)\t\nCharlson Comorbidity Index#\t0–3\t1\t(reference)\t1\t(reference)\t\n4–7\t1.17\t(0.36–3.83)\t1.27\t(0.36–4.56)\t\n8–11\t1.36\t(0.43–4.34)\t1.67\t(0.44–6.32)\t\n≥12\t2.98\t(0.67–13.33)\t3.17\t(0.56–17.97)\t\nHypertension¶\tNo\t1\t(reference)\t1\t(reference)\t\nYes\t1.30\t(0.86–1.96)\t0.66\t(0.31–1.40)\t\nMedication use at baselineπ\tNo ACEi or ARB, diuretic, PPI or NSAID\t1\t(reference)\t1\t(reference)\t\nACEi or ARB\t1.99\t(1.21–3.27)\t2.49\t(1.10–5.60)\t\nDiuretic\t2.15\t(1.25–3.72)\t2.61\t(1.21–5.60)\t\nPPI\t1.86\t(1.19–2.89)\t1.69\t(1.04–2.75)\t\nNSAID\t1.81\t(0.92–3.55)\t1.63\t(0.81–3.26)\t\nPrior chemotherapy or targeted therapyΔ\tNo\t1\t(reference)\t1\t(reference)\t\nYes\t1.41\t(0.92–2.16)\t1.41\t(0.90–2.21)\t\nCheckpoint inhibitor type■\tNivolumab\t1\t(reference)\t1\t(reference)\t\nIpilimumab\t1.72\t(0.83–3.57)\t2.31\t(1.03–5.20)\t\nPembrolizumab\t1.23\t(0.74–2.03)\t1.52\t(0.89–2.60)\t\nCombined therapya\t1.26\t(0.70–2.29)\t1.72\t(0.93–3.21)\t\nOther\t0.63\t(0.24–1.64)\t0.49\t(0.18–1.29)\t\nACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin-receptor blocker; eGFR, estimated glomerular filtration rate; NSAID, non-steroidal anti-inflammatory drug; NSCLC, non-small-cell lung carcinoma; PPI, proton pump inhibitor.\n\nAdjusted for sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, and NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n†Adjusted for age, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n‡Adjusted for age, sex, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n§Adjusted for age, sex, baseline eGFR, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n#Adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, and checkpoint inhibitor type.\n\n¶Adjusted for age, sex, baseline eGFR, malignancy type, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\nπAdjusted for age, sex, baseline eGFR, malignancy type, hypertension, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\nΔAdjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n■Adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, and Charlson Comorbidity Index.\n\naCombined therapy consisted of nivolumab and ipilimumab.\n\nRenal outcomes and mortality\n\nThe median time between baseline creatinine measurement and last creatinine measurement was 36 (IQR 14 to 77) weeks. Persistent renal dysfunction at the end of follow-up was seen in 34 (35.4%) patients and renal recovery in 62 (64.6%) patients of all patients who had developed AKI (Table 2). The incidences of persistent renal dysfunction in patients with ICPi-AKI (40.6%) and patients with non-ICPi-AKI (32.8%) were not different (p-value 0.45). Overall mortality was high in our cohort. After a median follow-up time of 44 (IQR 22 to 89) weeks, 314 (46.4%) patients had died (mortality rate 367 per 1000 person-years). After adjustment for potential confounders, all-cause AKI was associated with a 2.13-fold (95% CI 1.58 to 2.87) increased mortality risk. Further analysis differentiating between AKI etiologies showed that patients with non-ICPi-AKI had an increased risk of mortality (HR 2.87, 95% CI 2.04 to 4.04), but patients with ICPi-AKI (definite, probable, and possible) had no higher risk of mortality (HR 1.11, 95% CI 0.64 to 1.92) (Table 4).\n\n10.1371/journal.pone.0252978.t004 Table 4 AKI and mortality.\n\n\tHazard ratio (95% CI)\t\nCrude\tAdjusted\t\nNo AKI\tN = 580\t1\t(reference)\t1\t(reference)\t\nAKI\tN = 96\t2.18\t(1.62–2.93)\t2.13\t(1.58–2.87)\t\n ICPi-AKI\tN = 32\t1.17\t(0.68–2.03)\t1.11\t(0.64–1.92)\t\n Non-ICPi-AKI\tN = 64\t2.83\t(2.03–3.93)\t2.87\t(2.04–4.04)\t\nAKI, acute kidney injury; ICPi-AKI, immune checkpoint inhibitor-associated AKI.\n\nAdjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\nDiscussion\n\nIn this observational study, the overall incidence of AKI among 676 patients receiving ICPi was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, ACE-inhibitor or ARB, or proton pump inhibitor at baseline. AKI was ICPi-associated in one third of all patients with AKI. ICPi-AKI was mostly low-grade, occurred a median of 15 weeks after ICPi initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Although patients with all-cause AKI had a twofold increased mortality risk, ICPi-AKI was not associated with increased mortality.\n\nIncidence of AKI and ICPi-AKI\n\nThe incidence of AKI in our cohort was similar to the results of two other cohort studies on AKI in ICPi users by Meraz-Muñoz et al. and Seethapathy et al. [18,19]. These studies both reported an AKI incidence of 17%. With regard to ICPi-AKI, our observed incidence (4.7%) was higher than found in a meta-analysis by Cortazar et al. among a total of 3695 patients treated with ICPi in phase 2 and 3 clinical trials, where the estimated incidence of ICPi-AKI was 2.2% [15]. However, the true incidence of ICPi-AKI may have been underestimated in clinical trials, due to delay in AKI onset after ICPi initiation and inaccurate attribution of mild cases of ICPi-AKI to other etiologies. The ICPi-AKI incidence in our cohort differed from the incidences reported by Seethapathy et al. (3.0%) and Meraz-Muñoz et al. (9.7%) [18,19]. A possible explanation for the difference between the findings of Seethapathy et al. and our findings could be that Seethapathy et al. categorized AKI without a plausible etiology as “AKI of undetermined cause”, while in our study, this was recorded as possible ICPi-AKI. Both Seethapathy et al. and Meraz-Muñoz et al. only reviewed episodes of sustained AKI (i.e. AKI lasting ≥72 hours) for a potential relationship with ICPi, and episodes of transient AKI (i.e. AKI lasting <72 hours) were excluded. However, it is unlikely that this caused differences between our observed ICPi-AKI incidences, as in the study of Seethapathy et al., there were no cases of potential ICPi-AKI in patients with transient AKI, and only a minority (14%) of AKI patients in the study of Meraz-Muñoz had transient AKI. We did not differentiate sustained AKI from transient AKI, as a considerable number of patients in our cohort had intervals longer than 72 hours between creatinine measurements. These longer intervals between creatinine measurements might be explained by the low AKI stage in the majority of AKI patients.\n\nRisk factors for AKI\n\nAlthough a gynecologic malignancy was present in only a small number of patients, this baseline characteristic was the strongest predictor for AKI in ICPi recipients. While this result has not been reported by the other cohort studies, gynecologic cancers are known to increase risk of AKI and chronic kidney disease in the general oncology population by ureteral obstruction and retroperitoneal fibrosis caused by radiotherapy [28]. Indeed, in three out of seven (42.9%) patients with a gynecologic tumor and AKI, the cause of AKI was post-renal obstruction. Secondly, monotherapy with ipilimumab was associated with increased risk of AKI. Seethapathy et al. also reported ipilimumab use to increase AKI risk (HR 1.85, 95% CI 1.05 to 3.27), however, the calculated p-value (0.21) did not reach statistical significance [19]. The meta-analysis by Cortazar et al., comparing renal toxicity among ICPi, showed that the combination of ipilimumab plus nivolumab caused higher AKI rates (4.9%) than ipilimumab alone (2.0%) [14]. Additionally, a case-control study by Cortazar et al., with 138 biopsy-confirmed ICPi-AKI patients and 276 control patients without AKI, found combined ICPi treatment, and not ipilimumab monotherapy, to be a risk factor for ICPi-AKI [14]. Thirdly, the baseline use of specific medication, i.e. diuretics, ACE-inhibitors or ARBs, and proton pump inhibitors, was also associated with increased risk of AKI. Among these drugs, only proton pump inhibitor use has been previously described to be a risk factor for development of AKI and ICPi-AKI in patients using ICPi [14,19]. Although the causal pathway remains unknown, previous studies have hypothesized that ICPi do not only induce loss of host tolerance for self-antigens, but also for exogenous agents like proton pump inhibitors [29,30]. The association between AKI and diuretics, ACE-inhibitors, and ARBs has not been previously reported in ICPi users, however, the mechanism might be similar. Additionally, these drugs may induce pre-renal AKI. Finally, our study and previous observational studies on AKI in patients using ICPi found no significant effect of female sex on the risk of AKI nor ICPi-AKI [14,18,19]. These observations contrast with results of a large meta-analysis demonstrating that the risk of developing hospital-associated AKI is significantly greater in men than in women [31]. Furthermore, animal- and clinical studies have shown that premenopausal women are relatively protected from renal disease as compared with age-matched men. However, this effect seems to disappear with advancing age and menopause, suggesting a protective role of estrogen [32–34]. As female patients in our study had a median age of 61 (IQR 49 to 71) years, they would not benefit from such a potential renoprotective estrogen effect. In addition, risk factors for AKI in the general population could be different from those in our patients, who had advanced malignancies and received anticancer therapy.\n\nRenal outcomes and mortality\n\nThe association between AKI and renal recovery status is relevant, as the case-control study by Cortazar et al. showed that absence of renal recovery in patients with ICPi-AKI was independently associated with increased mortality [14]. The same study reported that complete and partial renal recovery occurred in 40 and 45% of patients with ICPi-AKI, respectively. Partial renal recovery was defined as a return of creatinine to less than twice the baseline value or discharge from renal replacement therapy regardless of the creatinine value. In our cohort, with the use of different criteria of renal recovery, patients with ICPi-AKI showed renal recovery in approximately 60% at the end of follow-up. This may indicate that ICPi-AKI more often progresses to long-term impairment of renal function than initially thought.\n\nThe only other cohort study exploring the association between AKI and mortality found that AKI was not associated with increased mortality among 309 patients receiving ICPi, using Kaplan-Meier survival analysis [18]. However, the risk of mortality was not adjusted for variables potentially confounding the association between AKI and mortality (such as medication use at baseline). Furthermore, the Kaplan-Meier model does not consider time-dependency in the relationship between AKI and subsequent mortality. In our cohort, AKI was associated with a twofold increased mortality risk using a time-dependent Cox proportional hazard regression model. Increased mortality risk was not seen in patients with ICPi-AKI, but only in patients with AKI with a non-ICPi-related etiology. The increased mortality risk in patients with non-ICPi-AKI might be a reflection of concurrent problems in these patients, such as infections and tumor progression. The fact that mortality did not increase with ICPi-AKI could be related to the low AKI stages in ICPi-AKI patients (>80% had stage 1 and no patients had stage 3). An alternative theory is that occurrence of irAE, including ICPi-AKI, represents effective antitumor response and hence might improve survival. This hypothesis is suggested by recent studies showing improved progression-free and overall survival in ICPi users who develop irAE [35,36].\n\nKidney biopsy\n\nSince the American Society of Clinical Oncology recommends to forego kidney biopsy and proceed directly with immunosuppressive therapy in case of suspected ICPi-related renal toxicity [37], patients with histopathological evidence of ICPi-AKI are scarce. In our study, as in the study of Seethapathy et al. [19], biopsy was performed in only one patient with suspected ICPi-AKI, showing acute tubulointerstitial nephritis. Unfortunately, no clinical characteristics accurately differentiate between ICPi-AKI and other causes of AKI. However, some characteristics are suggestive, e.g. sterile pyuria, non-kidney irAE, and eosinophilia [26]. Therefore, we chose to use the definition and classification system of ICPi-AKI proposed by Gupta et al., which incorporates these clinical characteristics and accordingly acknowledges several gradations of diagnostic uncertainty in the absence of a kidney biopsy [26]. In addition to the recommendation to forego kidney biopsy, the American Society of Clinical Oncology advises to empirically treat an increase in creatinine ≥2 times the baseline value by interrupting ICPi therapy and to start intravenous prednisone or equivalent after exclusion of other etiologies [37]. As the majority of patients with ICPi-AKI in our cohort had stage 1 AKI (i.e. creatinine elevation <2 times the baseline value), this could explain why treatment with corticosteroids and interruption of ICPi was only initiated in less than half of the patients.\n\nStrengths and limitations\n\nThis study has several strengths. We were able to demonstrate the incidence of AKI in a representative population of patients using a variety of ICPi classes. Patient data were collected using a comprehensive infrastructure of databases, and determination of AKI etiology was thoroughly performed by three researchers. A strength of the Cox regression was that we used time-dependent analyses to show the association between AKI and mortality. Furthermore, to the best of our knowledge, this is the first study to provide information on the association between ICPi-AKI and mortality. This study also has limitations that need to be addressed. First, as previously discussed, ICPi-AKI was confirmed by kidney biopsy in only one patient. It is possible that other episodes of ICPi-AKI were erroneously attributed to non-ICPi-related causes and vice versa. Furthermore, as data on serum creatinine levels of patients were retrospectively collected, it is possible that AKI events were unnoticed and the incidence of AKI was thus underestimated. However, the mean number of creatinine measurements after ICPi initiation was 18 per patient per year, indicating that our population was carefully monitored. Theoretically, AKI incidence might have been overestimated by ICPi-associated myositis leading to increase of serum creatinine. This was, however, not the case in our study, since among all patients meeting AKI criteria, only one patient was diagnosed with myositis and this diagnosis was established more than six months after the initial serum creatinine elevation. Additionally, our definition of AKI did not meet all KDIGO criteria, which demand that the increase of baseline creatinine should have occurred within seven days prior to AKI onset. However, as ICPi treatment was usually managed in an outpatient setting, the majority of patients experiencing AKI did not have a creatinine measurement shortly before presenting with AKI. Another limitation of our study was the limited power in the association between several baseline variables and AKI. There were specifically low numbers of patients with gynecologic cancer and patients receiving ipilimumab monotherapy. Another possible limitation was that adding potentially related confounders to the same multiple regression model could distort the risk estimates due to collinearity. However, excluding risk factors could lead to under-correction. Therefore, we presented full models with many potential confounders to decrease confounding. A final important limitation is the fact that, due to the observational methodology of this study, no conclusions can be drawn on causal relations between risk factors and AKI and between AKI and mortality, as unmeasured confounding is possible.\n\nIn conclusion, clinicians should be aware that AKI is frequently observed in patients using ICPi and that renal function should be monitored closely after initiation of treatment, especially in patients using specific medication. In this observational cohort study, ICPi-associated AKI was not associated with increased mortality.\n\nWe thank all the patients who contributed to this study.\n==== Refs\nReferences\n\n1 Hodi FS , O’Day SJ , McDermott DF , Weber RW , Sosman JA , Haanen JB , et al . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363 (8 ):711–23. doi: 10.1056/NEJMoa1003466 20525992\n2 Larkin J , Chiarion-Sileni V , Gonzalez R , Grob JJ , Cowey CL , Lao CD , et al . 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J Immunother Cancer. 2020;8 (1 ). doi: 10.1136/jitc-2019-000467 32601079\n19 Seethapathy H , Zhao S , Chute DF , Zubiri L , Oppong Y , Strohbehn I , et al . The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors. Clin J Am Soc Nephrol. 2019;14 (12 ):1692–700. doi: 10.2215/CJN.00990119 31672794\n20 ten Berg MJ , Huisman A , van den Bemt PM , Schobben AF , Egberts AC , van Solinge WW . Linking laboratory and medication data: new opportunities for pharmacoepidemiological research. Clin Chem Lab Med. 2007;45 (1 ):13–9. doi: 10.1515/CCLM.2007.009 17243908\n21 Charlson ME , Pompei P , Ales KL , MacKenzie CR . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40 (5 ):373–83. doi: 10.1016/0021-9681(87)90171-8 3558716\n22 Moreira A , Loquai C , Pfohler C , Kahler KC , Knauss S , Heppt MV , et al . Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106 :12–23. doi: 10.1016/j.ejca.2018.09.033 30453170\n23 Levey AS , Stevens LA , Schmid CH , Zhang YL , Castro AF 3rd , Feldman HI , et al . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150 (9 ):604–12. doi: 10.7326/0003-4819-150-9-200905050-00006 19414839\n24 KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int. 2012;2 (1 ):1–141.\n25 Xu J , Xu X , Shen B , Zhuang Y , Liu L , Wang Y , et al . Evaluation of five different renal recovery definitions for estimation of long-term outcomes of cardiac surgery associated acute kidney injury. BMC Nephrol. 2019;20 (1 ):427. doi: 10.1186/s12882-019-1613-6 31752748\n26 Gupta S , Cortazar FB , Riella LV , Leaf DE . Immune Checkpoint Inhibitor Nephrotoxicity: Update 2020. Kidney 360 2020. p. 130–40.\n27 Dekker FW , de Mutsert R , van Dijk PC , Zoccali C , Jager KJ . Survival analysis: time-dependent effects and time-varying risk factors. Kidney Int. 2008;74 (8 ):994–7. doi: 10.1038/ki.2008.328 18633346\n28 Malyszko J , Tesarova P , Capasso G , Capasso A . The link between kidney disease and cancer: complications and treatment. Lancet. 2020;396 (10246 ):277–87. doi: 10.1016/S0140-6736(20)30540-7 32711803\n29 Perazella MA , Shirali AC . Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do? Kidney Int. 2020;97 (1 ):62–74. doi: 10.1016/j.kint.2019.07.022 31685311\n30 Rosner MH , Perazella MA . Acute Kidney Injury in Patients with Cancer. N Engl J Med. 2017;377 (5 ):500–1. doi: 10.1056/NEJMc1707248 28767352\n31 Neugarten J , Golestaneh L . Female sex reduces the risk of hospital-associated acute kidney injury: a meta-analysis. BMC Nephrol. 2018;19 (1 ):314. doi: 10.1186/s12882-018-1122-z 30409132\n32 Bairey Merz CN , Dember LM , Ingelfinger JR , Vinson A , Neugarten J , Sandberg KL , et al . Sex and the kidneys: current understanding and research opportunities. Nat Rev Nephrol. 2019;15 (12 ):776–83. doi: 10.1038/s41581-019-0208-6 31586165\n33 Boddu R , Fan C , Rangarajan S , Sunil B , Bolisetty S , Curtis LM . Unique sex- and age-dependent effects in protective pathways in acute kidney injury. Am J Physiol Renal Physiol. 2017;313 (3 ):F740–F55. doi: 10.1152/ajprenal.00049.2017 28679590\n34 Coggins CH , Breyer Lewis J , Caggiula AW , Castaldo LS , Klahr S , Wang SR . Differences between women and men with chronic renal disease. Nephrol Dial Transplant. 1998;13 (6 ):1430–7. doi: 10.1093/ndt/13.6.1430 9641172\n35 Riudavets M BA , Maroto P , Sullivan IG , Anguera G , Paez D , et al . Correlation between immune-related adverse events (irAEs) and efficacy in patients with solid tumors treated with immune-checkpoints inhibitors (ICIs). J Clin Oncol. 2018;36.\n36 Rogado J , Sanchez-Torres JM , Romero-Laorden N , Ballesteros AI , Pacheco-Barcia V , Ramos-Levi A , et al . Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients. Eur J Cancer. 2019;109 :21–7. doi: 10.1016/j.ejca.2018.10.014 30682533\n37 Brahmer JR , Lacchetti C , Thompson JA . Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. 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{ "abstract": "Kaposi's varicelliform eruption is a cutaneous eruption caused by the herpes simplex virus and a few other viruses that infect persons with pre-existing dermatosis such as atopic dermatitis. We report the case of a 56-year-old man who was treated with the mammalian target of rapamycin inhibitor, everolimus, for metastatic renal cell carcinoma. He presented with painful, umbilicated vesicles and pustules on his face, genital region, forearms, and legs suggestive of Kaposi's varicelliform eruption. He did not have a history of any visceral viral disease and pre-existing dermatosis. The diagnosis was based on the clinical features. He was treated with acyclovir for 7 days, with improvement of his skin lesions. We discuss the clinical manifestations of the Kaposi varicelliform-like eruption in an immunocompromised patient treated with everolimus.", "affiliations": "Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea ; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea ; Department of Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea ; Department of Brain Korea 21 Project for Medical Science, Seoul, Korea.", "authors": "Hong\|Soojung\|S\|;Kim\|Eun Hye\|EH\|;Cho\|Sung Bin\|SB\|;Rha\|Sun Young\|SY\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000362925", "fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, [email protected] 10.1159/000362925cro-0007-0337Published online: May, 2014Kaposi's Varicelliform-Like Eruption in a Patient Treated with Everolimus for Metastatic Renal Cell Carcinoma: Report of a Rare Case Hong Soojung abKim Eun Hye bCho Sung Bin cRha Sun Young bdeaDepartment of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, KoreabDepartment of Internal Medicine, Yonsei University College of Medicine, Seoul, KoreacDepartment of Dermatology, Yonsei University College of Medicine, Seoul, KoreadDepartment of Institute for Cancer Research, Yonsei University College of Medicine, Seoul, KoreaeDepartment of Brain Korea 21 Project for Medical Science, Seoul, KoreaSun Young Rha, MD, PhD, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea), E-Mail [email protected] 2014 27 5 2014 27 5 2014 7 2 337 342 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Kaposi's varicelliform eruption is a cutaneous eruption caused by the herpes simplex virus and a few other viruses that infect persons with pre-existing dermatosis such as atopic dermatitis. We report the case of a 56-year-old man who was treated with the mammalian target of rapamycin inhibitor, everolimus, for metastatic renal cell carcinoma. He presented with painful, umbilicated vesicles and pustules on his face, genital region, forearms, and legs suggestive of Kaposi's varicelliform eruption. He did not have a history of any visceral viral disease and pre-existing dermatosis. The diagnosis was based on the clinical features. He was treated with acyclovir for 7 days, with improvement of his skin lesions. We discuss the clinical manifestations of the Kaposi varicelliform-like eruption in an immunocompromised patient treated with everolimus.\n\nKey words\nKaposi's varicelliform eruptionRenal cell carcinomaMammalian target of rapamycin inhibitor\n==== Body\nIntroduction\nKaposi's varicelliform eruption is a disseminated cutaneous infection usually caused by the herpes simplex virus (HSV). It predominantly occurs in patients with pre-existing active dermatosis [1] and is characterized by disseminated vesiculopustules and erosions. It is common in patients with atopic dermatitis and rarely develops in an immunocompromised host. There have been several case reports of Kaposi's varicelliform eruption occurring in patients with cutaneous T-cell lymphoma and multiple myeloma [2, 3]. Herein, we report a nonfatal case of Kaposi's varicelliform-like eruption occurring in an immunocompromised patient taking the mammalian target of rapamycin (mTOR) inhibitor, everolimus, for metastatic renal cell carcinoma (RCC).\n\nCase Report\nA 56-year-old man presented with a 6-day history of fever, chills, and severe forehead pain and 5 days of vesicular eruptions involving the skin of the forehead, both eyelids, and nose. The skin lesions spread to his chest, back, and bilateral upper and lower extremities over the subsequent 4 days (fig. 1a, b). The patient had not had chickenpox during childhood or any recent exposure to it.\n\nHe had been diagnosed with left RCC in June 2007. He underwent radical nephrectomy and the pathologic type was clear cell carcinoma with T3N0M0, stage III, Fuhrman grade II. The patient was given sorafenib 400 mg twice daily for 7 months as adjuvant treatment. Follow-up computed tomography of the abdomen and pelvis performed 8 months after surgery revealed recurrence of the lesion in the left renal fossa invading the tail of the pancreas, transverse colon, and spleen. He underwent splenectomy, distal pancreatectomy, and segmental resection of the transverse colon. Two months later, computed tomography showed three metastatic nodules in the liver, and the patient underwent liver metastasectomy. After surgery, he was started on 37.5 mg of sunitinib, which he took for 7 months. Eleven months after the liver surgery, disease progression involving the liver and lungs was detected, and the patient was enrolled in a clinical trial of second-line treatment using RAD001 (everolimus), which he took for 19 months. Thereafter, disease progressed in his lungs and the patient took palliative sunitinib on a 4-week-on and 2-week-off schedule. Seven months later, a whole-body bone scan revealed multiple bone metastases involving the left ribs, left proximal femur, left ischium, and right iliac bone. The patient underwent palliative radiation therapy (45 Gy) for the pain-causing left ribs and weight bearing both pelvic bones. After finishing the radiation therapy, the patient began everolimus as palliative treatment. He took everolimus for 10 days before the appearance of the rash. The patient had stopped the drug 3 days before admission.\n\nAt admission, the patient's temperature was 38.1°C, his blood pressure was 151/102 mm Hg, and the pulse rate was 110 beats/min. He had vesicles and pustules, with crusting and swelling on the skin of his forehead, both eyelids and nose. Both eyelids were also tender and red. Vesicles, pustules and scabs were present on his trunk and extremities as well. He also had grade 2 oral mucositis. No lymphadenopathy was present.\n\nThe patient's complete blood count revealed a white blood count of 4,640/μl (neutrophils 2,210/μl, lymphocytes 1,370/μl), hemoglobin of 13.0 g/dl, and platelet count of 79,000/μl presenting mild lymphopenia and thrombocytopenia. The C-reactive protein (CRP) was elevated at 85.8 mg/l (normal range, 0–8). The results of other laboratory studies, including routine biochemistry and chest X-rays, were normal. The CD4 and CD8 lymphocyte counts were 0.28 × 109/l and 0.64 × 109/l, respectively (CD4:CD8 ratio = 0.44). Serology for human immunodeficiency virus was negative. His serum IgM and IgG antibodies were negative for varicella-zoster virus. HSV type 1 and type 2 were also undetectable by polymerase chain reaction assay.\n\nA dermatologic clinical diagnosis of Kaposi's varicelliform eruption was made based on the patient's typical skin manifestations, including viral infection-like blisters and eruptions. The patient was intravenously administered 250 mg of acyclovir every 8 h. Twenty-four hours after initiation of treatment, there were no new vesicles, and the patient's clinical status improved. However, his fever did not completely resolve. We reconsulted the dermatologist, and skin biopsy was performed after 6 days of acyclovir.\n\nThe biopsy showed interstitial granulomatous dermatitis with a few eosinophils, extravasated red blood cells and basal vacuolization (fig. 2). There was no evidence of herpetic viral infection in the biopsy specimen. The pathologic findings were suggestive of a granulomatous drug eruption. Therefore, we concluded that the patient had an everolimus-induced drug eruption manifesting as Kaposi's varicelliform eruption considering both clinical presentation and pathologic findings.\n\nAfter stopping everolimus, a follow-up bone scan of the patient revealed new spinal metastases involving the T3 and L1 vertebrae and a compression fracture of L3. He had palliative radiation therapy (42 Gy) of his thoracic and lumbar spine. Three months later, the patient died of disease progression of the metastatic RCC.\n\nDiscussion\nKaposi's varicelliform eruption is characterized by dissemination of cutaneous infection of HSV, and some other viruses in patients with pre-existing dermatoses [2, 4]. It is also called eczema herpeticum because it is most commonly seen in patients with atopic dermatitis [5, 6]. Kaposi's varicelliform eruption has also been described in association not only with dermatologic conditions, such as psoriasis, lupus vulgaris, contact dermatitis, and rosacea, but also malignant diseases such as cutaneous T-cell lymphoma and multiple myeloma [2, 3, 7]. There has been a single report of a patient with Kaposi's varicelliform eruption associated with a drug reaction (phenytoin) [1].\n\nThe severity of Kaposi's varicelliform eruption appears to be unrelated to the extent of the eczematous lesions, and active dermatitis is not necessary for the development of eruption. Systemic viremia involving multiple organs, including the liver, lungs, brain, gastrointestinal tract, adrenal glands, and eyes, is the major cause of morbidity and mortality [8]. Transmission can occur through contact with infected persons or by dissemination of primary or recurrent herpes. Recurrent episodes may also occur because the virus persists in the host and periodically reactivates in the mucosa and skin; however, the manifestations of recurrent episodes are milder and usually not systemic [8].\n\nThe diagnosis of Kaposi's varicelliform eruption is mainly clinical. There are several tests that can be useful. A Tzanck smear can provide rapid diagnosis when it shows the characteristic epithelial multinucleated giant cells. Polymerase chain reaction assays can be used to detect a virus. Both biopsy and serology are of little diagnostic value, and these are not recommended as routine tests [5, 9].\n\nOur patient did not have pre-existing dermatitis, but was taking everolimus for the treatment of the metastatic RCC. As an mTOR inhibitor, everolimus modulates T-lymphocyte homeostasis [10], and is therefore used for immunosuppression after organ transplantation and as an anticancer therapeutic. The patient first took everolimus for 19 months in a clinical trial and achieved stable disease. At that time, he only had grade 1 mucositis, insomnia, and hypertriglyceridemia but no skin manifestations of toxicity. However, when taking everolimus for a second time, he developed a drug rash and pruritus after 10 days on everolimus, which were followed by clusters of umbilicated vesiculopustules. These progressed to painful hemorrhagic, crusted, and punched-out erosions. Administration of everolimus was stopped, and the patient started with the antiviral therapy. His condition improved after administration of acyclovir.\n\nThe exact factors for Kaposi's varicelliform eruption are still unclear. However, many studies commonly explained two factors. A defective epidermal barrier and immunosuppression associated with either therapy or a debilitated state of the patient may lead to disseminated HSV infection [1]. In a retrospective review of 100 atopic dermatitis patients with Kaposi's varicelliform eruption, a high IgE serum level was found to be a risk factor [5]. Defective cytokine secretion and decreased cell-mediated immunity is important in the control of primary and recurrent HSV infections [6]. The suppressed immunity and the loss of the epidermal barrier function as a result of everolimus may have contributed to the development of Kaposi's varicelliform-like eruption in our patient, who had an increasing tumor burden and a worsening performance status.\n\nSome investigators have shown that markers of tumor inflammation or host immune status, such as CRP and neutrophil-to-lymphocyte ratio, may be predictive to survival outcome [10, 11]. At admission, the patient had a high CRP level, mild lymphopenia, and a relatively high neutrophil-to-lymphocyte ratio, which taken together, reflected the poor condition of the patient.\n\nWe ultimately diagnosed the patient with Kaposi's varicelliform-like eruption associated with a drug eruption based on the pathologic findings, clinical manifestations, and the clinical course of the patient after everolimus treatment. Unfortunately, we were unable to confirm a viral infection, perhaps because of delays in performing the skin biopsy and other laboratory tests. However, we believe that the most important tool for the diagnosis of Kaposi's varicelliform eruption is clinical judgment.\n\nThis is a rare case of Kaposi's varicelliform-like eruption occurring as an everolimus-induced rash. Physicians need to be aware that patients with increasing tumor activity and decreasing immunity may be at risk for this problem. Early diagnosis, stopping the suspected medication and appropriate treatment of patients at risk for viral complications are very important medical considerations.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nS. Hong and E.H. Kim contributed equally to this work.\n\nFig. 1 Clusters of erythematous papules and crusts are seen on the patient's face (a). Erythematous papules and crusts are scattered on the other areas of the trunk (b).\n\nFig. 2 Skin biopsy showing interstitial granulomatous dermatitis with a few eosinophils, extravasated red blood cells and basal vacuolization.\n==== Refs\nReferences\n1 Ajith C Dogra S Handa S Kaposi's varicelliform eruption in a patient with phenytoin-induced drug rash Int J Dermatol 2006 45 1452 1453 17184260 \n2 Fukuzawa M Oguchi S Saida T Kaposi's varicelliform eruption of an elderly patient with multiple myeloma J Am Acad Dermatol 2000 42 921 922 10767705 \n3 Masessa JM Grossman ME Knobler EH Bank DE Kaposi's varicelliform eruption in cutaneous T cell lymphoma J Am Acad Dermatol 1989 21 133 135 2787337 \n4 Smith BD Son CB Wilson LD Disseminated herpes simplex after total skin electron beam radiotherapy for mycosis fungoides J R Soc Med 2003 96 500 501 14519729 \n5 Olson J Robles DT Kirby P Colven R Kaposi varicelliform eruption (eczema herpeticum) Dermatol Online J 2008 14 18 18700121 \n6 Peng WM Jenneck C Bussmann C Risk factors of atopic dermatitis patients for eczema herpeticum J Invest Dermatol 2007 127 1261 1263 17170734 \n7 Paradisi A Capizzi R Guerriero G Rotoli M Bussoletti C Amerio PL Kaposi's varicelliform eruption complicating allergic contact dermatitis J Am Acad Dermatol 2006 54 732 733 16546605 \n8 Shenoy MM Suchitra U Kaposi's varicelliform eruption Indian J Dermatol Venereol Leprol 2007 73 65 17323459 \n9 Hayashi S Yamada Y Dekio S Jidoi J Kaposi's varicelliform eruption in a patient with mycosis fungoides Clin Exp Dermatol 1997 22 41 43 9330054 \n10 Thiery-Vuillemin A Laheurte C Mansi L Immunomodulatory effects of everolimus in a long responsive patient with metastatic renal cell carcinoma J Immunother 2014 37 51 54 24316556 \n11 Santoni M De Giorgi U Iacovelli R Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma Br J Cancer 2013 109 1755 1759 24008663\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "7(2)", "journal": "Case reports in oncology", "keywords": "Kaposi's varicelliform eruption; Mammalian target of rapamycin inhibitor; Renal cell carcinoma", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "337-42", "pmc": null, "pmid": "24987353", "pubdate": "2014-05", "publication_types": "D002363:Case Reports", "references": "2787337;17170734;24316556;9330054;14519729;24008663;17323459;18700121;10767705;16546605;17184260", "title": "Kaposi's Varicelliform-Like Eruption in a Patient Treated with Everolimus for Metastatic Renal Cell Carcinoma: Report of a Rare Case.", "title_normalized": "kaposi s varicelliform like eruption in a patient treated with everolimus for metastatic renal cell carcinoma report of a rare case" }	[ { "companynumb": "PHHY2015KR033819", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID FOR 7 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CELL CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG, FOR 7 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash pustular", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Spinal compression fracture", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to spine", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Skin swelling", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metastatic renal cell carcinoma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Interstitial granulomatous dermatitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash vesicular", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metastases to lung", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Kaposi^s varicelliform eruption", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metastases to bone", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Blister", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RHA SY, HONG S, KIM EH, CHO SB. KAPOSI^S VARICELLIFORM-LIKE ERUPTION IN A PATIENT TREATED WITH EVEROLIMUS FOR METASTATIC RENAL CELL CARCINOMA: REPORT OF A RARE CASE. CASE REPORTS IN ONCOLOGY. 2014;7:337-342", "literaturereference_normalized": "kaposi s varicelliform like eruption in a patient treated with everolimus for metastatic renal cell carcinoma report of a rare case", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20150326", "receivedate": "20150326", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10958343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "A 37-year-old woman with a history of type II diabetes and Crohn's disease, status postcholecystectomy, presented with a >2-week history of cramping abdominal pain, nausea, non-bloody/non-bilious emesis and, later, diarrhoea. A flexible sigmoidoscopy was performed, revealing that 'a segmental pseudomembrane was found from rectum to sigmoid colon'. Clostridium difficile PCR on the stool was repeated twice and resulted negative both times. A food history prior to onset of symptoms was consistent with Staphylococcal food poisoning and a stool culture was positive for heavy growth of methicillin-resistant Staphylococcus aureus and the absence of enteric flora. The patient was successfully treated with oral vancomycin.", "affiliations": "Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, Florida, USA.;Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, Florida, USA.;Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, Florida, USA.", "authors": "Pressly\|Kalynn B\|KB\|;Hill\|Emilie\|E\|;Shah\|Kairav J\|KJ\|", "chemical_list": "D014640:Vancomycin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2016()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D004761:Enterocolitis, Pseudomembranous; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "27165998", "pubdate": "2016-05-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16208012;20567553;24405901;20567554;16086721;15356793;25769243;16891493;19727105", "title": "Pseudomembranous colitis secondary to methicillin-resistant Staphylococcus aureus (MRSA).", "title_normalized": "pseudomembranous colitis secondary to methicillin resistant staphylococcus aureus mrsa" }	[ { "companynumb": "US-BAYER-2016-115187", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019537", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": "5", "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pseudomembranous colitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KALYNN B PRESSLY, EMILIE HILL, KAIRAV J SHAH. PSEUDOMEMBRANOUS COLITIS SECONDARY TO METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA). BMJ CASE REPORTS,. 2016;(-)", "literaturereference_normalized": "pseudomembranous colitis secondary to methicillin resistant staphylococcus aureus mrsa", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160622", "receivedate": "20160622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12489404, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "Fentanyl induces pharmacological effects and abuse liability comparable to other prescription opioids and heroin. A surge in fentanyl-related fatalities has been periodically reported throughout the USA. The University of Florida Forensic Toxicology Laboratory observed a significant increase in fentanyl-related deaths starting in mid-2014. The present report evaluated toxicological findings, demographics of the decedents and circumstances of death in the postmortem cases that were submitted to the laboratory for toxicological analysis from July 2014 to January 2015 and that were tested for fentanyl in biological specimens. The cases originated from 6 of the 24 Florida Medical Examiner Districts, with the majority from District 12 (Desoto, Manatee and Sarasota counties). The specimens were analyzed for fentanyl by gas chromatography-mass spectrometry; the limit of detection (LOD) was 0.62 ng/mL and the limit of quantification (LOQ) was 2.5 ng/mL. During the 7-month period, the laboratory tested 143 postmortem cases for fentanyl and 50% had quantifiable fentanyl in postmortem blood. Fentanyl concentrations ranged from 2.5 to 68 ng/mL (n = 66; median: 9.8 ng/mL); six cases were positive for fentanyl >LOD but <LOQ. The majority of the cases (85%) had indications of possible drug abuse with heroin use being the most often suspected. Concurrent detection of 6-acetylmorphine, morphine and cocaine along with other opioids and benzodiazepines was common. Of the 59 deaths from District 12, the cause of death was accidental drug intoxication with fentanyl as a sole or contributing factor for 57 cases (two non-drug intoxication deaths). The median age of the 57 decedents was 35 (range: 19-63) years. Males represented 87% of the deaths and 96% were Whites. Most of the decedents (n = 53) had no prescription for fentanyl. Considering fentanyl's high potency and abuse liability, the recent rise in fentanyl-related deaths is a serious public health concern and signifies the urgent need to establish prevention and treatment efforts.", "affiliations": "Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA Houston Forensic Science Center, Houston, TX, USA.;Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA [email protected].", "authors": "Lee\|Dayong\|D\|;Chronister\|Chris W\|CW\|;Broussard\|Wilson A\|WA\|;Utley-Bobak\|Suzanne R\|SR\|;Schultz\|Daniel L\|DL\|;Vega\|Russell S\|RS\|;Goldberger\|Bruce A\|BA\|", "chemical_list": "D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D001569:Benzodiazepines; D003932:Heroin; D009020:Morphine; D003042:Cocaine; C026979:6-O-monoacetylmorphine; D005283:Fentanyl", "country": "England", "delete": false, "doi": "10.1093/jat/bkw087", "fulltext": null, "fulltext_license": null, "issn_linking": "0146-4760", "issue": "40(8)", "journal": "Journal of analytical toxicology", "keywords": null, "medline_ta": "J Anal Toxicol", "mesh_terms": "D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D001344:Autopsy; D001569:Benzodiazepines; D002423:Cause of Death; D003042:Cocaine; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D005431:Florida; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D003932:Heroin; D006801:Humans; D057230:Limit of Detection; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009022:Morphine Derivatives; D015995:Prevalence; D015813:Substance Abuse Detection; D055815:Young Adult", "nlm_unique_id": "7705085", "other_id": null, "pages": "588-594", "pmc": null, "pmid": "27702938", "pubdate": "2016-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Illicit Fentanyl-Related Fatalities in Florida: Toxicological Findings.", "title_normalized": "illicit fentanyl related fatalities in florida toxicological findings" }	[ { "companynumb": "US-MALLINCKRODT-T201605993", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077154", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TRANSDERMAL PATCH", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL TRANSDERMAL SYSTEM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "LEE D, CHRONISTER CW, BROUSSARD WA, UTLEY-BOBAK SR, SCHULTZ DL, VEGA RS, GOLDBERGER BA.. ILLICIT FENTANYL-RELATED FATALITIES IN FLORIDA: TOXICOLOGICAL FINDINGS.. JOURNAL OF ANALYTICAL TOXICOLOGY.. 2016;40 (8):588-594", "literaturereference_normalized": "illicit fentanyl related fatalities in florida toxicological findings", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20161129", "receivedate": "20161129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12984553, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" } ]
{ "abstract": "A 15-year-old boy with a posterior urethral valve received a deceased donor kidney transplant (KT) in March 2011. Basiliximab induction followed by tacrolimus-based triple medication was used as immunosuppression. Eleven months after KT, the graft function deteriorated and the biopsy demonstrated interstitial nephritis suggestive of acute rejection. BK polyomavirus (BKPyV) surveillance in urine and plasma was negative. The patient received methylprednisolone pulses and anti-thymocyte globulin. Immunohistochemistry was positive for simian virus 40 (SV40) large T-antigen (LTag) in the biopsies, and quantitative polymerase chain reaction for JC polyomavirus (JCPyV) indicated high viral loads in urine and borderline levels in plasma. Immunosuppression was reduced and follow-up biopsies showed tubular atrophy and interstitial fibrosis. Two years after KT, antibody-mediated rejection resulted in graft loss and return to hemodialysis. Retrospective serologic work-up indicated a primary JCPyV infection with seroconversion first for IgM, followed by IgG, but no indication of BKPyV infection. In the SV40 LTag positive biopsies, JCPyV deoxyribonucleic acid (DNA) with archetype noncoding control region was detected, while BKPyV DNA was undetectable. To the best of our knowledge, this is the first reported case of primary JCPyV infection as the cause of PyV-associated nephropathy in KT.", "affiliations": "Department of Virology, Helsinki University Hospital (HUSLAB) and University of Helsinki, Helsinki, Finland.", "authors": "Lautenschlager\|I\|I\|;Jahnukainen\|T\|T\|;Kardas\|P\|P\|;Lohi\|J\|J\|;Auvinen\|E\|E\|;Mannonen\|L\|L\|;Dumoulin\|A\|A\|;Hirsch\|H H\|HH\|;Jalanko\|H\|H\|", "chemical_list": "D004279:DNA, Viral; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1111/ajt.12945", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "14(12)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "biopsy; clinical research/practice; infection and infectious agents; infectious disease; kidney transplantation/nephrology; rejection: acute; rejection: antibody-mediated (ABMR); viral: BK/JC/polyoma", "medline_ta": "Am J Transplant", "mesh_terms": "D000293:Adolescent; D004279:DNA, Viral; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007577:JC Virus; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D009395:Nephritis, Interstitial; D027601:Polyomavirus Infections; D011183:Postoperative Complications; D011379:Prognosis; D006435:Renal Dialysis; D014412:Tumor Virus Infections; D019562:Viral Load", "nlm_unique_id": "100968638", "other_id": null, "pages": "2887-92", "pmc": null, "pmid": "25359127", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A case of primary JC polyomavirus infection-associated nephropathy.", "title_normalized": "a case of primary jc polyomavirus infection associated nephropathy" }	[ { "companynumb": "FI-ACCORD-026992", "fulfillexpeditecriteria": "1", "occurcountry": "FI", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "BASILIXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BASILIXIMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "KIDNEY TRANSPLANT REJECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, 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{ "abstract": "Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone.", "affiliations": "Department of Hematology, Nagaoka Red Cross Hospital, Japan.", "authors": "Hashimoto\|Shigeo\|S\|;Kuroha\|Takashi\|T\|;Yano\|Toshio\|T\|;Sato\|Naoko\|N\|;Furukawa\|Tatsuo\|T\|", "chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.55.6470", "fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.6470Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27746443Case ReportThe Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma Hashimoto Shigeo 1Kuroha Takashi 1Yano Toshio 1Sato Naoko 1Furukawa Tatsuo 11 Department of Hematology, Nagaoka Red Cross Hospital, JapanCorrespondence to Dr. Shigeo Hashimoto, [email protected]\n\n15 10 2016 55 20 3025 3028 27 8 2015 2 12 2015 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone. \n\nmultiple myelomabortezomibdexamethasonethalidomide\n==== Body\nIntroduction\nCombination therapy using bortezomib and dexamethasone (BD) is now widely considered to be the standard induction chemotherapy for newly-diagnosed or relapsed symptomatic multiple myeloma (1-5). Although the effect of this therapy is better than that of previous conventional therapies such as melphalan with prednisolone (MP), many patients may develop refractory disease or may only demonstrate a brief remission after BD therapy. We herein report five cases with multiple myeloma that were treated with BD therapy and subsequently experienced disease progression during BD therapy. In four of five cases, the addition of low-dose thalidomide (50 mg per day) to BD therapy [bortezomib, thalidomide, dexamethasone (VTD) 50] made refractory disease respond to therapy. One case was treated with the combination of four drugs (bortezomib, cyclophosphamide, dexamethasone and thalidomide) after the disease had become refractory to the three drug combination. After adding bortezomib to thalidomide, 50 mg/day, cyclophosphamide and dexamethasone, back pain was relieved quickly and the laboratory findings, including anemia and elevation of β2 microglobulin, showed continuous improvement since this four-drug combination was started. Several reports showed the effects of bortezomib, dexamethasone and thalidomide therapy for multiple myeloma as induction chemotherapy, consolidation chemotherapy after autologous stem cell transplantation and salvage chemotherapy (6,7). However, most of these reports used thalidomide at a dose of 100 mg to 200 mg per day. There are few reports of low-dose thalidomide in combination with BD therapy, and adding only 50 mg daily thalidomide (VTD 50) may be effective against multiple myeloma refractory to BD therapy. We herein report the results of VTD 50 therapy.\n\nCase Reports\nCase 1\nA 68-year-old man was referred to our hospital after the detection of an IgG λ elevation. The serum IgG level was 3,861 mg/mL, with all other globulins markedly suppressed. He had been diagnosed with stage I multiple myeloma according to the International Staging System (ISS) in January 2009. He had been treated with MP therapy first with a minimal response, and was subsequently treated with 100 mg of daily dose thalidomide with dexamethasone and MP plus thalidomide. The effect of that therapy with thalidomide was a minimal response. Computed tomography revealed the development of an interstitial shadow in both lung fields; therefore, BD therapy was not considered for primary therapy. In early 2011, weekly BD therapy (2.1 mg of bortezomib and 20 mg intravenous dexamethasone) was safely started, and IgG decreased markedly. The serum levels of IgG decreased from 3,806 mg/mL to 1,684 mg/mL within two months. He was considered to have attained a partial remission by February 2011. After weekly outpatient injections of bortezomib, the patient was later switched to two injections every three weeks, and he had neither any lung side effects nor severe sensory disturbances for over a half year. In October 2011, a rapid increase in the IgG levels was observed (3,066 mg/mL). He was given VTD 50 therapy, adding 50 mg of thalidomide daily, even though thalidomide previously had been ineffective when combined with dexamethasone or MP. We administered VTD 50 therapy with bortezomib due to concerns of potential sensory disturbance from the administration of both drugs. The combination of VTD 50 caused a decrease in the levels of IgG (down to 2,163 mg/mL in May 2013) and β2 microglobulin, which was considered to be a partial response, again with the disappearance of back pain and no sensory disturbance, and this partial response was maintained for eleven months. After a repeated deterioration of the laboratory findings, he refused further therapies using bortezomib or other combination chemotherapies. He has been treated with conventional therapy using melphalan, cyclophosphamide, and prednisolone and has since remained stable since that time.\n\nCase 2\nA 75-year-old woman was referred to our hospital in June 2010 after the detection of anemia and renal dysfunction. Her serum IgA level was 2,845 mg/mL. She was diagnosed with IgA λ myeloma, ISS stage III. She initially refused BD therapy, as she was concerned about potential side effects such as interstitial pneumonia. She had agreed to use weekly BD therapy (1.7 mg of bortezomib and 20 mg intravenous dexamethasone) when her IgA was elevated after several conventional therapies, including MP and dexamethasone monotherapy (serum level of IgA was up to 946 mg/mL in April 2011 from the normal range). Pancytopenia was observed after weekly bortezomib and dexamethasone injection with a marked decrease in the IgA levels (down to 73 mg/mL after one month), suggesting a very good partial response. Bortezomib therapy was changed to weekly, then monthly, and the patient was free of granulocytopenia and did not require transfusions. After continuing BD therapy for approximately one year, IgA and β2 microglobulin again became elevated. Biweekly injection of bortezomib became ineffective by early 2012. The patient's serum IgA level was 1,515 mg/mL in March 2012. She agreed to add thalidomide, 50 mg daily, to BD, according to our previous treatment experience (as in case 1). After VTD 50 was initiated, a rapid decrease in the IgA and β2 microglobulin levels was observed and the patient again attained a partial response (IgA level was reduced to 290 mg/mL in October 2012). These effects continued for eleven months without any sensory disturbance. After repeated deterioration of the laboratory data despite VTD 50 therapy, a rapid progressive disease status was observed, and other drugs such as lenalidomide had a minimal effect. She died from plasma cell leukemia in December 2013.\n\nCase 3\nA 62-year-old man was diagnosed with ISS stage III IgG κ myeloma in September 2007. He was treated with tandem autologous stem cell transplantation followed by several courses of vincristine, doxorubicin, and dexamethasone induction therapy from July through November 2008. No further treatment after transplantation was performed due to the development of a viral infection and pneumonia shortly after transplantation. After transplantation, he remained in a complete remission for several years. In February 2011, a routine examination revealed re-elevation of IgG (2,215 mg/mL), elevation of the atypical plasma cell ratio in the bone marrow, and positive monoclonal immunoelectrophoresis, leading to a diagnosis of relapsed myeloma. BD therapy (2.2 mg of bortezomib and 20 mg intravenous dexamethasone) was started in March 2011. Outpatient bortezomib was given on a weekly to biweekly basis. The IgG level increased again from the normal range to over 2,000 mg/mL in May 2012, suggesting a partial response after relapse. The patient began VTD 50 therapy in combination with BD therapy in July 2012. VTD 50 therapy decreased the IgG levels to 1,077 mg/mL by August 2011, again achieving a partial response with the disappearance of bone pain, and this response was maintained until June 2013, when the patient again developed progressive bone pain and IgG elevation. Lenalidomide plus dexamethasone or bortezomib, cyclophosphamide and dexamethasone combination therapy had no effect after progression. He eventually died from plasma cell leukemia in November 2013.\n\nCase 4\nA 58-year-old woman was transferred from another hospital with severe back pain in January 2012. She was diagnosed with ISS stage II IgG κ multiple myeloma. Her serum IgG level was 5,440 mg/mL at the initial visit. She initially refused up-front autologous stem cell transplantation at the diagnosis, and thus began biweekly BD therapy (2 mg of bortezomib and 20 mg intravenous dexamethasone) from April 2012 to January 2013, achieving a partial response. Progressive back pain and re-elevation of IgG were observed after ten months of BD therapy. The serum IgG level had increased to 2,364 mg/mL at that time. She agreed to take VTD 50 therapy with BD therapy. She had a rapid decrease of IgG and disappearance of back pain within two to three weeks after starting VTD 50 therapy. The IgG level was decreased to 1,208 mg/mL in May 2013, again achieving a partial response. This response was sustained for 10 months before progressive bone pain again developed in December 2013. The IgG level had increased to 1,825 mg/mL at that time. She was treated with 20 mg of lenalidomide for several months after VTD 50 therapy. Although lenalidomide controlled the IgG elevation, symptomatic bone pain had not disappeared completely. She then decided to undergo autologous stem cell transplantation after achieving a response after multiple salvage chemotherapies.\n\nCase 5\nA 63-year-old man was referred to our hospital following the detection of anemia in October 2011. He was diagnosed with ISS stage III Bence Jones λ multiple myeloma. Since all peripheral blood gamma-globulins were heavily suppressed, his disease status was followed according to symptoms of back pain, anemia, and elevation of β2 microglobulin (7.864 mg/L at the initial visit). He was not considered to be a candidate for up-front autologous stem cell transplantation due to a past history of cardiac bypass. Weekly to biweekly BD therapy (2 mg of bortezomib and 20 mg intravenous dexamethasone) was started in December 2011, which resulted in a rapid improvement in back pain, improvement in anemia, and a decrease in the β2 microglobulin levels within two weeks. In March 2013, his back pain returned, and in October 2013, β2 microglobulin increased rapidly (4.146 mg/L) accompanied by uncontrollable back pain. Increased cycles of BD with VTD 50 or treatment with lenalidomide plus dexamethasone had no effect. Morphine was required to reduce his severe pain, and within a short time, he could not walk. In December 2013, he developed worsening anemia and hypogammaglobulinemia, and further elevation of the β2 microglobulin levels (up to 5.685 mg/L) was observed, and he had to be admitted to our hospital. Treatment with cyclophosphamide (500 mg biweekly), thalidomide (50 mg daily), and dexamethasone (20 mg weekly) combination therapy briefly stabilized the β2 microglobulin levels, but his severe back pain persisted. Adding bortezomib (2 mg weekly) to the three-drug combination rapidly improved the back pain and decreased the β2 microglobulin levels. He has been treated with this four-drug combination (100 mg oral cyclophosphamide for four continuous days/every two weeks, 50 mg thalidomide daily, 20 mg oral dexamethasone weekly, and 2 mg bortezomib injected subcutaneously weekly) for over one and a half years maintaining stable disease without back pain, elevated β2 microglobulin levels (2 to 3 mg/mL by a biweekly routine examination), or further sensory disturbance beyond those present at the time of BD therapy.\n\nDiscussion\nBD therapy is considered a standard chemotherapy for multiple myeloma for autologous transplantation eligible patients (1-3), transplantation ineligible patients (4) and even patients with relapsed or refractory disease following previous therapy (5). In transplantation-eligible patients and refractory or relapsed patients, cyclophosphamide (VCD) or thalidomide (VTD) may be added to BD therapy to achieve optimal results (6). With VTD, peripheral neuropathy is one of the adverse effects, which is observed more often than with thalidomide and dexamethasone therapy (7). Both bortezomib and thalidomide have peripheral neurotoxicity. In particular, when these two drugs are used in combination, the thalidomide daily dose can range from 50 to 200 mg (6). A dose reduction of thalidomide (50 mg) may reduce this toxicity considerably (8,9). Among transplantation-ineligible patients, there are decision criteria according to the patients' clinical status or frailty (10). For induction, patients can be treated with monotherapy up to a three-drug combination. After induction, therapeutic options include bortezomib-based, lenalidomide-based or bortezomib and thalidomide-based combinations [such as bortezomib-melphalan-predinsone-thalidomide (VMPT)-bortezomib-thalidomide (VT) therapy (11)]. In frail patients, bortezomib, lenalidomide, dexamethasone and cyclophosphamide should be considered for dose reduction, however, dose reduction of thalidomide is excluded (6). Another report showed that the daily dose of thalidomide could be reduced 50 mg in two days to 100 mg per day for frail patients (12). According to the findings of our study, combination therapy with thalidomide and other drugs may be used for both transplantation-eligible and -ineligible patients with a wider range to reduce the daily dose of thalidomide than for other drugs while still achieving optimal effects. Our five cases were treated with a 50 mg daily dose of thalidomide together with BD therapy for refractory disease. Four of five cases showed improvement, including reduction of M protein and symptoms. One case showed improvement with combination therapy of bortezomib, thalidomide, cyclophosphamide, and dexamethasone. All five cases were treated with thalidomide, 50 mg daily, without excess peripheral neuropathy. Two of five cases were over 65 years of age. VTD 50 therapy safely induced a partial response of refractory disease and a rapid improvement of bone pain, together with simultaneous regression of M protein and β2 microglobulin. These findings were maintained for nearly one year in four of five cases. In two of five cases, the diseases eventually transformed into plasma cell leukemia after VTD 50 therapy. Further studies are required to find new strategies for further extending the response duration or maintaining stable disease using this drug combination.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Harousseau JL , Attal M , Avet-Loiseau H , et al \nBortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial . J Clin Oncol \n28 : 4621 -4629 , 2010 .20823406 \n2. Sonneveld P , Goldschmidt H , Rosiñol L , et al \nBortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials . J Clin Oncol \n31 : 279 -287 , 2013 .\n3. Nooka AK , Kaufman JL , Behera M , et al \nBortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials . Cancer \n119 : 4119 -4128 , 2013 .24005889 \n4. Palumbo A , Rajkumar SV , San Miguel JF , et al \nInternational Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation . J Clin Oncol \n32 : 587 -600 , 2014 .24419113 \n5. Kropff MH , Bisping G , Wenning D , et al \nBortezomib in combination with dexamethasone for relapsed multiple myeloma . Leuk Res \n29 : 587 -590 , 2005 .15755512 \n6. Ludwig H , Sonneveld P , Davies F , et al \nEuropean perspective on multiple myeloma treatment strategies in 2014 . Oncologist \n19 : 829 -844 , 2014 .25063227 \n7. Cavo M , Pantani L , Petrucci MT , et al \nBortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma . Blood \n120 : 9 -19 , 2012 .22498745 \n8. Pineda-Roman M , Zangari M , van Rhee F , et al \nVTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma . Leukemia \n22 : 1419 -1427 , 2008 .18432260 \n9. Glasmacher A , von Lilienfeld-Toal M \nThe current status of thalidomide in the management of multiple myeloma . Acta Haematol \n114 (Suppl 1 ): 3 -7 , 2005 .16166765 \n10. Palumbo A , Anderson K \nMultiple myeloma . N Engl J Med \n364 : 1046 -1060 , 2011 .21410373 \n11. Palumbo A , Bringhen S , Larocca A , et al \nBortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival . J Clin Oncol \n32 : 634 -640 , 2014 .24449241 \n12. Palumbo A , Bringhen S , Ludwig H , et al \nPersonalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN) . Blood \n118 : 4519 -4526 , 2011 .21841166\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "55(20)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": null, "medline_ta": "Intern Med", "mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000069286:Bortezomib; D003520:Cyclophosphamide; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D013792:Thalidomide; D016896:Treatment Outcome", "nlm_unique_id": "9204241", "other_id": null, "pages": "3025-3028", "pmc": null, "pmid": "27746443", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21410373;22498745;23897961;24449241;16166765;15755512;24005889;25063227;24419113;21841166;20823406;18432260", "title": "The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma.", "title_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma" }	[ { "companynumb": "JP-CELGENEUS-JPN-2016106786", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201207", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell leukaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "HASHIMOTO S. THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA. INTERNAL MEDICINE.. 2016;.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161129", "receivedate": "20161107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12917477, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "JP-CELGENEUS-JPN-2016106788", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "44320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE ORAL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "201112", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE IV" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "041", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201112", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE IV" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "201112", "drugstartdateformat": "610", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": "201112", "drugstartdateformat": "610", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "44320", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypogammaglobulinaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201312" } }, "primarysource": { "literaturereference": "HASHIMOTO S, HASHIMOTO S. THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA.. INTERNAL MEDICINE.. 2016;3025-3028.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161201", "receivedate": "20161201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12991382, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "JP-CELGENEUS-JPN-2016106782", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug effect decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2012" } }, "primarysource": { "literaturereference": "HASHIMOTO S. THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA.. INTERNAL MEDICINE. 2016;3025-3028.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161129", "receivedate": "20161107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12921045, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "JP-BAUSCH-BL-2016-026868", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "40069", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "200811", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201207", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LENALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201207", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40069", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201207", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BORTEZOMIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": "2.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BORTEZOMIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "40069", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "200811", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "200811", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HASHIMOTO S, KUROHA T, YANO T, SATO N, FURUKAWA T. THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA. INTERNATIONAL MEDICINE. 2016;55:3025-3028.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161104", "receivedate": "20161104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12914001, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]
{ "abstract": "BACKGROUND\nHepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.\n\n\nMETHODS\nIn children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.\n\n\nRESULTS\nAmong 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 109 l-1 ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).\n\n\nCONCLUSIONS\nPEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.", "affiliations": "Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.;Department of Pediatric Hematology and Oncology, H. C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.;Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.;Department of Pediatric and Adolescent Medicine, Turku University Hospital, Turku, Finland.;Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm, Sweden.;Department of Pediatrics, University Hospital North Norway, Tromsø, Norway.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.", "authors": "Toksvang\|Linea Natalie\|LN\|;De Pietri\|Silvia\|S\|;Nielsen\|Stine N\|SN\|;Nersting\|Jacob\|J\|;Albertsen\|Birgitte K\|BK\|;Wehner\|Peder S\|PS\|;Rosthøj\|Steen\|S\|;Lähteenmäki\|Päivi M\|PM\|;Nilsson\|Daniel\|D\|;Nystad\|Tove A\|TA\|;Grell\|Kathrine\|K\|;Frandsen\|Thomas L\|TL\|;Schmiegelow\|Kjeld\|K\|", "chemical_list": "D011092:Polyethylene Glycols; C042705:pegaspargase; D015122:Mercaptopurine; D001215:Asparaginase; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1002/pbc.26519", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(9)", "journal": "Pediatric blood & cancer", "keywords": "acute lymphoblastic leukemia; asparaginase; liver toxicity; maintenance therapy; sinusoidal obstruction syndrome", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016016:Proportional Hazards Models", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "28423235", "pubdate": "2017-09", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.", "title_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites" }	[ { "companynumb": "DK-MYLANLABS-2017M1057418", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Blood albumin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19. DOI: 10.1002/PBC.26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13596987, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057489", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "040594", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/ME2, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASPARGASE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980277, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "PHHY2017DK074971", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170614", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13603637, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051883", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Splenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595297, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051889", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"200750121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DURING DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595307, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017DK074974", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13603617, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057465", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, 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"drugdosagetext": "1,000 IU/M2 EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASPARGASE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { 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"drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980267, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003519", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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"drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609958, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051885", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595298, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017DK074990", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170611", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13640678, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003532", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568318, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003511", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563108, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057452", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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"literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568376, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057487", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 20MG/M2 WEEKLY STARTED AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", 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"3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1,000 IU/M2 EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASPARGASE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980276, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "PHHY2017DK074949", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", 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"activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13603626, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057474", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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"patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980266, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003525", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568336, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017DK075784", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170614", "receivedate": "20170603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609969, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057402", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609819, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057432", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980249, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-052002", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170608", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13625719, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017DK074996", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609822, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051891", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200750121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE AND INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", 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"drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ONCE WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Splenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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PEDIOTR BLOOD CANCER.. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563572, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057395", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609820, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051895", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ONCE WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE AND DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595330, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057530", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14, 60 MG/M2 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563205, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-TEVA-771768ACC", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L,DE PIETRI S,NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES..", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170614", "receivedate": "20170605", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13613365, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003537", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC 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null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568525, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017DK074987", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13607075, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003536", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568495, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003529", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980275, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-TEVA-771791ACC", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, 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"drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L,DE PIETRI S,NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES..", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13602325, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051882", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE AND DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ORALLY, MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M^2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "200750121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood albumin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Activated partial thromboplastin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Coagulation factor decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595295, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051897", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563251, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017DK075771", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, 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"drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETASON" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170615", "receivedate": "20170603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609971, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057491", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "040594", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 75MG/M2 DAILY AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", 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"medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14, 60 MG/M2 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 75MG/M2 DAILY AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASPARGASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980271, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003522", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563571, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ACCORD-051888", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"200750121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13562991, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017DK074977", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { 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"drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13603613, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051900", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULAR", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, 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WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568353, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057535", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DAUNORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DAUNORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 20MG/M2 WEEKLY STARTED AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, 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"drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980283, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-051892", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ONCE WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595313, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057408", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980253, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-051881", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, 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"medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" } ]
{ "abstract": "A 69-year-old male underwent elective percutaneous coronary intervention requiring placement of a drug-eluting stent to the first obtuse marginal artery. Four hours following the administration of a ticagrelor loading dose, he developed dyspnea and sinus pauses. Aminophylline was administered and resulted in immediate and sustained symptom resolution. Ticagrelor has been associated with dyspnea and bradyarrhythmias, both attributed to increased adenosine exposure. Ticagrelor inhibits reuptake of intracellular adenosine. Adenosine antagonists aminophylline and theophylline have been utilized to reverse the effects of adenosine and may relieve adenosine-mediated adverse effects induced by ticagrelor therapy. Aminophylline may be considered for reversal of dyspnea and bradyarrhythmia associated with ticagrelor therapy through alterations in adenosine exposure.", "affiliations": "1 Hospital Pharmacy Services, The University of Chicago Medicine, Chicago, IL, USA.;1 Hospital Pharmacy Services, The University of Chicago Medicine, Chicago, IL, USA.;2 Department of Cardiology, The University of Chicago Medicine, Chicago, IL, USA.;2 Department of Cardiology, The University of Chicago Medicine, Chicago, IL, USA.", "authors": "Minner\|Sarah A\|SA\|;Simone\|Pamela\|P\|;Chung\|Benjamin B\|BB\|;Shah\|Atman P\|AP\|", "chemical_list": "D058915:Purinergic P1 Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D000628:Aminophylline; D000077486:Ticagrelor; D000241:Adenosine", "country": "United States", "delete": false, "doi": "10.1177/0897190016680978", "fulltext": null, "fulltext_license": null, "issn_linking": "0897-1900", "issue": "31(1)", "journal": "Journal of pharmacy practice", "keywords": "acute coronary syndrome; aminophylline; bradyarrhythmia; dyspnea; ticagrelor/adverse effects", "medline_ta": "J Pharm Pract", "mesh_terms": "D000241:Adenosine; D000368:Aged; D000628:Aminophylline; D001919:Bradycardia; D004417:Dyspnea; D006801:Humans; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor", "nlm_unique_id": "8900945", "other_id": null, "pages": "112-114", "pmc": null, "pmid": "27920235", "pubdate": "2018-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful Reversal of Bradycardia and Dyspnea With Aminophylline After Ticagrelor Load.", "title_normalized": "successful reversal of bradycardia and dyspnea with aminophylline after ticagrelor load" }	[ { "companynumb": "US-PFIZER INC-2018346179", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "325 MG, UNK (GIVEN ORALLY WITHIN 15 MINUTES OF STENT DEPLOYMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "325", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TICAGRELOR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "180 MG, UNK (GIVEN ORALLY WITHIN 15 MINUTES OF STENT DEPLOYMENT)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICAGRELOR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ADENOSINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "022", "drugauthorizationnumb": "203883", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "180 UG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "180", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADENOSINE PHOSPHATE" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MINNER, S.. SUCCESSFUL REVERSAL OF BRADYCARDIA AND DYSPNEA WITH AMINOPHYLLINE AFTER TICAGRELOR LOAD. 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SUCCESSFUL REVERSAL OF BRADYCARDIA AND DYSPNEA WITH AMINOPHYLLINE AFTER TICAGRELOR LOAD. 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{ "abstract": "Left atrial appendage closure (LAAC) has evolved as a safe alternative to oral anticoagulation therapy for stroke prophylaxis. However, the presence of a patent foramen ovale (PFO) occluder device is considered a relative contraindication. Here we report a successful case of LAAC in the presence of a PFO occluder device. (Level of Difficulty: Beginner.).", "affiliations": "Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.", "authors": "Kousa\|Omar\|O\|;Mahfood-Haddad\|Toufik\|T\|;Patil\|Shantanu M\|SM\|;Agarwal\|Himanshu\|H\|;Abuissa\|Hussam\|H\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaccas.2021.01.017", "fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00110-8\n10.1016/j.jaccas.2021.01.017\nMini-Focus Issue: Electrophysiology\nCase Report: Clinical Case\nLeft Atrial Appendage Closure in a Patient With a Patent Foramen Ovale Septal Occluder Device\nKousa Omar MD [email protected]\n@OmarKousa12\n∗\nMahfood-Haddad Toufik MD\nPatil Shantanu M. MD\nAgarwal Himanshu MD\nAbuissa Hussam MD\nDepartment of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA\n∗ Address for correspondence: Dr. Omar Kousa, Department of Medicine, Creighton University, 7710 Mercy Road, Suite 202, Omaha, Nebraska 68124, USA. [email protected]@OmarKousa12\n17 3 2021\n3 2021\n17 3 2021\n3 3 508511\n1 6 2020\n22 12 2020\n8 1 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nLeft atrial appendage closure (LAAC) has evolved as a safe alternative to oral anticoagulation therapy for stroke prophylaxis. However, the presence of a patent foramen ovale (PFO) occluder device is considered a relative contraindication. Here we report a successful case of LAAC in the presence of a PFO occluder device. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nKey Words\n\nanticoagulation\natrial fibrillation\nelectrophysiology\ninterventional cardiology\nleft atrial appendage closure\npatent foramen ovale\nAbbreviations and Acronyms\n\nICE, intracardiac echocardiogram\nLAAC, left atrial appendage closure\nPFO, patent foramen ovale\nTEE, transesophageal echocardiogram\n==== Body\nHistory of presentation\n\nA 72-year-old woman was seen in our clinic for consideration of left atrial appendage closure (LAAC). She had an acute right parietal stroke 4 years earlier and underwent patent foramen ovale (PFO) closure using a 30-mm Amplatzer septal occluder device (Abbott, Abbott Park, Illinois) at an outside facility; cryptogenic stroke was the suspected underlying cause. Shortly after undergoing PFO closure, she reported episodes of palpitations and received a diagnosis of paroxysmal atrial fibrillation noted on an event monitor. She was managed with flecainide (50 mg, 2 times a day) for rhythm control and was started on oral anticoagulation therapy with warfarin (CHA2DS2-VASc score of 5: age, previous stroke, female sex, hypertension). Three years later, the patient received a diagnosis of chronic peptic ulcer disease evident on upper gastric endoscopy and had occult gastrointestinal bleeding (HAS- BLED score of 4: age, stroke, receiving anticoagulation therapy, previous major bleeding or predisposition to bleeding). Given her high risk of cardioembolic stroke and contraindication to anticoagulation, she was referred to our structural heart clinic for elective LAAC. On examination, she was afebrile, with a blood pressure of 127/60 mm Hg, a heart rate of 91 beats/min, a respiratory rate of 18 breaths/min, and oxygen saturation of 96% on room air. She had normal heart sounds, no murmurs, normal jugular venous pressure, and no peripheral edema.Learning Objectives\n\n• To understand the role of LAAC as an acceptable alternative to anticoagulation in nonvalvular atrial fibrillation patients who have bleeding complications that develop during anticoagulation therapy and who have a prior history of a PFO septal occluder device.\n\n• To emphasize on the role of ICE in performing precise transseptal puncture in the presence of a septal occluder device.\n\nPast Medical History\n\nHer past medical history consisted of stroke, PFO, atrial fibrillation, and chronic peptic ulcer disease.\n\nDifferential Diagnosis\n\nThe differential diagnosis was ischemic stroke secondary to atrial fibrillation versus PFO.\n\nInvestigations\n\nShe underwent a transesophageal echocardiogram (TEE), which showed normal left ventricular systolic function with a well-seated PFO closure device. The left atrial appendage displayed a “windsock” morphology. A shared decision-making discussion was made, and the patient elected to proceed with LAAC.\n\nManagement\n\nDuring the procedure, it was difficult to visualize the inferior part of the interatrial septum below the Amplatzer device by using the TEE, and we therefore decided to use an intracardiac echocardiogram (ICE). Multiple images were obtained, and they confirmed the presence of an adequate area inferior and posterior to the Amplatzer device (Figure 1, Video 1). Using ICE, TEE, and fluoroscopy, transseptal puncture was successfully performed. The needle was then removed and exchanged for a ProTrack Pigtail Wire (Baylis Medical, Austin, Texas), which was then advanced into the left atrium (Figure 2, Video 2). The dilator and sheath were then removed and exchanged for a HeartSpan MR0 transseptal sheath (Merit Medical, South Jordan, Utah), which was advanced into the left atrium. The dilator and sheath were then removed and exchanged for a 14-F double-curve Watchman Access System (Boston Scientific, Marlborough, Massachusetts), which was advanced over the ProTrack Pigtail Wire into the left atrium (Figure 3). A pigtail catheter was advanced into the sheath, and the latter wire was removed. We then advanced the 14-F Watchman Access System into the left atrial appendage over the pigtail catheter (Figure 4A, Video 3) and carefully removed the latter from the body while making sure to keep the catheter in position. A 27-mm Watchman left atrial appendage device attached to the Watchman delivery system was advanced through the sheath. The device was then deployed carefully under fluoroscopic (Figure 4B) and echocardiographic guidance using the standard technique. The device was released in the standard fashion after meeting the PASS (position, anchor, size, and seal) criteria.Figure 1 Intracardiac Echocardiogram Image Showing the Small Inferior Septal Space Below the PFO Occluder Device\n\nPFO = patent foramen ovale.\n\nFigure 2 Fluoroscopy Image Showing Transseptal Puncture Inferior to the PFO Occluder Device in the AP View and the ProTrack Pigtail Wire (Baylis Medical, Austin, Texas) in the Left Atrium\n\nAP = anteroposterior; TEE = transesophageal echocardiogram; other abbreviations as in Figure 1.\n\nFigure 3 TEE Image at the Midesophageal Level Showing the Transseptal Puncture Site and the Watchman Access System (Boston Scientific, Marlborough, Massachusetts) Below the PFO Occluder Device\n\nAbbreviations as in Figures 1 and2.\n\nFigure 4 Fluoroscopy Imaging Showing the Delivery Sheath and Watchman Device (Boston Scientific, Marlborough, Massachusetts)\n\n(A) Fluoroscopy image in the RAO caudal view confirming the position of the delivery sheath in the left atrial appendage. (B) Fluoroscopy image in the AP caudal view showing the Watchman device in the left atrial appendage. AP = anteroposterior; RAO = right anterior oblique; other abbreviations as in Figures 1 and2.\n\nDiscussion\n\nAtrial fibrillation is prevalent in the United States and is a common cause of thromboembolic events. The risk of thromboembolism increases with older age, female sex, and the presence of comorbidities. Oral anticoagulation agents are widely used to prevent stroke in patients with nonvalvular atrial fibrillation (1). However, these agents can cause bleeding complications in patients with older age, history of bleeding or falls, malignant disease, chronic renal and liver disease, alcohol abuse, thrombocytopenia, and concurrent use of antiplatelet agents. The left atrial appendage accounts for 90% of thrombi formed in the heart (2). The newer technique of LAAC is growing as a safe alternative option to anticoagulation. Studies have shown that it is noninferior to vitamin K antagonists in stroke risk reduction (3,4). Precise transseptal puncture is an essential limiting step for successful deployment of the LAAC device. The presence of a previous PFO closure device makes it challenging because it would reduce the operator maneuverability of access systems and safe deployment of the device in the left atrial appendage (5,6). Currently, there are 2 U.S. Food and Drug Administration–approved devices in the United States: the Amplatzer device by Abbott and Gore Cardioform Septal Occluder by Gore Medical (W. L. Gore and Associates, Newark, Delaware). The Amplatzer device is made of 2 discs connected by a bond bridge. Each disc consists of a nitinol wire mesh that makes it more difficult to puncture. In contrast, the Gore Cardioform Septal Occluder device is made of polytetrafluoroethylene fabric on a nitinol framework and offers a more favorable medium to puncture (7,8). To our knowledge, only 2 cases of LAAC in patients with previous septal occluder device implantation have been published. Nadel et al. (5) have reported a successful transseptal puncture inferior and anterior to the device, whereas Gafoor et al. (6) have reported successful LAAC after PFO occlusion through an inferior and posterior approach. In our case, we used ICE because it was difficult to visualize the inferior part of the interatrial septum below the PFO occluder device when using only the TEE. Of note, computed tomography imaging may be performed to complement TEE imaging; however, this could not be used in our particular case secondary to potential artifact caused by the device. An inferior and posterior approach was used and proved to be a very satisfactory position despite the large size of the device. To our knowledge, this is the first case of ICE use to facilitate transseptal puncture in patients with an existing PFO closure device.\n\nFollow-Up\n\nA TEE was performed after 6 weeks, and it showed a well-seated device in the left atrial appendage with a nonsignificant 2-mm peridevice leak. There was no thrombus or residual interatrial shunt, and warfarin was discontinued. She was subsequently maintained on dual antiplatelet therapy for 4.5 months and on aspirin 325 mg daily thereafter.\n\nConclusions\n\nLAAC is a good alternative in patients with nonvalvular atrial fibrillation who are at high risk for thromboembolism and have a contraindication to anticoagulation. A previous history of atrial septal closure should not preclude proceeding with LAAC. By using appropriate imaging techniques, including ICE, transseptal puncture can be safely performed.\n\nFunding Support and Author Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nICE Showing the Small Inferior Septal Space Below the PFO Occluder Device\n\nSupplemental Video 2\n\nProTrack Pigtail Wire (Baylis Medical, Austin, Texas) in the Left Atrium After Successful Transseptal Puncture\n\nSupplemental Video 3\n\nLeft Atrial Appendage Angiogram After Successful Watchman Device (Boston Scientific, Marlborough, Massachusetts) Deployment\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 January C.T. Wann L.S. Alpert J.S. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society J Am Coll Cardiol 64 2014 e1 e76 24685669\n2 Blackshear J.L. Odell J.A. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation Ann Thorac Surg 61 1996 755 759 8572814\n3 Holmes D.R. Doshi S.K. Kar S. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis J Am Coll Cardiol 65 2015 2614 2623 26088300\n4 Holmes D.R. Kar S. Price M.J. Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial J Am Coll Cardiol 64 2014 1 2 24998121\n5 Nadel J. Subbiah R. Jacobs N. Muller D.W. Gunalingam B. Successful left atrial appendage closure in a patient with prior patent foramen ovale occlusion HeartRhythm Case Rep 5 2019 183 30997330\n6 Gafoor S. Franke J. Boehm P. Leaving no hole unclosed: left atrial appendage occlusion in patients having closure of patent foramen ovale or atrial septal defect J Interv Cardiol 27 2014 414 422 25059287\n7 Messas N. Ibrahim R. The Amplatzer Amulet Device: technical considerations and procedural approach Interv Cardiol Clin 7 2018 213 218 29526289\n8 Thomson J.D. Hildick-Smith D. Clift P. Patent foramen ovale closure with the Gore septal occluder: initial UK experience Catheter Cardiovasc Interv 83 2014 467 473 23766247\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2666-0849", "issue": "3(3)", "journal": "JACC. Case reports", "keywords": "ICE, intracardiac echocardiogram; LAAC, left atrial appendage closure; PFO, patent foramen ovale; TEE, transesophageal echocardiogram; anticoagulation; atrial fibrillation; electrophysiology; interventional cardiology; left atrial appendage closure; patent foramen ovale", "medline_ta": "JACC Case Rep", "mesh_terms": null, "nlm_unique_id": "101757292", "other_id": null, "pages": "508-511", "pmc": null, "pmid": "34317569", "pubdate": "2021-03", "publication_types": "D002363:Case Reports", "references": "23766247;29526289;8572814;26088300;25059287;30997330;24998121;24685669", "title": "Left Atrial Appendage Closure in a Patient With a Patent Foramen Ovale Septal Occluder Device.", "title_normalized": "left atrial appendage closure in a patient with a patent foramen ovale septal occluder device" }	[ { "companynumb": "US-CIPLA LTD.-2021US02777", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "090935", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLECAINIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "ARRHYTHMIA SUPRAVENTRICULAR", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLECAINIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peptic ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Contraindication to medical treatment", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOUSA O, MAHFOOD?HADDAD T, PATIL SM, AGARWAL H, ABUISSA H.. LEFT ATRIAL APPENDAGE CLOSURE IN A PATIENT WITH A PATENT FORAMEN OVALE SEPTAL OCCLUDER DEVICE. J AM COLL CARDIOL CASE REP. 2021?3 (3):508 TO 511", "literaturereference_normalized": "left atrial appendage closure in a patient with a patent foramen ovale septal occluder device", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210415", "receivedate": "20210415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19137867, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TARO-2021TAR00405", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40301", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peptic ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOUSA O, MAHFOOD?HADDAD T, PATIL SM, AGARWAL H, ABUISSA H. LEFT ATRIAL APPENDAGE CLOSURE IN A PATIENT WITH A PATENT FORAMEN OVALE SEPTAL OCCLUDER DEVICE. JACC CASE REP. 2021?3(3):508?511", "literaturereference_normalized": "left atrial appendage closure in a patient with a patent foramen ovale septal occluder device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210428", "receivedate": "20210428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19190165, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-033610", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "009218", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN SODIUM." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KOUSA O, MAHFOOD?HADDAD T, PATIL SM, AGARWAL H, ABUISSA H. LEFT ATRIAL APPENDAGE CLOSURE IN A PATIENT WITH A PATENT FORAMEN OVALE SEPTAL OCCLUDER DEVICE. JACC: CASE REPORTS. 2021?3(3):508?11", "literaturereference_normalized": "left atrial appendage closure in a patient with a patent foramen ovale septal occluder device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210415", "receivedate": "20210415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19137983, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Several fluoroquinolone antibiotics have been associated with cardiac adverse effects, leading to the withdrawal of some of these agents from the market. Cardiac side effects such as QT prolongation and torsades de pointes (TdP) have also been observed with fluoroquinolones currently on the market. In order to evaluate the cardiac risk of fluoroquinolones as a class, and the comparative risk for each individual drug, we conducted a systematic review, meta-analysis, and network meta-analysis.\n\n\n\nMEDLINE, EMBASE and the Cochrane Library were searched, up to March 2018, for randomized controlled trials, cohort studies, and case-control studies that investigated the association between fluoroquinolone treatment and the risk of cardiovascular events and cardiovascular mortality. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random effects models. Direct and indirect comparisons in network meta-analysis were performed using frequentist methods.\n\n\n\nThirteen studies were included in our analyses. Fluoroquinolone use was associated with a statistically significant 85% increase in the risk for arrhythmia (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.22-2.81) and 71% increase in the risk for cardiovascular mortality (OR 1.71; 95% CI 1.39-2.09). Moxifloxacin ranked most likely to have the highest risk for arrhythmia (P-score 0.99) and for cardiovascular mortality (P-score 0.95) by network meta-analysis.\n\n\n\nOur findings show a significant association between fluoroquinolone use and an increased risk for arrhythmia and cardiovascular mortality. Moxifloxacin ranked with the highest probability for cardiovascular adverse events. Further study is required to determine how to reduce the risk for fluoroquinolone-associated cardiac toxicity.", "affiliations": "Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;The Department of Medicine, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.;The Department of Medicine, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel. [email protected].", "authors": "Gorelik\|Einat\|E\|;Masarwa\|Reem\|R\|;Perlman\|Amichai\|A\|;Rotshild\|Victoria\|V\|;Abbasi\|Momen\|M\|;Muszkat\|Mordechai\|M\|;Matok\|Ilan\|I\|", "chemical_list": "D024841:Fluoroquinolones", "country": "New Zealand", "delete": false, "doi": "10.1007/s40264-018-0751-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0114-5916", "issue": "42(4)", "journal": "Drug safety", "keywords": null, "medline_ta": "Drug Saf", "mesh_terms": "D002318:Cardiovascular Diseases; D002319:Cardiovascular System; D016022:Case-Control Studies; D015331:Cohort Studies; D024841:Fluoroquinolones; D006801:Humans; D000071076:Network Meta-Analysis; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors", "nlm_unique_id": "9002928", "other_id": null, "pages": "529-538", "pmc": null, "pmid": "30368737", "pubdate": "2019-04", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review", "references": "19622511;21079043;16331522;24428853;29095256;15687478;24615307;25409476;29625780;17241772;26011799;18478129;16510739;19236122;11909831;22865870;8203853;26920666;19680025;10671353;22008217;15891266;11779516;26227148;12832320;15843667", "title": "Fluoroquinolones and Cardiovascular Risk: A Systematic Review, Meta-analysis and Network Meta-analysis.", "title_normalized": "fluoroquinolones and cardiovascular risk a systematic review meta analysis and network meta analysis" }	[ { "companynumb": "IL-JNJFOC-20181101203", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020634", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myocardial infarction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease risk factor", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GORELIK E, MASARWA R, PERLMAN A, ROTSHILD V, ABBASI M, MUSZKAT M, ET AL. FLUOROQUINOLONES AND CARDIOVASCULAR RISK: A SYSTEMATIC REVIEW, META-ANALYSIS AND NETWORK META-ANALYSIS. SPRINGER NATURE SWITZERLAND AG 2018 27-OCT-2018:-.", "literaturereference_normalized": "fluoroquinolones and cardiovascular risk a systematic review meta analysis and network meta analysis", "qualification": "3", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20181109", "receivedate": "20181109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15603095, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]
{ "abstract": "The objective of this study was to characterize the clinical features, course, and treatment of essential tremor (ET) in children.\nA retrospective chart review was conducted over 25 years (1984-2011). Inclusion criteria were age <21 years and satisfying the core diagnostic criteria for ET. Primary exclusion criteria included other neurological findings, tremorogenic medications, sudden onset/stepwise progression, primary orthostatic tremor, and isolated task specificity; and secondary exclusion criteria were abnormal neuroimaging or metabolic/thyroid studies. Cases were reviewed for age, sex, family history, tremor characteristics, functional impairment, treatment, and follow-up.\nIn total, 211 children had ET, including 130 males and 81 females. The mean ± standard deviation age was at diagnosis was 14.09 ± 5.0 years, the age of onset was 9.71 ± 5.62 years, and the age of onset was birth in 7 children. One hundred ninety-nine children had bilateral hand tremor, 34 had asymmetry, 9 had unilateral onset but later became bilateral. Twelve children had voice tremors, 13 had leg tremors, 5 had head tremors, and 7 had trunk tremors. Tremor at rest was present in 20 children. Thirty-five percent of the children had a family history of ET, including in a father (n = 21), mother (n = 13), brother (n = 6), sister (n = 3), and other family member (n = 28). Fifty-five percent of patients had functional disabilities, including writing (n = 66), eating (n = 28) drinking from a cup (n = 13), typing (n = 4), playing instruments (n = 6), buttoning (n = 6), and playing (n = 3). For treatment, 33 patients received propranolol, 1 received atenolol, 13 received primidone, 3 received metoprolol, and 1 received nadolol. In total, 99 patients were followed for a mean ± standard deviation of 1.82 ± 2.21 years.If left untreated, tremor remained unchanged in 33 patients, and 7 had an apparent short-term improvement. On propranolol, 15 of 20 patients significantly improved.\nThis is the largest series to date of ET in children. The current findings indicate that onset at birth is possible, family history is less common in children than in adults, and tremor at rest is possible. Functional disability was noted in 55% of children, and 29.4% required medication.", "affiliations": "Departments of Neurology and Pediatrics Nationwide Children's Hospital Ohio State University Medical Center Columbus Ohio USA.;Pediatric Neurology Center Children's Hospital Cleveland Clinic Cleveland Ohio USA.;Department of Pediatrics New York Metropolitan Hospital New York New York USA.;Pediatric Neurology Center Children's Hospital Cleveland Clinic Cleveland Ohio USA.;Pediatric Neurology Center Children's Hospital Cleveland Clinic Cleveland Ohio USA.", "authors": "Ghosh\|Debabrata\|D\|;Brar\|Harmeet\|H\|;Lhamu\|Ugen\|U\|;Rothner\|A David\|AD\|;Erenberg\|Gerald\|G\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/mdc3.12385", "fulltext": null, "fulltext_license": null, "issn_linking": "2330-1619", "issue": "4(2)", "journal": "Movement disorders clinical practice", "keywords": "action tremor; parkinsonism; postural tremor; rest tremor; voice tremor", "medline_ta": "Mov Disord Clin Pract", "mesh_terms": null, "nlm_unique_id": "101630279", "other_id": null, "pages": "231-236", "pmc": null, "pmid": "30363473", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "10854345;18973247;12671944;9452318;23064782;19795473;9115044;17043291;15834855;19473370;11746623;3975748;15133816;19725596;18344392;11487191;16721753;17116212;16991147;8628453;15520096;6736976", "title": "A Series of 211 Children with Probable Essential Tremor.", "title_normalized": "a series of 211 children with probable essential tremor" }	[ { "companynumb": "US-DRREDDYS-USA/USA/17/0091734", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PRIMIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040862", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL TREMOR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRIMIDONE TABLETS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GHOSH D, BRAR H, LHAMU U, ROTHNER A, ERENBERG G. A SERIES OF 211 CHILDREN WITH PROBABLE ESSENTIAL TREMOR. MOV DISORD CLIN PRACT. 2017;4(2):231-6.", "literaturereference_normalized": "a series of 211 children with probable essential tremor", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20171129", "receivedate": "20171129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14235512, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]
{ "abstract": "Pathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.", "affiliations": "Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.;Pediatric Nephrology Service, La Paz University Hospital, Madrid, Spain.;Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.;Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.;Pediatric Hepatology Service, La Paz University Hospital, Madrid, Spain.;Pathology Department, La Paz University Hospital, Madrid, Spain.;Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.;Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.", "authors": "López-Trascasa\|Margarita\|M\|;Alonso-Melgar\|Ángel\|Á\|;Melgosa-Hijosa\|Marta\|M\|;Espinosa-Román\|Laura\|L\|;Lledín-Barbancho\|María Dolores\|MD\|;García-Fernández\|Eugenia\|E\|;Rodríguez de Córdoba\|Santiago\|S\|;Sánchez-Corral\|Pilar\|P\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fimmu.2021.751093", "fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.751093\nImmunology\nCase Report\nCase Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient\nLópez-Trascasa Margarita 1 2 \n\nAlonso-Melgar Ángel 3\nMelgosa-Hijosa Marta 2 3\n\nEspinosa-Román Laura 2 3\n\nLledín-Barbancho María Dolores 4\nGarcía-Fernández Eugenia 5\nRodríguez de Córdoba Santiago 6 7\n\nSánchez-Corral Pilar 2 7\n\n1 Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain\n2 Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain\n3 Pediatric Nephrology Service, La Paz University Hospital, Madrid, Spain\n4 Pediatric Hepatology Service, La Paz University Hospital, Madrid, Spain\n5 Pathology Department, La Paz University Hospital, Madrid, Spain\n6 Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain\n7 Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain\nEdited by: Guido Moll, Charité–Universitätsmedizin Berlin, Germany\n\nReviewed by: Giuseppe Remuzzi, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Italy; Johan Vande Walle, Ghent University, Belgium\n\nCorrespondence: Margarita López-Trascasa, [email protected]\nThis article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology\n\n14 10 2021\n2021\n12 75109331 7 2021\n27 9 2021\nCopyright © 2021 López-Trascasa, Alonso-Melgar, Melgosa-Hijosa, Espinosa-Román, Lledín-Barbancho, García-Fernández, Rodríguez de Córdoba and Sánchez-Corral\n2021\nLópez-Trascasa, Alonso-Melgar, Melgosa-Hijosa, Espinosa-Román, Lledín-Barbancho, García-Fernández, Rodríguez de Córdoba and Sánchez-Corral\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nPathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.\n\natypical hemolytic uremic syndrome\ncomplement\nfactor B\ncombined liver-kidney transplantation\nrare diseases\n==== Body\npmcIntroduction\n\nHemolytic uremic syndrome (HUS) is characterized by the triad of hemolytic anemia, acute kidney failure, and thrombocytopenia. Most cases are children with infections by Escherichia Coli 0157:H7, Shigella or Salmonella, and generally evolve satisfactorily in a few weeks. Less frequently, HUS develops in the absence of a clear etiologic agent and has a worse evolution; these cases are denominated as atypical Hemolytic Uremic Syndrome (aHUS), which is very uncommon and is considered an ultrarare disease (1). Around 50-60% of aHUS patients have pathogenic variants in the complement genes CFH, MCP, CFI, C3 and CFB, or circulating anti-factor H autoantibodies (2). Moreover, pathogenic variants outside the complement system have been described in thrombomodulin, DGKE and plasminogen genes.\n\nMutations in complement CFH, CFI, C3 or CFB generate anomalies in the corresponding proteins, which are mainly produced in the liver and secreted into plasma; these anomalies persist after kidney transplantation, a reason that can explain the high level of disease recurrence in transplanted patients. Most of these complement pathogenic variants were described on the beginning of this century, when the complement inhibitor Eculizumab was not yet accessible, and combined liver-kidney transplantation was considered a therapy to cure HUS in patients with mutations in CFH or CFI (3).\n\nCFB mutations were first described in aHUS patients in 2007 (4). In this paper, two different mutations in complement factor B (FB) were identified. A pedigree with several members affected shared mutation F286L, while the second mutation, K323E, was a “de novo” mutation in an unrelated patient. The two mutations generated hyperfunctional FB proteins which gave rise to a more active C3bBb convertase and an important C3 consumption in plasma, which was particularly evident in the patient carrying the K323E mutation. The follow-up of one patient from the F286L pedigree has been recently described (5); this patient underwent a kidney transplant without Eculizumab treatment in 2011 and has not suffered HUS relapses.\n\nThe patient carrying the K323E mutation underwent a combined liver kidney transplantation (CLKT) in March 2009; a short summary of the evolution during the first three months post-transplantation has been previously reported (6). In this work, we fully describe the clinical evolution, transplantation history and complement levels of this patient, throughout his 20 years of life. The patient presented HUS when he was 4-months old, suffered multiple recurrences and incidents for 8 years, and received a combined liver kidney transplantation (CLKT) at the age of 9 years. This CLKT restored complement levels as well as kidney and liver functions after the transplant surgery. The patient had several transplant related complications such as a B-cell non-Hodgkin lymphoma, and a chronic liver rejection that required a second liver graft 11 years after CLKT. In spite of these complications, CLKT was at that time the only opportunity for improving the critical situation of the patient, and the function of the kidney graft has remained normal all the time.\n\nCase Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up and Outcomes\n\nA 4-month-old male was diagnosed with HUS and treated with peritoneal dialysis from the 5th day of disease onset. The patient had a bad evolution, with renal failure, anemia, severe hypertension, and peritonitis by Staphylococcus Epidermidis, and after 20 days he suffered a second HUS episode and was transferred to our Hospital. At that moment, in addition to altered hematologic parameters, complement analysis indicated very low C3 levels (35,4 mg/dL; normal range: 77-135) with normal C4 (43,8 mg/dL; normal range: 14-60); Factor H, Factor I, and MCP levels were on the normal range. Hematological parameters and glomerular filtration normalized after 1 month, but hypertension remained partially uncontrolled and hemolysis markers such as haptoglobin were persistently low. After 6 months, the patient suffered a third episode with severe hypertension which required as many as six hypotensive drugs. Moreover, he endured two episodes of acute pulmonary edema with respiratory distress caused by hypertensive crisis. He developed a severe anemia that required 17 erythrocyte concentrates, mild thrombocytopenia, proteinuria in the nephrotic range, and cardiac insufficiency. He also suffered acute renal failure which required diuretic and hemodialysis support. A renal biopsy performed during this episode indicated thrombotic microangiopathy, with major vascular involvement and mild glomerular damage ( Supplementary Figure 1 ).\n\nThe patient suffered 5 subsequent HUS episodes; treatment with immunosuppressive drugs (vincristine and prednisone) and several plasma exchanges courses were tried without success. Uncontrolled hypertension with hemodynamic instability required prolonged hospitalizations. He underwent chronic dialysis at the age of three years, and 10 months later both kidneys were removed in an attempt to avoid the severe complications associated to HUS episodes ( Figure 1 ). Nonetheless, the hypertension continued after bilateral nephrectomy, and the patient had several episodes of acrocyanosis on all the fingers of the lower extremities (Raynaud’s phenomenon) because of systemic microangiopathy ( Supplementary Figure 2 ).\n\nFigure 1 Clinical evolution since HUS onset to bilateral nephrectomy. Timeline of HUS episodes, treatments and renal outcome along the first four years of life of the patient. Supportive treatments included blood transfusions and plasma therapy, as well as different combinations of hypotensive drugs (Hydralazine, Atenolol, Furosemide, Nifedipine, Minoxidil and Enalapril); immunosuppressive drugs (Vincristine and M-Prednisolone) were used occasionally. The patient entered into chronic dialysis at the age of 36 months, and at the age of 46 months both kidneys had to be removed to avoid further HUS episodes. PD, Peritoneal Dialysis; HD, Hemodialysis; PE, Plasma Exchange; PI, Plasma Infusion.\n\nAlthough hematological parameters normalized after bilateral nephrectomy, the clinical course of the patient under chronic hemodialysis continued to be torpid, with severe hypertension with cardiac repercussion, stroke-like episodes not clearly explained, and bad tolerance to hemodialysis sessions. All the time, plasma levels of complement C3 were low, while levels of C4 and C5 were normal. When he was 5 years-old, a pathogenic gain-of-function variant in complement Factor B (FB) was identified (4); genetic studies also showed the presence of the two aHUS-risk haplotypes CFH(H3) y MCPggaac in heterozygosis. This molecular diagnosis opened the possibility of a combined liver kidney transplantation (CLKT), since by that time complement inhibition with Eculizumab was not available. While waiting for CLKT, the patient continued with a regimen of hemodialysis and plasma infusions.\n\nAt the age of 9 years, the patient received a CLKT from an 8-year-old child. Immediately before the surgery, he was treated with intensive plasma exchange to ensure removal of his circulating FB; two other plasma exchange sessions were performed the third- and fourth-days post-transplantation, coinciding with mild anemization without signs of hemolysis. Systemic heparinization was used as part of our liver transplant protocol. Normal kidney and liver functions were evident 2 weeks post-transplantation ( Figure 2 ), and plasma levels of complement C3 reached normal values for the first time in the patient’s life ( Figure 3 ). The patient remained in hospital for 30 days. Suspicion of hepatic acute rejection in early postoperative period was treated with a pulse of metilprednisolone, with good response; histopathology of the biopsy discarded the rejection. The patient continued stable for 4 years under immunosuppressive treatment (induction with Basiliximab, and maintenance with corticosteroids, tacrolimus and mycophenolate mofetil).\n\nFigure 2 Evolution of renal and hepatic function after combined liver-kidney transplantation. Follow up of Creatinine, Prothrombin and Alaninaminotransferase (ALT) levels in the patient before and after transplantation. Creatinine levels dropped immediately after transplant surgery, reaching normal levels 5 days later. The hepatic function normalized during the second week.\n\nFigure 3 Complement profile from 2000 to 2020. Evolution of C3 and C4 levels, and of the C3/C4 ratio, in plasma samples from patient HUS21 since HUS onset in 2000, at the age of 4 months. The horizontal dashed lines indicate the lower limit of normal values. The boxes in the X axis mark the dates of the liver-kidney transplantation (March 2009), and of the second liver transplant (February 2020).\n\nOn September 2013, the patient was diagnosed with a diffuse large B cell non-Hodgkin’s lymphoma stage 3, with infiltration in scalp and skull, and was treated with chemotherapy (R-CHOP/R-COPDAM) and rituximab. At the beginning of the treatment, he suffered a septic shock and endured at Intensive Care Unit for 9 days. The infectious episode induced coagulopathy and multiorgan failure (with hepatic, kidney, and cardiac involvement) with good outcome. After 3 months, the chemotherapy was ended with evident signs of remission. All along the chemotherapy treatment, tacrolimus and mycophenolate mofetil were stopped and only corticosteroids were maintained.\n\nOn February 2014, he suffered from a liver graft dysfunction with a light increase of transaminases without ultrasonographic signs of dilated biliary tract. He received intravenous antibiotics and ursodeoxycholic acid by suspicion for cholangitis. Liver biopsy showed moderate periportal fibrosis, but no histological features of chronic rejection. Subsequently to liver rejection in 2014, the patient developed high levels of de novo donor-specific antibodies (DSA) against DQ9 (MFI: 21705). These DSA were maintained with a similar MFI (between 21000 and 32000) at least until February 2020, just before the second liver graft; moreover, serological viral studies were negative. Sirolimus was included in the immunosuppressive treatment, and the corticosteroids and ursodeoxycholic acid doses were increased. Following several cholangitis and infectious episodes, in 2018 a second liver biopsy showed ductal proliferation with inflammation and branding fibrosis. Diagnosis of chronic liver rejection was established, and tacrolimus and mycophenolate mofetil were reintroduced. Percutaneous transhepatic cholangiography showed multiple biliary structures of the biliary tree without obstruction in the anastomotic site. Several biliary dilatations and external biliary drainage were performed, and finally, a biliary stent was positioned. However, the patient continued suffering cholangitis episodes by multidrug-resistant bacteria, requiring frequent hospitalization. During all this period, the glomerular filtration rate decreased during the acute infection episodes but normalized afterwards, with no signs of kidney rejection. On February 2020, the patient received a second cadaveric liver graft. By that moment, creatinine-based glomerular filtration rate was normal (> 90 ml/min/1.73 m2).\n\nCurrently, the patient has a good clinical condition, although he displays a low height for its expected genetic height (height: 158.5 cm (-3.18SD); weight: 56.2Kg (-1.79 SD); data related to Spanish population). He receives immunosuppressive treatment with corticosteroids, tacrolimus and mycophenolate mofetil, with maintained hepatic function after his second liver graft: AST 34 UI/L (<40); ALT 48 UI/L (<35); GGT 30 UI/L (<73); total bilirubin 0.79 mg/dL (0.30-1.20), albumin 4.3 g/dL (2.9-5.2). Kidney function is also good, with a normal GFR calculated both by Creatinine and by Cystatin C (creatinine 1 mg/dl (0.70-1.30); GFR calculated by CKD-EPI >90 ml/min/1.73 m2 (N >75); Cystatin C 1.20 mg/L (0.64-1.23); GFR calculated by CKD-EPI Cyst C 72 mL/min/1.73m2 (N>60); protein/creatinine ratio 0.08 (N<0.2).\n\nThe main clinical and treatment events after CLKT are shown in Figure 4 ; as shown in Figure 3 , plasma levels of C3, C4, and the C3/C4 ratio, have always remained within the normal range. Now, the patient is under the supervision on a different hospital (adult section) for the hepatic and kidney post-transplantation follow-up.\n\nFigure 4 Post-transplant clinical evolution. The main clinical episodes after combined liver-kidney transplantation (CLKT) are indicated. The first complication, 4 years after transplantation, was a lymphoproliferative disease, which was treated with chemotherapy and reduction/abrogation of the immunosuppressive regimen. Immunosuppression was reintroduced 5 months later, after a hepatic failure and detection of high levels of anti-HLA-II antibodies. Taking into account the bad evolution of the liver graft, the patient underwent a second liver transplant in 2020, which remains functional until now. In spite of these findings, the renal function has remained stable since the CLKT in 2009.\n\nDiscussion, Take-Away Lessons\n\nIn the last 20 years, there has been an important improvement in the comprehension of the molecular bases underlying atypical Hemolytic Uremic Syndrome. The complement system was initially considered an important mediator of the endothelial damage characteristic of this rare disease, and the subsequent identification of pathogenic variants and/or polymorphisms in one or more complement genes further strengthen its role as disease causative (2). In the aHUS patient described here, the identification of a gain-of-function mutation in complement Factor B explained the high and constitutive consumption of complement C3 in the patient´s plasma.\n\nThe fact that the liver is the main source of plasma Factor B (7) anticipated HUS recurrence after an isolated kidney transplantation, thus hampering this possibility for our patient. By that time, several aHUS patients with mutations in Factor H, most of them children, underwent CLKT. Although initial experiences had a fatal outcome (8–10), the introduction of pre-emptive plasmapheresis with plasma exchange proved to be very successful (11–13). At the light of these experiences, and in the absence of other therapies, it was decided that the CKLT was the only curative option for our patient with the Factor B mutation. This decision was adopted after a consensus meeting between nephrologists, hepatologists, surgeons, and immunologists from Hospital La Paz, and complement researchers involved in the case. In spite of its risks, the intervention was accepted by the patient’s parents, and it could be done in 2009, upon the availability of liver and kidney grafts from a donor of the same age that the patient. The CLKT allowed immediate restoration of the renal function in the patient, who remained without problems under immunosuppressive treatment for four years.\n\nA B-cell lymphoma was the first complication of the patient. The B-cell lymphoma could be related with the immunosuppressive treatment, but the association of immunosuppression with subsequent complications after CLKT is only partially understood (14–16). The risk of tumor appearance induced by the immunosuppression treatment increases with postransplantation time. The overall incidence of tumors in the pediatric age after a solid organ transplantation is around 6%, with values of 7% in liver and around 3% in renal grafts. There are few data on combined transplantation, but tumor incidence seems to be like that of single liver transplantation, around 8% (17). These percentages raise when the follow-up is prolonged into adulthood. In all solid organ transplantation, between 80 and 90% of the tumors are of lymphoid origin. In addition, in our patient, the immunosuppression received prior to transplantation could increase the tumor risk.\n\nThe immunosuppression regimes in CLKT and isolated kidney transplantation are very similar; moreover, in CLKT the liver graft confers immunoprotection to the kidney graft. This effect was first observed in experimental animals (18) and later on in patients (19). The presence of DSA was considered a predisposition factor to graft rejection in isolated kidney transplantation (20, 21). However, in the case of CLKT, the liver graft protects the kidney from the hyperacute reaction, and it also decreases the acute cellular response (22). In a more recent cooperative study, the authors evidenced that the presence of DSA antibodies in CLKT rises the mortality, but they did not find a clear relationship with the kidney and liver graft evolution (23).\n\nCholangitis associated to chronic liver rejection was an additional and severe complication in the patient, with a 6-year evolution that conducted to a second liver graft in 2020 that remains functional. Although the patient suffered several complications along the post-transplant period, in 2009 CLKT was the only therapeutic approach, since complement inhibitors such as Eculizumab were not available. The combined transplantation allowed the patient to leave dialysis and to improve his social and academic life; currently, he is enrolled on a university degree. Further complications were solved in a tertiary hospital, and the patient continues under immunosuppressive therapy with adequate follow-up.\n\nTo correct the complement dysregulation and the very low C3 levels caused by the gain-of-function mutation in Factor B was an important consideration when discussing the therapeutic options for our patient. Our conclusion was that, although liver transplantation would add additional risks to kidney transplantation, the CLKT was the only available option to completely normalize complement activation. Nowadays, our patient would have likely been approached with an isolated kidney transplantation and the use of Eculizumab. However, during the last 15 years it has been an extraordinary progress in the development of drugs inhibiting different levels of the complement cascade, providing novel therapeutic options to aHUS patients. In this changing scenario, a next generation of complement inhibitors acting upstream of C5 activation would soon be available for the treatment of complement dysregulation disorders. One of these novel drugs, which may be better and more appropriate than Eculizumab for some patients, is Pegcetacoplan (24, 25), a PEGylated pentadecapeptide that binds to C3 and C3b, and regulates the activation of C3 and the activity of the AP C3 convertase. Pegcetacoplan has been recently approved by the FDA for the treatment of adults with paroxysmal nocturnal hemoglobinuria (26).\n\nCLKT is still nowadays a valid therapeutic option for aHUS patients. Thus, the experts recommend not to completely discard CLKT (which could be the only option in countries or situations where Eculizumab is not available), and to discuss all the options with patients and families (27). CLKT in aHUS patients with complement mutations has been extensively reviewed by Zuber et al. in 2013 (28), and by Saland et al. in 2014 (29); these papers included 16 cases with CFH mutations (14 successful), one with C3 mutation (unsuccessful), one with CFB mutation (this patient), 2 cases with a hybrid CFH::CFHR1 gene (one successful), and an additional case as personal communication (28).\n\nFunctional characterization of the Factor B K323E variant purified from the patient’s plasma showed increased resistance of the C3 convertase to dissociation by the complement regulators Factor H and DAF (4). The gain-of-function consequences of the K323E variant were confirmed in another study where Factor B pathogenic variants identified in other aHUS patients were functionally characterized (30). Further characterization of recombinant Factor B K323E showed that it is functionally very similar to a C3 nephritic factor, which most of the times does not allow activation of the complement terminal pathway (31). Two aHUS patients with another Factor B pathogenic variant and very low C3 levels in plasma have been recently described (32), and the authors consider that the excessive activation of the fluid-phase C3 convertase could predispose to aHUS or to C3 glomerulonephritis, depending on the presence of additional predisposing genes or environmental factors. In this context, it could be relevant that the aHUS-risk haplotype MCPgggac is present in our patient with the K323E mutation in Factor B, and in all the affected members of the family carrying the F286L mutation (4). One of the members of that family is a girl who presented HUS at the age of 3 months and had a bad clinical evolution, comparable in many aspects to the evolution of our patient with the K323E mutation. Nonetheless, C3 levels in the girl’s plasma were never as low as observed in our patient; this could reflect that the K323E mutation is more pathogenic for Factor B function than the F286L mutation. The girl with the F286L mutation received a kidney graft in 2011 and has remained stable without Eculizumab prophylaxis (5). It is likely that the absence of the MCPggaac aHUS-risk haplotype in the kidney graft have contributed to the successful evolution of this patient after transplantation. In the case of the patient with the K323E mutation, further genetic studies showed that donor and receptor shared the MCPggaac aHUS-risk haplotype but not the CFH(H3) haplotype; the absence of the CFH-risk polymorphism in addition to the presence of wild-type Factor B in the liver graft likely contributed to a better regulation of the C3 convertase in the receptor.\n\nIn conclusion, we describe the clinical evolution and therapeutic strategy in a boy with a gain–of-function mutation in complement Factor B. CLKT as a therapeutic option was justified because of a torpid evolution during 8 years, with several life-threatening events and the unavailability of complement-inhibiting drugs at that time. CLKT allowed the immediate restauration of kidney function and a stable evolution for four years, but after a B-cell lymphoma and a liver rejection, the patient needed a second liver graft 11 years later. Renal function and complement levels have remained normal all the time since the CKLT, and the patient has not suffered any aHUS recurrence.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Comité de Ética del Hospital Universitario “La Paz”. Hospital La Paz. Madrid. Spain. Written informed consent to participate in this study was provided by the patient or their parents.\n\nAuthor Contributions\n\nÁA-M, MM-H, LE-R, and DL-B gathered clinical data. EG-F contributed to the analysis of the biopsy. PS-C, ÁA-M, MM-H, and ML-T prepared figures. ML-T compiled the data for the case-study, and wrote the first draft of the manuscript. SRC and PS-C revised the initial draft of the paper. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nML-T, SRC, and PS-C are supported by the Spanish Autonomous Region of Madrid (Complement II-CM network; B2017/BMD-3673).\n\nAuthor Disclaimer\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe thank Irene Delgado and Fernando Corvillo for helpful contribution on the preparation of graphic materials. We want to especially acknowledge all the clinicians from Hospital Infantil La Paz who were involved in the treatment of this patient along these years. We also appreciate the support from doctors Mercedes Navarro and Paloma Jara, two mentors of our hospital, who were pioneers in the Paediatrics field, and encouraged all the clinical decisions on the patient’s treatment. We acknowledge Dr. Esther Mancebo (Immunology Department. Hospital 12 de Octubre. Madrid) for the valued contribution on the anti-HLA antibodies studies. Finally, we would like to thank the patient and his family for their confidence on the medical decisions, and for their admirable attitude towards the difficult and critical experiences during all this time.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.751093/full#supplementary-material\n\nSupplementary Figure 1 Kidney biopsy. (A) Hematoxylin and Eosin staining of a glomerulus, showing mesangiolysis with fragmented red blood cells and double contours in capillary walls. (B) Masson trichrome staining, showing small arteries with intimal thickening, mucoid intimal edema, and endothelial swelling.\n\nClick here for additional data file.\n\nSupplementary Figure 2 Acrocyanosis on the feet fingers. The two images correspond to a microangiopathy episode occurring after the patient underwent bilateral nephrectomy.\n\nClick here for additional data file.\n\nAbbreviations\n\naHUS, atypical Hemolytic Uremic syndrome; DGKE, Diacylglycerol kinase Epsilon; CLKT, combined liver kidney transplantation; DSA, donor specific antibodies; MFI, median fluorescence intensity.\n==== Refs\nReferences\n\n1 Cody EM Dixon BP . Hemolytic Uremic Syndrome. Pediatr Clin North Am (2019) 66 (1 ):235–46. doi: 10.1016/j.pcl.2018.09.011\n2 Nester CM Barbour T de Cordoba SR Dragon-Durey MA Fremeaux-Bacchi V Goodship TH . Atypical aHUS: State of the Art. Mol Immunol (2015) 67 (1 ):31–42. doi: 10.1016/j.molimm.2015.03.246 25843230\n3 Saland JM Ruggenenti P Remuzzi G Consensus Study Group. Liver-Kidney Transplantation to Cure Atypical Hemolytic Uremic Syndrome. J Am Soc Nephrol (2009) 20 (5 ):940–9. doi: 10.1681/ASN.2008080906\n4 Goicoechea de Jorge E Harris CL Esparza-Gordillo J Carreras L Arranz EA Garrido CA . Gain-Of-Function Mutations in Complement Factor B Are Associated With Atypical Hemolytic Uremic Syndrome. Proc Natl Acad Sci U S A (2007) 104 (1 ):240–5. doi: 10.1073/pnas.0603420103\n5 Sánchez-Moreno A de la Cerda F Rodríguez-Barba A Fijo J Bedoya R Arjona E . Is the Atypical Hemolytic Uremic Syndrome Risk Polymorphism in Membrane Cofactor Protein MCPggaac Relevant in Kidney Transplantation? A Case Report. Pediatr Transplant (2021) 25 (3 ):e13903. doi: 10.1111/petr.13903 33217135\n6 Alonso Melgar A Melgosa M López-Trascasa M Navarro M de la Vega A and Sánchez-Corral P . Successful Combined Liver and Kidney Transplantation in a Child With Hypocomplementemic Atypical Haemolytic Uremic Syndrome (aHUS) Due to a Factor B Mutation. 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Kidney Int (2020) 98 (5 ):1265–74. doi: 10.1016/j.kint.2020.05.028\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-3224", "issue": "12()", "journal": "Frontiers in immunology", "keywords": "atypical hemolytic uremic syndrome; combined liver-kidney transplantation; complement; factor B; rare diseases", "medline_ta": "Front Immunol", "mesh_terms": null, "nlm_unique_id": "101560960", "other_id": null, "pages": "751093", "pmc": null, "pmid": "34721423", "pubdate": "2021", "publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't", "references": "27105881;15816899;24362724;23380861;16889549;19092117;12020532;17182750;4988655;12614293;33730455;30454746;14986080;34342834;19235662;23160511;12451237;29308663;23937869;17973958;33217135;24652797;33305113;19005013;26270957;33464651;827931;26924059;32540405;25843230;19328954", "title": "Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic 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"URSODIOL" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Complications of transplanted liver", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130901" } }, "primarysource": { "literaturereference": "Lopez-Trascasa M, Alonso-Melgar, A, Melgosa-Hijosa, M et al.. Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient. Front. 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"drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Liver transplant rejection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS" } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic coagulopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130101" } }, "primarysource": { "literaturereference": "Lopez-Trascasa M, Alonso-Melgar A, Melgosa-Hijosa M, Espinosa-Roman L, Lledin-Barbancho MD, Garcia-Fernandez E, et al.. Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.. 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{ "abstract": "Idarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran, a Direct Oral Anticoagulant. Despite recent trials demonstrating reversal of clinically relevant bleeding, there is a paucity of data on use outside the trial setting. This manuscript describes the use of Idarucizumab to reverse dabigatran in two patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH).\nPatients were identified through retrospective review of medication dispensing systems and electronic medical records.\nTwo cases of Idarucizumab use were identified. Case 1 was of a 63-year-old male who presented following a motorcycle crash. Case 2 was of a 77-year-old male who presented with a 3-week history of ataxia and recurrent falls. Both patients were taking dabigatran for atrial fibrillation (AF). CT Brain revealed acute SDH with clinical indications for urgent surgical evacuation. Serum dabigatran levels were obtained on arrival in the emergency department with levels of 155 ng/ml and 110 ng/ml (reference range 117-275 ng/ml). Idarucizumab for dabigatran reversal was commenced; Case 1 received 5 g Idarucizumab as an intravenous bolus dose, while Case 2 received 5 g Idarucizumab as two 2.5 g intravenous infusions. Serum dabigatran levels for Cases 1 and 2 were 0 ng/ml at 75 min and 340 min post Idarucizumab administration respectively. Both patients proceeded to craniotomy with evacuation of the SDH. There was no extension of the SDH in either case. Anticoagulation was withheld until outpatient clinic review, and both patients transferred for rehabilitation prior to discharge home.\nIdarucizumab was clinically effective for reversing dabigatran, resulting in undetectable serum levels, and should be considered in patients presenting to hospital with clinically significant bleeding associated with dabigatran therapy.", "affiliations": "Pharmacy Department, The Alfred Hospital, Melbourne, Australia.;Pharmacy Department, The Alfred Hospital, Melbourne, Australia.;Department of Neurosurgery, The Alfred Hospital, Melbourne, Australia.;Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia.", "authors": "Edwards\|Gail\|G\|;Roman\|Cristina\|C\|;Jithoo\|Rondhir\|R\|;Mitra\|Biswadev\|B\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.tcr.2017.12.003", "fulltext": "\n==== Front\nTrauma Case RepTrauma Case RepTrauma Case Reports2352-6440Elsevier S2352-6440(17)30080-810.1016/j.tcr.2017.12.003ArticleUse of Idarucizumab for dabigatran reversal: Emergency department experience in two cases with subdural haematoma Edwards Gail [email protected]⁎Roman Cristina abJithoo Rondhir cMitra Biswadev bdea Pharmacy Department, The Alfred Hospital, Melbourne, Australiab Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australiac Department of Neurosurgery, The Alfred Hospital, Melbourne, Australiad Department of Epidemiology & Preventative Medicine, Monash University, Melbourne, Australiae National Trauma Research Institute, Melbourne, Australia⁎ Corresponding author at: Pharmacy Department, The Alfred Hospital, 55 Commercial Road, Melbourne 7000, Australia.Pharmacy DepartmentThe Alfred Hospital55 Commercial RoadMelbourne7000Australia [email protected] 12 2017 2 2018 29 12 2017 13 46 49 26 12 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nIdarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran, a Direct Oral Anticoagulant. Despite recent trials demonstrating reversal of clinically relevant bleeding, there is a paucity of data on use outside the trial setting. This manuscript describes the use of Idarucizumab to reverse dabigatran in two patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH).\n\nMethods\nPatients were identified through retrospective review of medication dispensing systems and electronic medical records.\n\nResults\nTwo cases of Idarucizumab use were identified. Case 1 was of a 63-year-old male who presented following a motorcycle crash. Case 2 was of a 77-year-old male who presented with a 3-week history of ataxia and recurrent falls. Both patients were taking dabigatran for atrial fibrillation (AF). CT Brain revealed acute SDH with clinical indications for urgent surgical evacuation. Serum dabigatran levels were obtained on arrival in the emergency department with levels of 155 ng/ml and 110 ng/ml (reference range 117–275 ng/ml). Idarucizumab for dabigatran reversal was commenced; Case 1 received 5 g Idarucizumab as an intravenous bolus dose, while Case 2 received 5 g Idarucizumab as two 2.5 g intravenous infusions. Serum dabigatran levels for Cases 1 and 2 were 0 ng/ml at 75 min and 340 min post Idarucizumab administration respectively. Both patients proceeded to craniotomy with evacuation of the SDH. There was no extension of the SDH in either case. Anticoagulation was withheld until outpatient clinic review, and both patients transferred for rehabilitation prior to discharge home.\n\nConclusion\nIdarucizumab was clinically effective for reversing dabigatran, resulting in undetectable serum levels, and should be considered in patients presenting to hospital with clinically significant bleeding associated with dabigatran therapy.\n\nKeywords\nIdarucizumabDabigatranIntracranial haemorrhageWounds and injuriesEmergency department\n==== Body\nIntroduction\nIn-hospital mortality in the setting of disorders of coagulation and traumatic brain injury (TBI) has been reported to be approaching 50% [1] Timely normalization of coagulopathy has also been associated with improved outcomes [2] Dabigatran, a direct thrombin inhibitor, is a novel anticoagulant. Patients treated with dabigatran who present with major bleeding or need urgent surgical intervention are at risk of severe complications due to the anticoagulation effects [3] Idarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran [4], [5], [6] The Therapeutic Goods Administration approved the use of Idarucizumab in Australia in June 2016.\n\nEarly studies in healthy young patients and those between 45 and 80 years old with mild to moderate renal impairment have demonstrated idarucizumab rapidly reverse the anticoagulant effects of dabigatran and achieve haemostasis without pro-thrombotic effects. However, the safety and efficacy in patients with serious bleeding or who require urgent surgery is not known.\n\nThis case series documents the use of Idarucizumab to reverse dabigatran in patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH).\n\nMethods\nPatients were identified through retrospective review of medication dispensing systems and electronic medical records. Two cases were identified from 1/1/2016 to 1/6/2016 and informed consent to present this report obtained. The study was approved by The Alfred Hospital Research and Ethics Committee.\n\nResults\nTwo cases were identified for inclusion. Case 1 was of a 63-year-old male who was transferred from a regional centre following a motorcycle crash. He had a history of atrial fibrillation for which he was prescribed dabigatran. Computed tomography (CT) imaging following the crash showed a SDH with mass effect. Fresh Frozen Plasma and a 3-factor prothrombin complex concentrate were administered prior to transfer. Upon arrival at our centre, and following analysis of laboratory data and multi-disciplinary medical team discussions, a decision to administer Idarucizumab was made. Laboratory results are listed in Table 1 and a timeline of events in Fig. 1. A single 5g-bolus dose of Idarucizumab was administered. The patient proceeded to the operating theatre where he underwent a craniotomy and evacuation of the SDH. Surgery was successful and haemostasis was achieved. Post-operative complications involved residual dysphasia, which resolved within 2 weeks post discharge. There was evidence of residual SDH on CT scans performed at 2 and 4 weeks post the crash but with no acute component. Anticoagulation was withheld and the patient was discharged into the care of his local medical officer who was advised to restart anticoagulation if there had been no extension of SDH on a follow-up CT scan to be performed 6 weeks post crash.Fig. 1 Case 1 Timeline.\n\nFig. 1Table 1 Case 1 laboratory data.\n\nTable 1Laboratory markers (reference ranges)\tAdmission\tPost Idarucizumab Administration\n(T = 75 min from administration)\t\nDabigatran\n(117–275 ng/ml)\t155\t0\t\nPT\n(10.6–15.3 s)\t17.4\t14.1\t\nAPTT\n(26–38 s)\t63\t35.5\t\nINR\n(0.9–1.3)\t1.4\t1.1\t\nTCT\n(14–24 s)\t133.4\t18.1\t\n\n\nCase 2 was of a 77-year-old male who presented with an ataxic gait and recurrent falls, increasing in frequency in the preceding 3 days. He had a history of atrial fibrillation for which he was prescribed dabigatran. CT imaging revealed an acute on chronic SDH. Laboratory investigations confirmed active anticoagulation (Table 2) and a timeline of events outlined in Fig. 2. Multi-disciplinary medical discussions resulted in a decision to administer Idarucizumab. The patient was prescribed a 5 g dose of Idarucizumab, administered as two 2.5 g bolus doses spaced 5 min apart. No other blood products were administered to achieve haemostasis. The patient proceeded to the operating theatre for a frontoparietal mini craniotomy and evacuation of the SDH. The post-operative course was uncomplicated but routine CT follow-up at 4 weeks showed some residual SDH, although the patient was asymptomatic. A decision was made to remain off anticoagulation until a repeat CT was performed in 8 weeks time. CT scans performed seven months following injury show near complete resolution of SDH. However, the patient remained off anticoagulation under the guidance of the neurosurgical and cardiology teams.Fig. 2 Case 2 Timeline.\n\nFig. 2Table 2 Case 2 laboratory results.\n\nTable 2Laboratory markers (reference ranges)\tAdmission\tPost Idarucizumab Administration\n(T = 340 min from administration)\t\nDabigatran\n(117–275 ng/ml)\t110\t0\t\nPT\n(10.6–15.3 s)\t17.2\t15\t\nAPTT\n(26–38 s)\t48.4\t28.6\t\nINR\n(0.9–1.3)\t1.4\t1.2\t\nTCT\n(14–24 s)\tN/A\t16.5\t\n*PT = prothrombin time, APTT = activated partial thromboplastin time, INR = International normalised Ratio, TCT = thrombin clotting time.\n\n\n\nDiscussion\nThis manuscript describes two cases of successful reversal of the effects of dabigatran following administration of Idarucizumab. Both patients were taking dabigatran and sustained severe traumatic brain injuries requiring urgent surgical intervention. There were no obvious adverse effects observed.\n\nAlternate options for reversal of the effects of dabigatran such as haemodialysis or waiting until anticoagulation effects cease by normal elimination, were not feasible in these cases, as rapid return to haemostasis was required. In patients with normal renal function dabigatran has a half-life of 12–14 h extending in those with renal impairment [7]. Therefore, ceasing treatment 24–48 h prior to planned procedures is a valid treatment strategy. Similarly, haemodialysis can be also considered for reversal of dabigatran effects in specific patient scenarios [8].\n\nIdarucizumab has been developed as a specific antidote to dabigatran and is approved for use when the rapid reversal of anticoagulation effects is required for emergency surgery, urgent procedures, and in life threatening or uncontrollable bleeding. It is a humanized monoclonal antibody that binds specifically and potently to dabigatran to neutralise its effects [9]. The affinity of Idarucizumab binding to dabigatran is around 350 times greater than that of dabigatran for thrombin [9], [10]. Both free and thrombin-bound dabigatran can be bound by Idarucizumab to neutralise anticoagulation activity [10]. Idarucizumab does not bind thrombin or its substrates nor does it activate platelets or convert fibrinogen to fibrin [4]. Benefits of Idarucizumab include a low rate of adverse effects, no increase risk of thrombosis and its short half-life allows for the resumption of anticoagulation therapy early after the acute episode of bleeding has resolved [6].\n\nAn important consideration when deciding on the use of Idarucizumab is the timing of the last dabigatran dose. It was confirmed with both cases that doses had been taken on the morning of their presentations and this was reflected through serum dabigatran levels measured on admission. Given the short half-life of dabigatran, if doses had been missed, it is possible that it no longer contributes to bleeding.\n\nReversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) is a prospective cohort study to examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran in patients who presented with serious bleeding or who required urgent surgery or intervention. In the interim analysis of the RE-VERSE AD study, Idarucizumab was administered to around 25% of patients who had normal coagulation tests making it difficult to ascertain the benefit gained from Idarucizumab in this cohort [4], [10].\n\nThe dose prescribed and administered of Idarucizumab varied between our two cases with one patient receiving a 5 g intravenous bolus dose and the other patient receiving two 2.5 g intravenous bolus doses. It is believed a 5 g total dose of Idarucizumab will reverse all available dabigatran up to the 99th percentile of dabigatran plasma concentrations measured in patients enrolled in the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial [4], [10]. RE-VERSE ED administers Idarucizumab as two 2.5 g intravenous bolus doses no more than 15 min apart. While dosing of Idarucizumab in our case series did not follow the regimen of this current Phase 3 trial, it still produced undetectable serum dabigatran levels and improvement in other markers of coagulation post administration. A study by Glund et al. conducted in healthy elderly or with mild-moderate renal impairment found that administration of 5 g or two 2.5 g Idarucizumab doses led to the sustained reversal of dabigatran induced anticoagulation [5]. Standardised dosing of Idarucizumab is of benefit in the busy clinical environment and future research could assess the efficacy of a single 5 g Idarucizumab doses to further simplify treatment.\n\nOngoing assessment will provide better understanding of optimal timing of serum dabigatran and coagulation laboratory tests. Timing of post Idarucizumab administration laboratory data varied in our two cases. RE-VERSE AD is performing measures between 10 and 30 min and at 1, 2, 4, 12, and 24 h following the second infusion [10]. In the busy clinical setting of an emergency department or theatre suite it may not be practical or achievable to perform laboratory testing as frequently as this. Thus, clear guidelines need to be established for clinical practice reflecting both real life data and clinical trial literature.\n\nConclusion\nThe two cases described support the use of Idarucizumab, rapidly reversing the anticoagulant effects of dabigatran. Idarucizumab can be considered in patients treated with dabigatran who present with uncontrollable or life-threatening bleeding or in need of urgent surgical intervention.\n==== Refs\nReferences\n1 Epstein D.S. Mitra B. Cameron P.A. Fitzgerald M. Rosenfeld J.V. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: definition, incidence and outcomes Br. J. Neurosurg. 2014 1 5 \n2 Epstein D.S. Mitra B. Cameron P.A. Fitzgerald M. Rosenfeld J.V. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury J. Clin. Neurosci. 29 2016 64 69 26947341 \n3 Thomas P.A. Schaerf N.B. Rosenfeld J.V. Dabigatran-neurosurgical anathema? Med. J. Aust. 199 4 2013 238 240 \n4 Eikelboom J.W. Quinlan D.J. van Ryn J. Weitz J.I. Idarucizumab Circulation 132 25 2015 2412 2422 26700008 \n5 Glund S. Stangier J. Schmohl M. Moschetti V. Haazen W. De Smet M. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects Blood 124 21 2014 344 24914142 \n6 Gottlieb M. Khishfe B. Idarucizumab for the reversal of dabigatran Ann. Emerg. Med. 69 2017 554 558 28110992 \n7 Dabigatran Boehringer Ingelheim Inc. [Available from] http://files.boehringer.com.au/files/PI/Pradaxa \n8 Chang D.N. Dager W.E. Chin A.I. Removal of dabigatran by hemodialysis Am. J. Kidney Dis. 61 3 2013 487 489 23219111 \n9 Glund S. Stangier J. Schmohl M. Gansser D. Norris S. van Ryn J. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial Lancet 386 9994 2015 680 690 26088268 \n10 Pollack C.V. Jr. Reilly P.A. Eikelboom J. Glund S. Verhamme P. Bernstein R.A. Idarucizumab for dabigatran reversal N. Engl. J. Med. 373 6 2015 511 520 26095746\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2352-6440", "issue": "13()", "journal": "Trauma case reports", "keywords": "Dabigatran; Emergency department; Idarucizumab; Intracranial haemorrhage; Wounds and injuries", "medline_ta": "Trauma Case Rep", "mesh_terms": null, "nlm_unique_id": "101711730", "other_id": null, "pages": "46-49", "pmc": null, "pmid": "29644298", "pubdate": "2018-02", "publication_types": "D002363:Case Reports", "references": "23219111;26700008;28110992;26095746;26947341;25153987;26088268;23984772", "title": "Use of Idarucizumab for dabigatran reversal: Emergency department experience in two cases with subdural haematoma.", "title_normalized": "use of idarucizumab for dabigatran reversal emergency department experience in two cases with subdural haematoma" }	[ { "companynumb": "AU-B.I. 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{ "abstract": "The occurrence of a pneumothorax using supraglottic device is a rare complication during general anesthesia. Moreover, less than 2% of pneumothoraxes can be related to lung metastases, most due to soft tissue sarcoma. We present the case of a 45-year-old female diagnosed with metastatic sarcoma who developed a bilateral pneumothorax after general anesthesia with supraglottic device. Different causes of pneumothorax were discussed.", "affiliations": "Department of Anesthesia and Intensive Care, Careggi University Hospital, Florence, Italy.;Department of Anesthesia and Intensive Care, Careggi University Hospital, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.", "authors": "Gianesello\|Lara\|L\|;Boccaccini\|Alberto\|A\|;Rostagno\|Carlo\|C\|https://orcid.org/0000-0002-7764-8919", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2050313X19833258", "fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1983325810.1177_2050313X19833258Case ReportBilateral pneumothorax after general anesthesia in patient with pleomorphic sarcoma of soft tissue Gianesello Lara 1Boccaccini Alberto 1https://orcid.org/0000-0002-7764-8919Rostagno Carlo 21 Department of Anesthesia and Intensive Care, Careggi University Hospital, Florence, Italy2 Department of Experimental and Clinical Medicine, University of Florence, Florence, ItalyCarlo Rostagno, AOU Careggi, Largo Brambilla 3, 50134 Firenze, Italy. Email: [email protected] 2 2019 2019 7 2050313X1983325813 9 2018 29 1 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).The occurrence of a pneumothorax using supraglottic device is a rare complication during general anesthesia. Moreover, less than 2% of pneumothoraxes can be related to lung metastases, most due to soft tissue sarcoma. We present the case of a 45-year-old female diagnosed with metastatic sarcoma who developed a bilateral pneumothorax after general anesthesia with supraglottic device. Different causes of pneumothorax were discussed.\n\nPneumothoraxmetastatic sarcomamechanical ventilationcover-dateJanuary-December 2019\n==== Body\nIntroduction\nSecondary pneumothorax due to metastatic sarcoma is often associated with advanced disease or systemic chemotherapy.1,2 From the case series reported in the literature, the prevalence of spontaneous pneumothorax in sarcoma is 1.9%.3 The first case was described by De Barrin4 in 1937 associated with advanced disease-metastatic osteosarcoma. We present a case of a 45-year-old female suffering from metastatic sarcoma who developed a bilateral pneumothorax after general anesthesia with supraglottic device.\n\nCase report\nA 45-year-old female, with a history of thyroid nodules, noticed 2 months before hospitalization a tumefaction of her right thigh. Magnetic resonance (MR) imaging showed a vascularized mass measuring 20 × 8.5 × 7 cm3 with intra-fascial edema of vastus lateralis and vastus medialis.\n\nThree weeks later, a new MR showed an increase in the size of the mass surrounding the femur with irregular profile of the femoral cortical. Computed tomographic (CT) scan of the chest did not show lung metastasis. An incisional biopsy of the mass demonstrated a high-grade pleomorphic sarcoma.\n\nResection of the femur with quadriceps muscle was performed and a total femoral prosthesis was implanted. Pathologic diagnosis was high-grade pleomorphic sarcoma with widespread necrotic-bleeding aspects and infiltration of striated muscle and bone tissue.\n\nForty days later, she was readmitted for the treatment two eschars within the surgical scar associated with peri-prosthetic abscess. No other pulmonary CT scan was performed before re-admission. Arthrocentesis and superficial debridement were conducted under general anesthesia. A lubricated laryngeal mask airway (LMA) Supreme™ n.4 was inserted successfully at the first attempt without difficulty using the standard insertion technique (The LMA Supreme Instruction Manual, Intravent Orthofix Ltd, Maidenhead, 2007). The cuff of the LMA Supreme was inflated with air (30 mL) to obtain a pressure of 60 cm H2O. After insertion, the device was connected to a closed-circuit breathing system under pressure-controlled ventilation (PCV) with an inspiratory pressure 16 cm H2O, a positive end-expiratory pressure (PEEP) of 5 cm H2O, a respiration rate (RR) of 12 breaths/min, an inspiratory ratio of 1:2 and fresh gas flow (oxygen/air) of 3 L/min. Successful placement was defined as a square wave tracing on the capnography with an end-tidal CO2 (EtCO2) value of 32–35 mmHg. There was not gas leakage at a positive pressure. Anesthesia was maintained with sevoflurane (end-tidal concentration of 2.5%) and remifentanil (0.15–0.20 µg/kg/min). The patient was in the supine position and hemodynamic and respiratory parameters were stable during the surgery. The surgery was uneventful and the duration of anesthesia was 60 min. After surgery, the patient was admitted to post-anesthesia care unit for postoperative monitoring and thereafter transferred to the ward in stable conditions.\n\nNext morning, she developed respiratory distress with sudden desaturation (SpO2 85%) associated with intense thoracic pain located in right scapular area. CT scan showed right massive pneumothorax and left pneumothorax of 6 cm depth (Figure 1). Bilateral thoracic drainage was needed. Following lung re-expansion, a CT scan of the chest showed bilateral lung pulmonary metastasis, some of these located in sub-pleural region (Figure 2). No further complications occurred and the patient was discharged after 10 days of hospitalization with indication to chemotherapy and radiotherapy.\n\nFigure 1. CT scan with right massive pneumothorax and left pneumothorax.\n\nFigure 2. CT scan. Black arrow shows a sub-pleural metastasis.\n\nDiscussion\nPneumothorax is a rare complication during general anesthesia. It can be due to surgical or anesthetic procedures that damage the pleural surface. The incidence of barotrauma in postoperative patients has been reported to be as low as 0.5%.5 Several studies reported that a peak airway pressure above 50 cm H2O is associated with increased risk of alveolar rupture during ventilation.6 Although high PEEP values had been reported to be associated with pneumothorax,7 contrasting data have been reported.8,9\n\nThe development of the pneumothorax during general anesthesia with supraglottic devices is rarer than general anesthesia with endotracheal intubation; it has previously been reported only twice in the medical literature. Choy and Pescod10 described a case of spontaneous pneumothorax during general anesthesia while a patient was breathing spontaneously through a supraglottic airway device. Similar experience was reported by Sandor and Tolas.11 In both cases, the patient responded to surgical stimulation with an episode of cough which preceded the onset of the pneumothorax. Cough may generate intrapleural and intra-alveolar pressures up to 400 cm H2O12 and cause sub-pleural bleb rupture, resulting in a pneumothorax.\n\nOur patient was suffering from sarcoma that is a neoplasm originating from tissue of mesenchymal origin.13 Metastatic soft tissue sarcoma is often exclusively located in the lung. The time from presentation to development of pulmonary metastases is difficult to ascertain. Most patients developed lung metastases within 1 year after presentation. Metastases-free intervals were significantly lower with the increase in the grade of disease.14 Secondary pneumothorax due to metastatic sarcoma is often associated with advanced disease or systemic chemotherapy and these patients have poor prognoses unless promptly treated.1 The incidence of spontaneous pneumothorax is difficult to ascertain from the literature, but several case series report a prevalence in sarcoma of 1.9%.3 The first patient was described by De Barrin in 1937.4 Tariq et al.15 reported a case of simultaneous bilateral spontaneous pneumothorax in a young patient with fibular osteosarcoma. Gan et al.16 described a similar case of a patient with osteosarcoma of the right mandible who developed bilateral pneumothorax. In both cases, the formation of bullae in pulmonary metastases and bilateral pneumothorax was produced after chemotherapy.\n\nIn the literature, several hypotheses were made to understand the pathophysiological mechanism of metastasis-related pneumothorax. Necrosis of metastatic nodules, spontaneous or induced by chemotherapy, may be followed by rupture in the pleural space. Moreover, patients who receive chemotherapy have a higher risk of spontaneous pneumothorax than those who do not.17 It has been hypothesized that pneumothorax was the result of ruptures of the necrotic sub-pleural micrometastasis in patients treated with chemiotherapy.18 Other mechanism may be the compression by neoplastic nodules that determine a valve stenosis mechanism of peripheral bronchi with hyperinflation and subsequent rupture in pleura. Finally, infiltration of a pre-existing benign cysts may be responsible for the development of a solution of continuity of the visceral pleura.1,19\n\nIn our case, at the time of spontaneous pneumothorax, the patient had not yet been undergoing chemotherapy. During the surgery, we used protective mechanical ventilation; it is unlikely that a sub-pleural bleb may rupture at low inflation pressures. Furthermore, whether the development of pneumothorax occurred during ventilation with laryngeal mask, it should have been associated with intraoperative hypoxemia.\n\nThe pneumothorax developed the following day; probably, the irritation of the oropharynx, determined by the supraglottic device, induced the cough that caused the bubbles’ breaking.\n\nIn conclusion, in our patient, pneumothorax is likely due to the progression of the disease with the presence of lung metastases rather than a barotrauma due to general anesthesia. Malignancies, in patient with sarcoma of soft tissue, should be considered in the differential diagnosis of pneumothorax after general anesthesia. We should take into account that supraglottic device could trigger an irritative cough which can cause the sub-pleural bleb rupture.\n\nL.G. and C.R. contributed to the concept; L.G. and A.B. designed the study; L.G. and C.R. performed data collection and/or processing; L.G. performed the literature search; L.G and C.R. wrote the manuscript; and A.B and C.R. performed critical reviews.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient for his anonymized information to be published in this article.\n\nORCID iD: Carlo Rostagno \nhttps://orcid.org/0000-0002-7764-8919\n==== Refs\nReferences\n1 \nFurrer M Althaus U Ris HB. \nSpontaneous pneumothorax from radiographically occult metastatic sarcoma . Eur J Cardiothorac Surg \n1997 ; 11 (6 ): 1171 –1173 .9237605 \n2 \nUpadya A Amoateng-Adjepong Y Haddad RG. \nRecurrent bilateral spontaneous pneumothorax complicating chemotherapy for metastatic sarcoma . South Med J \n2003 ; 96 (8 ): 821 –823 .14515929 \n3 \nHoag JB Sherman M Fasihuddin Q et al \nA comprehensive review of spontaneous pneumothorax complicating sarcoma . Chest \n2010 ; 138 (3 ): 510 –518 .20382720 \n4 \nDe Barrin MJ \nHemopneumothorax spontane dans une metastase pulmonaire de sarcoma osseux . Bul Mem Soc Rad Med Fr \n1937 ; 25 : 73 –76 .\n5 \nNoppen M Schramel F. \nPneumothorax . Eur Respir Rev \n2002 ; 7 : 279 –296 .\n6 \nPetersen GW Baier H. \nIncidence of pulmonary barotraumas in a medical ICU . Crit Care Med \n1983 ; 11 : 67 –69 .6337021 \n7 \nGammon RB Shin MS Buchalter SE. \nPulmonary barotraumas in mechanical ventilation. Patterns and risk factors . Chest \n1992 ; 102 : 568 –572 .1643949 \n8 \nCullen DJ Caldera DL. \nThe incidence of ventilator-induced pulmonary barotrauma in critically ill patients . Anesthesiology \n1979 ; 50 (3 ): 185 –190 .373507 \n9 \nKumar A Pontoppidan H Falke KJ et al \nPulmonary barotraumas during mechanical ventilation . Crit Care Med \n1973 ; 1 : 181 –186 .4587509 \n10 \nChoy MCK Pescod D \nPneumothorax in association with spontaneous ventilation general anesthesia . Anesth Intensive Care \n2007 ; 35 (2 ): 270 –273 .\n11 \nSandor GK Tolas A. \nSpontaneous tension pneumothorax following outpatient general anesthesia . J Oral Maxillofac Surg \n1982 ; 40 (9 ): 596 –600 .6955479 \n12 \nFontana GA. \nMotor mechanisms and the mechanics of cough . In: Chung KF Widdicombe JG Boushey HA (eds) Causes, mechanisms and therapy . Oxford : Blackwell , 2003 , pp. 193 –206 .\n13 \nMason RJ Broaddus VC Murray JF et al \nMurray and Nadel’s textbook of respiratory medicine . 4th ed \nPhiladelphia, PA : Elsevier Saunders , 2005 .\n14 \nSongur N Dinc M Ozdilekcan C et al \nAnalysis of lung metastasis in patients with primary extremity sarcoma . Sarcoma \n2003 ; 7 : 63 –67 .18521370 \n15 \nTariq U Sohail MS Fatima Z et al \nSimultaneous bilateral spontaneous pneumothorax: a rare complication of osteosarcoma . Cureus \n2018 ; 10 (6 ): e2745 .30087821 \n16 \nGan Z Lin S Han K et al \nBilateral spontaneous pneumothorax in an osteosarcoma patient with pulmonary metastases: a case report . Oncol Lett \n2016 ; 11 (2 ): 1179 –1180 .26893715 \n17 \nSmevik B Klepp O. \nThe risk of spontaneous pneumothorax in patients with osteogenic sarcoma and testicular cancer . Cancer \n1982 ; 49 (8 ): 1734 –1737 .6950803 \n18 \nD’Angiò GJ Iannoccone G. \nSpontaneous pneumothorax as a complication to pulmonary metastases in malignant tumors of childhood . Am J Roentgenol Radium Ther Nucl Med \n1961 ; 86 : 1092 –1102 .\n19 \nYamamoto T Mizuno K. \nSpontaneous pneumothorax without any detectable pulmonary metastasis in a patient with osteosarcoma . Int Orthop \n1999 ; 23 (6 ): 361 –362 .10741526\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2050-313X", "issue": "7()", "journal": "SAGE open medical case reports", "keywords": "Pneumothorax; mechanical ventilation; metastatic sarcoma", "medline_ta": "SAGE Open Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101638686", "other_id": null, "pages": "2050313X19833258", "pmc": null, "pmid": "30834120", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "10741526;13882968;14515929;1643949;17444319;18521370;20382720;26893715;30087821;373507;4587509;6337021;6950803;6955479;9237605", "title": "Bilateral pneumothorax after general anesthesia in patient with pleomorphic sarcoma of soft tissue.", "title_normalized": "bilateral pneumothorax after general anesthesia in patient with pleomorphic sarcoma of soft tissue" }	[ { "companynumb": "IT-MYLANLABS-2019M1081619", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "REMIFENTANIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020630", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.15?0.20 ?G/KG/MIN", "drugenddate": null, "drugenddateformat": null, "drugindication": "MAINTENANCE OF ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REMIFENTANIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SEVOFLURANE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LIQUID", "drugdosagetext": "2.5 PERCENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SEVOFLURANE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Chest pain", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumothorax", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oxygen saturation", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GIANESELLO L, BOCCACCINI A, AND ROSTAGNO C. 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{ "abstract": "The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5.", "affiliations": "Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Morinomiya University of Medical Sciences, Osaka, Japan.", "authors": "Higaki\|Jitsuo\|J\|;Komuro\|Issei\|I\|;Shiki\|Kosuke\|K\|;Lee\|Ganghyuck\|G\|;Taniguchi\|Atsushi\|A\|;Ikeda\|Hiroshi\|H\|;Kuroki\|Daisuke\|D\|;Nishimura\|Seiichiro\|S\|;Ogihara\|Toshio\|T\|", "chemical_list": "D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D004338:Drug Combinations; C548840:telmisartan amlodipine combination; D006852:Hydrochlorothiazide; D017311:Amlodipine; D000077333:Telmisartan", "country": "England", "delete": false, "doi": "10.1038/hr.2016.124", "fulltext": "\n==== Front\nHypertens ResHypertens. ResHypertension Research0916-96361348-4214Nature Publishing Group UK London 27761000BFhr201612410.1038/hr.2016.124ArticleEffect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study Higaki Jitsuo [email protected] 1Komuro Issei 2Shiki Kosuke 3Lee Ganghyuck 3Taniguchi Atsushi 3Ikeda Hiroshi 3Kuroki Daisuke 3Nishimura Seiichiro 3Ogihara Toshio 41 grid.255464.40000 0001 1011 3808Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime Japan 2 grid.26999.3d0000 0001 2151 536XDepartment of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo Japan 3 grid.459839.a0000 0004 4678 1308Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan 4 grid.440914.c0000 0004 0649 1453Morinomiya University of Medical Sciences, Osaka Japan 20 10 2016 20 10 2016 2017 40 3 251 258 20 4 2016 23 7 2016 18 8 2016 © The Author(s) 2017This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5.\n\nSupplementary information\nThe online version of this article (doi:10.1038/hr.2016.124) contains supplementary material, which is available to authorized users.\n\nKeywords\namlodipinecombination therapyhydrochlorothiazidetelmisartanSubject terms\nClinical pharmacologyRandomized controlled trialsHypertensionCombination drug therapyissue-copyright-statement© The Japanese Society of Hypertension 2017\n==== Body\nIntroduction\nAccording to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014), it is estimated that ∼43 million people are affected by hypertension in Japan.1 It is concerning that the number of people with hypertension may continue to increase with aging of the population. In a survey of 4000 hypertensive subjects, the proportion with controlled blood pressure was 34.9% in 2006, and this improved to 50% in 2009; however, blood pressure control remains inadequate.2 Another survey conducted in 3000 subjects in 1994, 2001 and 2010 showed that the mean number of prescribed agents per patient increased gradually from 1.64 in 1994 to 1.79 in 2001 and to 2.04 in 2010.3 For many patients, a combination of two or more treatments, or an increased dose of combination therapy, is required to achieve any antihypertensive effect.1\n\nAngiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors, calcium channel blockers (CCBs) and diuretics are first-line drugs for the management of hypertension.1 CCBs and ARBs lower blood pressure by vasodilating effects. Diuretics increase the excretion of excess water and sodium, thereby decreasing peripheral vascular resistance.\n\nAmong these first-line drugs, ARB/CCB combination therapy is widely used for hypertensive patients as a second-line treatment. In a phase III study, a combined antihypertension treatment containing 80 mg of the ARB telmisartan and 5 mg of the CCB amlodipine (Micamlo combination tablets BP; Nippon Boehringer Ingelheim) reduced diastolic blood pressure (DBP) to ⩽90 mm Hg in 70.1% of patients compared with 41.5% of patients taking telmisartan monotherapy (data on file, Nippon Boehringer Ingelheim, Tokyo, Japan).\n\nFor patients with hypertension refractory to ARB/CCB, the use of an additional antihypertensive drug with a different mode of action, such as a low dose of a diuretic, is recommended.1 However, diuretics are infrequently used to treat Japanese hypertensive patients. We designed this study to determine the effects of adding the diuretic hydrochlorothiazide to an ARB/CCB combination therapy.\n\nThe aim of this prospective, randomized, double-blind, active-control, parallel-group comparison study was to examine the efficacy and safety of telmisartan (80 mg), amlodipine (5 mg) and hydrochlorothiazide (12.5 mg) (T80/A5/H12.5) for the treatment of hypertensive patients whose hypertension is uncontrolled with telmisartan (80 mg) and amlodipine (5 mg) (T80/A5).\n\nMaterials and Methods\nPatients\nJapanese patients aged ⩾20 years were enrolled in this study if they had essential hypertension, were already taking two or three antihypertensive drugs (at the time of the visit for signing the informed consent form), had a mean (of three measurements in one visit) seated DBP ⩾90 and ⩽114 mm Hg at week −6 and week 0 (see Figure 1 for details of visits), had a mean seated systolic blood pressure (SBP) ⩽200 mm Hg at week −6 and week 0, were an outpatient, were able to stop all current antihypertensive drugs (other than study medication) from week −6 through to the end of the study without risk and if they provided informed consent. Patients were excluded if they had any of the following: known or suspected secondary hypertension, cardiac disorders, a history of stroke or transient ischemic attack within the past 6 months, hepatic or renal dysfunctions, biliary atresia or cholestasis, hyperkalemia, anuria or blood dialysis, hyponatremia, malignant tumor or a disease requiring immunosuppressants. Patients were also excluded if they were <80% or >120% compliant during the run-in period. The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was acquired from all institutional review boards and all patients provided written informed consent that they were free to withdraw at any time during the study.Figure 1 Study design. DBP, diastolic blood pressure; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg/amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\n\n\nPrescribed treatments for concomitant diseases, except for those known to affect blood pressure, were not discontinued during the study. Patient compliance was measured at each visit by counting the number of tablets returned to the investigation and calculating the percentage of medication taken in relation to the amount that should have been taken.\n\nStudy design\nThis study was designed as an 8-week, multicenter (30 sites), randomized, double-blind, active-control, parallel-group comparative phase III clinical study conducted between 8 November 2013 and 12 July 2014 to verify the superiority of T80/A5/H12.5 over T80/A5 for the reduction in blood pressure. Patients entered a 6-week open-label run-in period that involved the oral administration of a once-daily T80/A5 fixed-dose combination tablet. At the end of the run-in period (week 0), patients whose trough-seated DBP remained ⩾90 mm Hg after treatment with T80/A5 were randomly assigned to one of two groups: once-daily, orally administered T80/A5 fixed-dose combination tablet+H12.5 (T80/A5/H12.5) or T80/A5 fixed-dose combination tablet+placebo (T80/A5). The treatment period lasted 8 weeks (Figure 1). Randomization and appropriate supply of study medication to patients was performed using Interactive Response Technology.\n\nStudy endpoints\nEfficacy\nThe primary endpoint of this study was the reduction from the reference baseline in mean seated DBP at trough after 8 weeks of the double-blind period. The key secondary endpoint was the reduction from the reference baseline in mean seated SBP at trough after 8 weeks of the double-blind period. The other secondary endpoint was the proportion of patients with seated DBP <90 mm Hg and seated SBP <140 mm Hg at trough after 8 weeks of the double-blind period. Other endpoints included the seated DBP control rate (percentage of patients with DBP <90 mm Hg) and SBP control rate (percentage of patients with SBP <140 mm Hg) at trough after 8 weeks of the double-blind period and seated DBP response rate (percentage of patients with DBP <90 mm Hg or a reduction in DBP of ⩾10 mm Hg) and SBP response rate (percentage of patients with SBP <140 mm Hg or a reduction in SBP of ⩾20 mm Hg) at trough after 8 weeks of the double-blind period from the reference baseline.\n\nBlood pressure and heart rate measurements\nAll blood pressure measurements were taken with a standard mercury sphygmomanometer, recorded on the same arm by the same operator where possible. Blood pressure and pulse rate at trough were measured ∼24 h (±3 h) after the last dose of the study drugs on the previous day. Seated blood pressure was calculated as the mean of three measurements.\n\nSeated blood pressure and pulse rate were measured at weeks −6, 0, 4 and 8. Blood pressure and pulse rate were measured in seated, supine and standing positions at weeks −6, 0 and 8. DBP was taken at the disappearance of repetitive sound (Korotkoff phase 5). In those in whom the sound continued until the zero point, the blood pressure at the distinct muffling of the repetitive sounds (Korotkoff phase 4) was to be recorded as the DBP.\n\nSafety\nTo ensure the safety of the study participants, the parameters were analyzed during the study, while maintaining blind, to identify potential safety concerns, including the incidence of adverse events, changes in blood pressure and pulse rate following position change, seated pulse rate and general laboratory tests (blood biochemistry, hematology and urinalysis).\n\nStatistical analyses\nThe sample size of 300 (150 per group; allocation ratio 1:1) was determined to achieve superiority of the T80/A5/H12.5 group to the T80/A5 group with two-sided significance level of 5% and power of >80% provided that the seated DBP reduction would differ between treatment groups by 2.8 mm Hg with s.d. of 8.5 mm Hg.\n\nIn this study, three analysis sets were defined for analyzing data, including the treated set, the full analysis set (FAS) and the per-protocol set (PPS). The treated set was defined as all patients (1) randomly assigned to one of two treatment groups and (2) taking at least one dose of T80/A5/H12.5 or T80/A5. The FAS was defined as all patients (1) included in the treated set and (2) taking measurements of seated DBP at reference baseline and at one or more time points during the double-blind period. The PPS was defined as a collection of patients (1) included in the FAS and (2) observing no important protocol violation that might affect the efficacy evaluation during the double-blind period.\n\nFor the primary and key secondary endpoints, an analysis of covariance (ANCOVA) was performed on the FAS to analyze the blood pressure reduction after 8 weeks of treatment in the T80/A5/H12.5 and T80/A5 groups. The model includes treatment and center as fixed effects, and reference baseline as a covariate. The last observation carried forward (LOCF) approach was used to impute missing data. The treatment effect was tested and estimated by the adjusted mean and its 95% confidence interval (CI) obtained from the model. The sensitivity analyses were performed using an ANCOVA on the PPS, and using mixed-effects model repeated measures (MMRM) on the FAS without the LOCF approach. The other secondary endpoint and other endpoints, including the proportion of patients with trough-seated DBP/SBP ⩽90/140 mm Hg, DBP/SBP control rates and DBP/SBP response rates after 8 weeks of the double-blind period, were analyzed by treatment group and compared between groups using logistic regression analysis with noncompleters considered failure imputation. (Clinical trial registration: NCT01975246.)\n\nResults\nPatients\nWe enrolled 442 male and female Japanese patients in this study. Of these, 309 patients had uncontrolled blood pressure despite treatment with T80/A5 during the run-in period (Figure 2). The study population consisted predominantly of males (83.2%) and people aged <65 years (85.4%), with the mean (s.d.) age of all patients being 54.7 (9.4) years (Table 1). The majority of patients had hypertension severity grade I or II (72.8% and 24.6%, respectively) according to JSH 2014.1 The mean (s.d.) body mass index of the study population was 26.92 (4.34) kg m−2 and the mean (s.d.) waist circumference was 92.90 (10.76) cm. In total, 73.8% of the treated patients had abdominal obesity. Overall, of the 309 patients in the treated set, 93.5% had at least one concomitant diagnosis; the most frequent was metabolic and nutrition disorders (72.2%), followed by hepatobiliary disorders (27.8%).Figure 2 Patient disposition. AE, adverse event; T80/A5, telmisartan 80 mg+amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\nTable 1 Demographic and reference baseline characteristics of the treated set\n\n\tT80/A5/H12.5\tT80/A5\tTotal\t\nN\t149\t160\t309\t\nGender, N (%)\t\n Male\t127 (85.2)\t130 (81.3)\t257 (83.2)\t\n Female\t22 (14.8)\t30 (18.8)\t52 (16.8)\t\nAge, years\t\n Mean (s.d.)\t54.4 (9.1)\t55.0 (9.7)\t54.7 (9.4)\t\n Median (range)\t54.0 (27–80)\t54.5 (30–83)\t54.0 (27–83)\t\nAge, N (%)\t\n <65 Years\t130 (87.2)\t134 (83.8)\t264 (85.4)\t\n ⩾65 Years\t19 (12.8)\t26 (16.3)\t45 (14.6)\t\nReference baseline BMI, kg m−2\t\n Mean (s.d.)\t27.10 (4.16)\t26.76 (4.51)\t26.92 (4.34)\t\n Median (range)\t26.96 (17.5–44.6)\t26.12 (16.8–43.8)\t26.66 (16.8–44.6)\t\nBMI, N (%)\t\n <25.0 kg m−2\t46 (30.9)\t67 (41.9)\t113 (36.6)\t\n ⩾25.0 To <30.0 kg m−2\t70 (47.0)\t60 (37.5)\t130 (42.1)\t\n ⩾30.0 kg m−2\t33 (22.1)\t33 (20.6)\t66 (21.4)\t\nAbdominal obesitya, N (%)\t\n No\t34 (22.8)\t47 (29.4)\t81 (26.2)\t\n Yes\t115 (77.2)\t113 (70.6)\t228 (73.8)\t\nReference baseline blood pressure (mm Hg)\t\n DBP mean (s.d.)\t96.5 (5.6)\t95.7 (5.1)\t96.1 (5.3)\t\n SBP mean (s.d.)\t142.3 (12.9)\t142.3 (12.1)\t142.3 (12.4)\t\nDuration of hypertension, N (%)\t\n ⩽1 Year\t11 (7.4)\t5 (3.1)\t16 (5.2)\t\n >1–5 Years\t36 (24.2)\t44 (27.5)\t80 (25.9)\t\n >5–10 Years\t46 (30.9)\t43 (26.9)\t89 (28.8)\t\n >10 Years\t56 (37.6)\t68 (42.5)\t124 (40.1)\t\nHypertension severityb\nat reference baseline, N (%)\t\n Grade I\t107 (71.8)\t118 (73.8)\t225 (72.8)\t\n Grade II\t36 (24.2)\t40 (25.0)\t76 (24.6)\t\n Grade III\t5 (3.4)\t2 (1.3)\t7 (2.3)\t\n Missing\t1 (0.7)\t0 (0.0)\t1 (0.3)\t\neGFR (ml min−1\n1.73 m−2), N (%)\t\n ⩾90 (Normal)\t24 (16.1)\t32 (20.0)\t56 (18.1)\t\n ⩾60 To <90 (mild)\t109 (73.2)\t104 (65.0)\t213 (68.9)\t\n ⩾30 To <60 (moderate)\t16 (10.7)\t24 (15.0)\t40 (12.9)\t\n <30 (Severe)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nConcomitant diagnoses, N (%)\t137 (91.9)\t152 (95.0)\t289 (93.5)\t\nNumber of previous antihypertensives used, N (%)\t\n Two\t125 (83.9)\t129 (80.6)\t254 (82.2)\t\n Three\t24 (16.1)\t31 (19.4)\t55 (17.8)\t\nAbbreviations: BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg/amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\naAbdominal obesity: Yes= reference baseline waist circumference >85 cm (male) and >90 cm (female).\n\nbHypertension severity: grade I=seated SBP 140 to <160 mm Hg or seated DBP 90 to <100 mm Hg; Grade II=seated SBP 160 to <180 mm Hg or seated DBP 100 to <110 mm Hg; Grade III=seated SBP ⩾180 mm Hg or seated DBP ⩾110 mm Hg.\n\n\n\nIn accordance with the inclusion criteria, patients were previously treated with two (82.2%) or three (17.8%) antihypertensive drugs. In 74.4% of patients, this consisted of an ARB and a CCB, and for 10.7% it consisted of an ARB, a CCB and a diuretic. The mean (s.d.) seated DBP at reference baseline was 96.5 (5.6) mm Hg and 95.7 (5.1 mm Hg) in the T80/A5/H12.5 and the T80/A5 groups, respectively. The mean seated SBP at reference baseline was 142.3 (12.9) and 142.3 (12.1) mm Hg in the T80/A5/H12.5 and the T80/A5 groups, respectively. In general, the demographic and reference baseline characteristics of both groups were similar (Table 1).\n\nThe disposition of the study patients is shown in Figure 2. Of the 442 enrolled patients, 393 entered the run-in period and 49 were excluded, largely because of violations of the inclusion/exclusion criteria. Following the run-in period, 309 patients were randomly assigned to T80/A5/H12.5 (N=149) and T80/A5 (N=160) groups and 84 were excluded, mainly because of not meeting the blood pressure inclusion/exclusion criteria. Of the 309 patients who entered the treatment period, 303 (98.1%) patients completed the 8-week treatment period, and the proportion of patients who completed the study was similar between groups (145 [97.3%] and 158 [98.8%] for the T80/A5/H12.5 and T80/A5 groups, respectively). The most frequent cause for discontinuation was adverse events that occurred in 2 (1.3%) and 1 (0.6%) patients in the T80/A5/H12.5 and T80/A5 groups, respectively (Figure 2).\n\nDBP change\nAfter 8 weeks of treatment, the adjusted mean (s.e.) reduction in trough-seated DBP was 8.4 (0.6) mm Hg in the T80/A5/H12.5 group compared with 4.5 (0.5) mm Hg in the T80/A5 group in the FAS (ANCOVA with LOCF). The T80/A5/H12.5 group showed a statistically significantly greater adjusted mean reduction in seated DBP compared with the T80/A5 treatment group, with a difference of −3.9 mm Hg (95% CI: −5.3 to −2.4; P<0.0001). Figure 3a shows the results of a sensitivity analysis performed using a MMRM on the FAS that provided results that were consistent with those of the primary analysis. An ANCOVA on the PPS also provided results consistent with those of the primary analysis. In addition, the adjusted mean (s.e.) change from reference baseline in trough-seated DBP at week 4 based on the MMRM analysis was −6.6 (0.5) mm Hg in the T80/A5/H12.5 group and −3.2 (0.5) mm Hg in the T80/A5 group. Compared with T80/A5, T80/A5/H12.5 had a greater reduction in trough-seated DBP, with a treatment difference of −3.5 mm Hg (95% CI: −4.8 to −2.1; P<0.0001). These data indicate that treatment with the combination T80/A5/H12.5 achieved a superior reduction in seated DBP compared with treatment with T80/A5.Figure 3 Change in trough-seated DBP and SBP from reference baseline using a mixed-effects model for repeated measures on the full analysis set with no imputation. (a) Adjusted mean change in DBP compared with reference baseline at 4 and 8 weeks for both treatment groups in the FAS. (b) Adjusted mean change in SBP compared with reference baseline at 4 and 8 weeks of treatment for both treatment groups in the FAS. DBP, diastolic blood pressure; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg+amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg+amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\n\n\nSBP change\nFollowing 8 weeks of treatment, the adjusted mean (s.e.) reduction in trough-seated SBP was 12.3 (0.8) mm Hg in the T80/A5/H12.5 group compared with 6.9 (0.8) mm Hg in the T80/A5 group in the FAS (ANCOVA with LOCF). The T80/A5/H12.5 group showed a statistically significantly greater adjusted mean reduction in SBP compared with the T80/A5 group, with a difference of −5.3 mm Hg (95% CI: −7.6 to −3.1; P<0.0001). The sensitivity analysis, including a MMRM analysis on the FAS (Figure 3b), provided results that were consistent with those of the primary analysis. Furthermore, the adjusted mean (s.e.) change from reference baseline in trough-seated SBP at week 4 based on the MMRM analysis was −9.7 (0.8) mm Hg in the T80/A5/H12.5 group and −5.2 (0.8) mm Hg in the T80/A5 group. Compared with the T80/A5 group, the T80/A5/H12.5 group had a greater reduction in trough-seated SBP, with a treatment difference of −4.5 mm Hg (95% CI: −6.6 to −2.3; P<0.0001; MMRM analysis; Figure 3b). These data indicate that treatment with the combination T80/A5/H12.5 achieved a superior reduction in SBP compared with treatment with T80/A5.\n\nOther outcomes\nFollowing 8 weeks of treatment, the proportion of patients who achieved a trough-seated DBP/SBP of <90/140 mm Hg was 51.7% in the T80/A5/H12.5 group and 36.9% in the T80/A5 group (Table 2). Based on logistic regression analysis, patients in the T80/A5/H12.5 group were estimated to be 2.1 times more likely to achieve a DBP/SBP of <90/140 mm Hg than were patients in the T80/A5 group (95% CI: 1.2 to 3.4). In addition, more patients achieved trough-seated DBP control (DBP <90 mm Hg) in the T80/A5/H12.5 group than in the T80/A5 group (Table 2). The probability of achieving DBP control at week 8 was estimated to be 1.9 times higher in the T80/A5/H12.5 group than in the T80/A5 group (95% CI: 1.2 to 3.2) on the basis of a logistic regression analysis.Table 2 DBP and SBP control rates and response rates in the full analysis set\n\n\t\tT80/A5/H12.5\tT80/A5\t\t\t\nEndpoint\tWeek\tN\tn\t(%)\tN\tn\t(%)\tORa\t95% CI\t\nDBP control\t4\t147\t70\t47.6\t160\t47\t29.4\t2.4\t(1.5–4.1)\t\n\t8\t\t83\t56.5\t\t68\t42.5\t1.9\t(1.2–3.2)\t\nSBP control\t4\t76\t37\t48.7\t89\t27\t30.3\t2.3\t(1.2–4.8)\t\n\t8\t\t48\t63.2\t\t40\t44.9\t2.5\t(1.2–5.3)\t\nDBP <90 mm Hg or decrease by 10 mm Hg\t4\t147\t80\t54.4\t160\t49\t30.6\t3.0\t(1.8–5.0)\t\n8\t\t98\t66.7\t\t72\t45.0\t2.8\t(1.7–4.8)\t\t\nSBP <140 mm Hg or decrease by 20 mm Hg\t4\t76\t41\t53.9\t89\t30\t33.7\t2.4\t(1.2–4.8)\t\n8\t\t54\t71.1\t\t40\t44.9\t4.1\t(1.9–9.1)\t\t\nDBP/SBP <90/140 mm Hg\t4\t147\t66\t44.9\t160\t39\t24.4\t2.9\t(1.7–5.1)\t\n8\t\t76\t51.7\t\t59\t36.9\t2.1\t(1.2–3.4)\t\t\nAbbreviations: CI, confidence interval; DBP, diastolic blood pressure; OR, odds ratio; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg/amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\nOnly patients in the full analysis set with a trough-seated DSB of ⩾90 mm Hg or a SBP of ⩾140 mm Hg at reference baseline were included in the analysis.\n\naFor T80/A5/H12.5 vs. T80/A5.\n\n\n\nOf the patients within the FAS who had SBP ⩾140 mm Hg at reference baseline, a greater portion achieved trough-seated SBP control (SBP <140 mm Hg) by week 8 in the T80/A5/H12.5 group compared with patients in the T80/A5 group (Table 2). The probability of achieving SBP control at week 8 was estimated to be 2.5 times higher in the T80/A5/H12.5 group than in the T80/A5 group (95% CI: 1.2 to 5.3) on the basis of a logistic regression analysis. Furthermore, the proportion of patients who had an adequate response in trough-seated DBP (DBP <90 mm Hg or a reduction in DBP of ⩾10 mm Hg) at week 8 was larger in the T80/A5/H12.5 group than in the T80/A5 group. Of the patients within the FAS who had SBP ⩾140 mm Hg at reference baseline, more had an adequate response in trough-seated SBP (SBP <140 mm Hg or a reduction in SBP of ⩾20 mm Hg) at week 8 in the T80/A5/H12.5 group than in the T80/A5 group.\n\nSubgroup analysis\nWithin the treatment groups, patients were divided into subgroups based on patient characteristics, including age (<65, ⩾65 years), sex, body mass index (<25, 25–<30 and ⩾30 kg m−2), hypertension severity, hypertension duration (⩽1, >1–5, >5–10 and >10 years) and the number of previous antihypertension drugs used (two or three). The reductions in both DBP and SBP in each subgroup tended to be greater in patients treated with T80/A5/H12.5 than in patients treated with T80/A5 (Supplementary Tables 1 and 2).\n\nSafety\nAdverse events and laboratory findings\nThe number of patients who experienced adverse events during the double-blind 8-week period was higher in the T80/A5/H12.5 group (41.6%) than in the T80/A5 group (28.1%) (Table 3). The most common adverse events were increased blood uric acid levels, nasopharyngitis and hyperuricemia. Higher incidences in the T80/A5/H12.5 group compared with the T80/A5 group were seen for increased blood uric acid levels and hyperuricemia.Table 3 Summary of AEs and frequency of drug-related AEs experienced by ⩾1% of the patients in any one of the treatment groups in the treated set\n\n\tT80/A5/H12.5\tT80/A5\t\nVariable\tN\t%\tN\t%\t\nNumber of patients\t149\t100\t160\t100\t\nPatients with an AE\t62\t41.6\t45\t28.1\t\nPatients with investigator-defined drug-related AEs\t35\t23.5\t6\t3.8\t\nPatients with other significant AEs\t2\t1.3\t1\t0.6\t\nPatients with AEs leading to discontinuation\t2\t1.3\t1\t0.6\t\nSystem organ class and preferred term\t\n Metabolic and nutrition disorders\t10\t6.7\t1\t0.6\t\n Hyperuricemia\t8\t5.4\t1\t0.6\t\n Dyslipidemia\t2\t1.3\t0\t0.0\t\n Investigations (laboratory data abnormalities)\t21\t14.1\t4\t2.5\t\n Blood uric acid increased\t20\t13.4\t3\t1.9\t\n Blood creatinine increased\t2\t1.3\t0\t0.0\t\n Blood urea increased\t2\t1.3\t0\t0.0\t\nAbbreviations: AE, adverse event; T80/A5, telmisartan 80 mg+amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg+amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\n\n\nThe frequencies of drug-related adverse events are shown in Table 3. The incidences of drug-related adverse events were higher in the T80/A5/H12.5 group (23.5%) compared with the T80/A5 group (3.8%). This difference in the number of drug-related adverse events was largely because of the higher incidence of increased uric acid levels in the T80/A5/H12.5 group compared with the T80/A5 group (13.4% vs. 1.9%).\n\nIndeed, regarding laboratory parameters (Supplementary Table 3), noteworthy differences between groups were observed for the mean change from reference baseline in uric acid (1.0 mg dl−1 in the T80/A5/H12.5 group vs. 0.2 mg dl−1 in the T80/A5 group). In patients who had no abnormalities at reference baseline, possible clinically relevant abnormalities included the development of high triglycerides and high total cholesterol that were detected in 11.2% and 4.3% of patients in the T80/A5/H12.5 group, respectively, and 7.3% and 5.9% of the patients in the T80/A5 group, respectively.\n\nThe adverse events experienced by patients were mild or moderate in severity and no severe adverse events or deaths were reported in either treatment group. Two patients in the T80/A5/H12.5 group discontinued the study because of adverse events: atrial fibrillation and tachycardia (one patient) and hypotension (one patient). In the T80/A5 group, one patient discontinued because of ventricular extrasystoles. For all three patients, the adverse events were mild in intensity.\n\nAdherence\nThe overall compliance during the double-blind period was >80% in both treatment groups; 2 (1.3%) of the 149 patients in the T80/A5/H12.5 group and none of the 160 patients in the T80/A5 group had a compliance rate of <80%.\n\nVital signs and other safety parameters\nFollowing the 8-week treatment period, no clinically relevant changes in DBP, SBP or pulse rate following a position change were detected in either group compared with reference baseline. Furthermore, the seated pulse rate and pulse rate after a position change remained relatively unchanged at week 8 (Supplementary Table 4). Overall, both T80/A5/H12.5 and T80/A5 were well tolerated.\n\nDiscussion\nHypertension is a disease with a high incidence in Japan. The currently used monotherapies, including ARBs, CCBs and diuretics, are effective only in a limited proportion of patients. For those who remain resistant to therapy, a combination of antihypertensive agents is required.1 The aim of this study was to investigate the efficacy and safety of a combination of T80/A5/H12.5 for the treatment of hypertension in patients with an inadequate response to telmisartan 80 mg and amlodipine 5 mg. The results indicate that the T80/A5/H12.5 group achieved significantly greater reductions in seated DBP and SBP relative to those achieved in the T80/A5 group. In addition, significantly more patients achieved DBP and SBP control in the T80/A5/H12.5 group compared with patients treated with T80/A5.\n\nThe adverse events reported in this study were mild or moderate in severity, and those events were already observed in those receiving monotherapy or two-agent combination therapy. The incidence of drug-related adverse events was higher in the T80/A5/H12.5 group than in the T80/A5 group. The frequent drug-related adverse events in the T80/A5/H12.5 group were elevated uric acid levels and hyperuricemia. The cause of the increase in uric acid can likely be explained by the addition of hydrochlorothiazide, because elevated uric acid is a common side effect of diuretics.4 These adverse events were manageable and did not pose a health risk.\n\nIn this study, each patient received two tablets: T80/A5 fixed-dose combination and H12.5 or T80/A5 fixed-dose combination and placebo. It is possible that a single tablet T80/A5/H12.5 combination treatment would improve patient adherence. Previous studies reported that the fixed combination of valsartan/amlodipine/hydrochlorothiazide or olmesartan/amlodipine/hydrochlorothiazide improved adherence and persistence compared with administration of each drug as individual tablets.5, 6, 7 This suggests that the fixed combination of T80/A5/H12.5 may increase the adherence relative to a combination of three individual treatments.\n\nA similarly designed study of a combination of losartan 50 mg, hydrochlorothiazide 12.5 mg and amlodipine 5 mg compared with coadministration of losartan 50 mg plus amlodipine 5 mg in Japanese patients with essential hypertension did not demonstrate a significant difference in DBP reduction with hydrochlorothiazide 12.5 mg at week 8 (additional effect of −1.1 mm Hg; 95% CI: −2.7 to 0.6; P=0.205).8 However, there was a significant additional effect of hydrochlorothiazide 12.5 mg on SBP reduction at week 8 (−3.2 mm Hg; −5.7 to −0.8; P=0.011).8 The difference between the results of the losartan study and ours is possibly because of the profile of ARBs, that is, usual dosage range, terminal half-life and volume of distribution.9 The high-dose ARB with a large volume of distribution is suitable to completely inhibit the renin–angiotensin system activated by CCBs and diuretics.10 Among ARBs, telmisartan is a long-acting antihypertensive drug that may provide sustained reductions in blood pressure throughout a 24-h dosing period.9, 11\n\nThe results of this study should be considered in light of its limitations. The main limitation of this study was that the mean age of the patients was 54.7 years and only 14.6% of patients were ⩾65 years old. Therefore, the efficacy and safety profiles of T80/A5/H12.5 in older patients could not be determined. The study was also only conducted in institutions within Japan, and hence the results are not generalizable to populations of other ethnicities. Another limitation was the short duration of the study, as 8 weeks may not have been sufficient to observe the full benefit provided by the combination therapy, or the benefits may have been reduced over a longer period. Finally, we did not include patients with severe impaired kidney function (estimated glomerular filtration rate <30 ml min−1 1.73 m−2) who may also require combination therapies to manage hypertension.\n\nConclusions\nThe results from this phase III study indicate that the combination of telmisartan, amlodipine and hydrochlorothiazide is more effective than that of only telmisartan and amlodipine at reducing blood pressure in hypertensive patients. The addition of hydrochlorothiazide to a ARB/CCB combination therapy provides clinicians with a suitable treatment option for patients unresponsive to ARB/CCB combinations. This triple combination therapy is effective and well tolerated.\n\nSupplementary information\n\nSupplementary Information (DOC 268 kb)\n\n \n\n\nSupplementary Information accompanies the paper on Hypertension Research website\n\nAcknowledgements\nWe thank all investigators involved in this study: Shinichi Higashiue, MD (Kishiwada Tokushukai Hospital, Cardiovascular Surgery, Osaka, Japan); Kousuke Mabuchi, MD (Kanda Clinic, Internal Medicine, Tokyo, Japan); Shigeo Sawai, MD (Sawai Medical Clinic, Internal Medicine, Tokyo, Japan); Fumiki Oh, MD (Shinden Higashi Clinic, Internal Medicine, Miyagi, Japan); Isao Uchimura, MD (Chiyodahoujin Clinic, Internal Medicine, Tokyo, Japan); Masafumi Sugawara, MD (Dynamedical Nezu Clinic, Internal Medicine, Tokyo, Japan); Yoshihiro Tokeshi, MD (Chubu Tokushukai Hospital, Internal Medicine, Okinawa, Japan); Satoshi Inoue, MD (OCROM Clinic, Osaka, Japan); Katsuji Hashimoto, MD (AMC Nishiumeda Clinic, Internal Medicine, Osaka, Japan); Yoji Takatsuka, MD (Motomachi Takatsuka Naika Clinic, Internal Medicine, Kanagawa, Japan); Hiroshi Shimomura, MD (Musashino Polyclinic, Internal Medicine, Tokyo, Japan); Kazuko Takahashi, MD (Takahashi Clinic, Internal Medicine, Hokkaido, Japan); Fumihiko Takeda, MD (Riverside clinic, Internal Medicine, Hokkaido, Japan); Sohji Nagase, MD (Nagase Medical Clinic, Internal Medicine, Ibaraki, Japan); Toru Kihara, MD (Fukuoka Rehabilitation Hospital, Internal Medicine, Fukuoka, Japan); Toshiki Fukui, MD (NTT West Takamatsu Hospital, Internal Medicine, Kagawa, Japan); Takafumi Kondo, MD (Kaisei Hospital, Internal Medicine, Kagawa, Japan); Arihiro Kiyosue, MD (Tokyo-Eki Center-building Clinic, Internal Medicine, Tokyo, Japan); Takahiko Tokuyama, MD (Tokuyama Clinic, Internal Medicine, Chiba, Japan); Akira Numata, MD (Ikebukuro Metropolitan Clinic, Internal Medicine, Tokyo, Japan); Atsushi Hirayama, MD (Nihon University Itabashi Hospital, Division of Cardiovascular Medicine, Tokyo, Japan); Hideki Takizawa, MD (Teine Keijinkai Clinic, Kidney Internal Medicine, Hokkaido, Japan); Teruaki Mita, MD (Mita Internal Medicine Cardiology Clinic, Internal Medicine, Hokkaido, Japan); Chiaki Noguchi, MD (Shinkoiwa Ekimae Clinic, Internal Medicine, Tokyo, Japan); Yuichiro Nakamura, MD (Nakamura Cardiovascular Clinic, Cardiovascular Medicine, Fukuoka, Japan); Norimasa Sato, MD (Umeda Oak Clinic, Internal Medicine, Osaka, Japan); Takayuki Azuma, MD (Yaesu Sakura-dori Clinic, Internal Medicine, Tokyo, Japan); Nobuaki Onizawa, MD (Kaijo Bill Clinic, Internal Medicine, Tokyo, Japan); Koichi Yamamoto, MD (Osaka University Hospital, Presbyo-hypertension, Osaka, Japan); Yoshinori Seko, MD (The Institute for Adult Diseases, Asahi Life Foundation, Cardiovascular Internal Medicine, Tokyo, Japan). Treatments were developed by Nippon Boehringer Ingelheim. This study was funded by Nippon Boehringer Ingelheim. We thank Mami Mori of Nippon Boehringer Ingelheim for publication management and editorial support, and John Gibbins of Edanz Group for providing medical writing support. This medical writing assistance was funded by Nippon Boehringer Ingelheim.\n\nCompeting interests\nJH received consulting and lecture fees and/or research funding from Astellas Pharmaceutical, Nippon Boehringer Ingelheim, Mochida Pharmaceutical, Daiichi Sankyo, Sumitomo Dainippon Pharmaceutical, MSD, Novartis Pharmaceutical, Teijin Pharmaceutical and Takeda Pharmaceutical. IK has received lecture fees, research funding and/or scholarship grants from Daiichi Sankyo, Sumitomo Dainippon Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Astellas Pharmaceutical, Teijin Pharmaceutical, Sanofi, Kowa Company, Bayel Yakuhin and TOA EIYO. TO declares no conflict of interest. JH and IK were the Medical Experts and TO was the Coordinating Investigator of this study. KS, GL, AT, HI, DK and SN are employees of Nippon Boehringer Ingelheim.\n==== Refs\nReferences\n1 Shimamoto K Ando K Fujita T Hasebe N Higaki J Horiuchi M Imai Y Imaizumi T Ishimitsu T Ito M Ito S Itoh H Iwao H Kai H Kario K Kashihara N Kawano Y Kim-Mitsuyama S Kimura G Kohara K Komuro I Kumagai H Matsuura H Miura K Morishita R Naruse M Node K Ohya Y Rakugi H Saito I Saitoh S Shimada K Shimosawa T Suzuki H Tamura K Tanahashi N Tsuchihashi T Uchiyama M Ueda S Umemura S Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014) Hypertens Res 2014 37 253 390 10.1038/hr.2013.80 24705419 \n2 Teramoto T Toshiro F Japan guideline assessment panel-2 (J-GAP2) Prog Med (Tokyo) 2010 30 1437 1449 \n3 Nakagawa M Masuda A Ura N Tanaka S Transition of achievement rate for lowering blood pressure target level and situation of prescription for antihypertensive drug J Blood Press 2011 18 73 77 \n4 Moore MJ Gong Y Hou W Hall K Schmidt SOF Curry RW Beitelshees AL Chapman A Turner ST Schwartz GL Bailey K Boerwinkle E Gums JG Cooper-DeHoff RM Johnson JA Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide Pharmacotherapy 2014 34 1132 1140 10.1002/phar.1483 25202885 \n5 Oparil S Melino M Lee J Fernandez V Heyrman R Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: the TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study Clin Ther 2010 32 1252 1269 10.1016/j.clinthera.2010.07.008 20678674 \n6 Mohan JC Jain R Chamle V Bhargava A Short term safety and tolerability of a fixed dose combination of olmesartan, amlodipine and hydrochlorothiazide J Clin Diagn Res 2015 9 OC10 OC13 26435982 \n7 Machnicki G Ong SH Chen W Wei ZJ Kahler KH Comparison of amlodipine/valsartan/hydrochlorothiazide single pill combination and free combination: adherence, persistence, health care utilization and costs Curr Med Res Opin 2015 31 2287 2296 10.1185/03007995.2015.1098598 26397178 \n8 Rakugi H Tsuchihashi T Shimada K Numaguchi H Nishida C Yamaguchi H Shirakawa M Azuma K Fujita KP Add-on effect of hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension uncontrolled with losartan 50 mg and amlodipine 5 mg Hypertens Res 2015 38 329 335 10.1038/hr.2015.3 25716649 \n9 Chrysant SG Chrysant GS Desai A Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan J Hum Hypertens 2005 18 172 183 \n10 Konoshita TM Makino Y Kimura T Fuji M Wakahara S Arakawa K Inoki I Nakamura H Miyamori I Genomic Disease Outcome Consortium (G-DOC) Study Investigators A new-generation N/L-type calcium channel blocker leads to activation of the renin-angiotensin system compared with conventional L type calcium channel blocker J Hypertens 2010 28 2156 2160 10.1097/HJH.0b013e32833d01dd 20625317 \n11 Neutel J Smith DH Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database J Clin Hypertens 2003 5 58 63 10.1111/j.1524-6175.2003.01612.x\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0916-9636", "issue": "40(3)", "journal": "Hypertension research : official journal of the Japanese Society of Hypertension", "keywords": null, "medline_ta": "Hypertens Res", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017311:Amlodipine; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D000077333:Telmisartan; D016896:Treatment Outcome", "nlm_unique_id": "9307690", "other_id": null, "pages": "251-258", "pmc": null, "pmid": "27761000", "pubdate": "2017-03", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": "26397178;12556655;20625317;26435982;25716649;25202885;24705419;20678674;15660122", "title": "Effect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study.", "title_normalized": "effect of hydrochlorothiazide in addition to telmisartan amlodipine combination for treating hypertensive patients uncontrolled with telmisartan amlodipine a randomized double blind study" }	[ { "companynumb": "JP-ALLERGAN-1819281US", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020504", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE UNK" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE\\TELMISARTAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "5+80 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE W/TELMISARTAN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIGAKI J, KOMURO I, SHIKI K, LEE G, TANIGUCHI A, IKEDA H, KUROKI D, NISHIMURA S, OGIHARA T.. EFFECT OF HYDROCHLOROTHIAZIDE IN ADDITION TO TELMISARTAN/AMLODIPINE COMBINATION FOR TREATING HYPERTENSIVE PATIENTS UNCONTROLLED WITH TELMISARTAN/AMLODIPINE: A RANDOMIZED, DOUBLE-BLIND STUDY. 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{ "abstract": "Steroid-refractory chronic graft-versus-host disease (cGVHD) is associated with high morbidity. To date, there is no standard therapy for patients who fail to respond to steroids. In this nonrandomized, open-label, single-arm, multicenter prospective phase II study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF) to treat sclerotic/fibrotic type cGVHD. The primary endpoint was the overall response rate (ORR) to imatinib mesylate plus MMF in 1 year, and the secondary endpoints included safety, quality of life, discontinuation of steroids, and overall survival (OS) rate. A total of 13 patients were enrolled, with a median age of 10.4 years (range, 5.0 to 20.1 years). All patients received a myeloablative conditioning regimen. Specifically, 6 of these patients had previously experienced acute GVHD. The most frequently affected organs were the eyes, lungs, skin, and liver. There were 2 premature deaths. One patient died of pulmonary infection and progression of cGVHD, and the other patient died from neuroblastoma progression and septic shock. The ORR was 76.9% (10 of 13 patients), and the median steroid dose was decreased from 1.0 mg/kg/day to 0.21 mg/kg/day. One-year OS was 84.6% (n = 13), and common adverse events included elevated liver enzyme and serum creatinine levels and fever. Although our sample size was limited, treatment of cGVHD with imatinib mesylate plus MMF shows promising results with acceptable toxicity.", "affiliations": "Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, Republic of Korea.;Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea.;Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea.;Department of Pediatrics, College of Medicine, Yeungnam University, Daegu, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Electronic address: [email protected].", "authors": "Choi\|Jung Yoon\|JY\|;Kim\|Hyery\|H\|;Baek\|Hee Jo\|HJ\|;Kook\|Hoon\|H\|;Lee\|Jae Min\|JM\|;Kim\|Bo Kyung\|BK\|;An\|Hong Yul\|HY\|;Hong\|Kyung Taek\|KT\|;Shin\|Hee Young\|HY\|;Kang\|Hyoung Jin\|HJ\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jtct.2021.07.019", "fulltext": null, "fulltext_license": null, "issn_linking": "2666-6367", "issue": "27(11)", "journal": "Transplantation and cellular therapy", "keywords": "Children; Chronic graft-versus-host disease; Imatinib mesylate; Mycophenolate mofetil", "medline_ta": "Transplant Cell Ther", "mesh_terms": null, "nlm_unique_id": "101774629", "other_id": null, "pages": "925.e1-925.e7", "pmc": null, "pmid": "34314892", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Open-Label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Pediatric Patients with Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-Host Disease.", "title_normalized": "open label multicenter phase ii study of combination therapy of imatinib mesylate and mycophenolate mofetil in pediatric patients with steroid refractory sclerotic fibrotic type chronic graft versus host disease" }	[ { "companynumb": "KR-ALKEM LABORATORIES LIMITED-KR-ALKEM-2021-05027", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB MESYLATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Choi JY, Kim H, Baek HJ, Kook H, et al. Open-label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in pediatric patients with Steroid-Refractory Sclerotic/fibrotic Type Chronic Graft-versus-host disease. Transplantation and Cellular Therapy. 2021;Unk:Unk", "literaturereference_normalized": "open label multicenter phase ii study of combination therapy of imatinib mesylate and mycophenolate mofetil in pediatric patients with steroid refractory sclerotic fibrotic type chronic graft versus host disease", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20211223", "receivedate": "20211223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20220659, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "KR-ALKEM LABORATORIES LIMITED-KR-ALKEM-2021-05028", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB MESYLATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Choi JY, Kim H, Baek HJ, Kook H, et al. Open-label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in pediatric patients with Steroid-Refractory Sclerotic/fibrotic Type Chronic Graft-versus-host disease. Transplantation and Cellular Therapy. 2021;Unk:Unk", "literaturereference_normalized": "open label multicenter phase ii study of combination therapy of imatinib mesylate and mycophenolate mofetil in pediatric patients with steroid refractory sclerotic fibrotic type chronic graft versus host disease", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20211223", "receivedate": "20211223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20220660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "A case of spontaneous fetal bladder rupture occurring in a woman with SARS-CoV-2 pneumonia receiving invasive ventilatory support is reported.\nA 33-year-old woman was admitted at 30.6 weeks' gestation with the diagnosis of severe pneumonia due to COVID-19. The patient required invasive mechanical ventilation on day 2. Propofol, fentanyl, midazolam, and dexmedetomidine were administered for sedation, pain relief, and to improve patient-ventilator interaction. A bedside ultrasound on day 3 revealed fetal megacystis. Follow-up scan two days later showed urinary ascites and a collapsed bladder. The diagnosis of fetal bladder rupture was confirmed postpartum. Bladder repair was performed on day 5, with an uneventful recovery.\nTransplacental transfer of opioids during invasive ventilatory support in pregnancy may cause acute fetal bladder atony leading to severe urine retention and, potentially, bladder rupture. This can be a serious complication of adjunctive therapy in women with severe SARS-CoV-2 pneumonia.", "affiliations": "Department of Obstetrics and Gynecology, Clinica Indisa, Santiago, Chile.;FETALMED-Maternal-Fetal Diagnostic Center, Santiago, Chile.;Department of Pediatric Urology, Clinica Indisa, Santiago, Chile.;Department of Obstetrics and Gynecology, Clinica Indisa, Santiago, Chile.;Neonatal Intensive Care Unit, Clinica Indisa, Santiago, Chile.", "authors": "Gutierrez\|Jorge\|J\|;Sepulveda\|Waldo\|W\|https://orcid.org/0000-0002-3856-574X;Ramirez\|Raul\|R\|;Acosta\|Gina\|G\|;Ambiado\|Sergio\|S\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/15513815.2021.1963359", "fulltext": null, "fulltext_license": null, "issn_linking": "1551-3815", "issue": null, "journal": "Fetal and pediatric pathology", "keywords": "COVID-19; SARS-CoV-2 pneumonia; fetal bladder rupture; prenatal diagnosis", "medline_ta": "Fetal Pediatr Pathol", "mesh_terms": null, "nlm_unique_id": "101230972", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "34369260", "pubdate": "2021-08-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Fetal Bladder Rupture as a Complication of Adjunctive Therapy in Severe Maternal SARS-CoV-2 Pneumonia.", "title_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia" }	[ { "companynumb": "CL-FRESENIUS KABI-FK202109602", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "210762", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "210762", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021 AUG 09?.", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210908", "receivedate": "20210908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19809497, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-ALVOGEN-2021-ALVOGEN-117446", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "202097", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "202097", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TRANSDERMAL SYSTEM", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", 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"drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "2.55", "reaction": [ { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Peritonitis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug withdrawal syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021. DOI: 10.1080/15513815.2021.1963359.", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19812927, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-HQ SPECIALTY-CL-2021INT000152", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.5 UG/KG,1 HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "206628", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 UG/KG,1 HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE HYDROCHLORIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 UG/KG,1 HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206628", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE HYDROCHLORIDE." } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Apgar score low", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W.. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021?1?5", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210831", "receivedate": "20210831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19768830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-PFIZER INC-202101062933", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL CITRATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "019115", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 UG/KG PER HOUR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL CITRATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL CITRATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "019115", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL CITRATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SEPULVEDA, W.. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021?10.1080/15513815.2021.1963359", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210909", "receivedate": "20210831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19769380, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-TEVA-2021-CL-1955184", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "020747", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020747", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL?PEDIATR?PATHOL 2021?:NO PAGINATION.", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210917", "receivedate": "20210917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19846440, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "CL-WEST THERAPEUTIC DEVELOPMENT-2021WTD00015", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE OF 0.3 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE 3.5 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "022569", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE WAS 2 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL PEDIATR PATHOL. 2021", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210831", "receivedate": "20210831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19771183, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]
{ "abstract": "A 69-year-old man was admitted to our hospital with a 1-year history of progressive easy fatigability while walking. He presented with proximal muscle weakness dominant in the lower extremities, hoarseness, and mild dysphagia. Muscle pseudo-hypertrophy was observed in the gastrocnemius. A biopsy specimen from the left deltoid muscle revealed amyloid deposition in the blood vessels and ring-like fibers. These findings suggested amyloid myopathy. The serum and urine immunofixation electrophoresis detected κ type Bence-Jones proteins, and bone marrow examination showed an increase in atypical plasma cells; thus, we established a diagnosis of multiple myeloma. Thereafter, he experienced frequent diarrhea, and the gastrointestinal endoscopy revealed extensive amyloid deposition in the upper and lower digestive tract. We started treatment with lenalidomide and dexamethasone; however, his condition worsened, and he died of aspiration pneumonia. Amyloid myopathy indicated systemic AL amyloidosis; therefore, muscle biopsy was necessary in this case.", "affiliations": "Department of Neurology, Toyonaka Municipal Hospital.;Department of Neurology, Toyonaka Municipal Hospital.;Department of Neurology, Toyonaka Municipal Hospital.;Department of Internal Medicine (Hematology), Toyonaka Municipal Hospital.;Department of Neurology, Osaka Toneyama Medical Center.;Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP).;Department of Neurology, Toyonaka Municipal Hospital.", "authors": "Yata\|Tomohiro\|T\|;Miwa\|Takashi\|T\|;Araki\|Katsuya\|K\|;Kida\|Toru\|T\|;Toyooka\|Keiko\|K\|;Nishino\|Ichizo\|I\|;Tatsumi\|Chikao\|C\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.5692/clinicalneurol.cn-001339", "fulltext": null, "fulltext_license": null, "issn_linking": "0009-918X", "issue": "60(1)", "journal": "Rinsho shinkeigaku = Clinical neurology", "keywords": "AL amyloidosis; amyloid myopathy; multiple myeloma; muscle biopsy", "medline_ta": "Rinsho Shinkeigaku", "mesh_terms": "D000368:Aged; D001706:Biopsy; D017809:Fatal Outcome; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D008297:Male; D009101:Multiple Myeloma; D009132:Muscles", "nlm_unique_id": "0417466", "other_id": null, "pages": "60-63", "pmc": null, "pmid": "31852873", "pubdate": "2020-01-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of systemic AL amyloidosis diagnosed on muscle biopsy.", "title_normalized": "a case of systemic al amyloidosis diagnosed on muscle biopsy" }	[ { "companynumb": "JP-CELGENEUS-JPN-20200101172", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "66", "reaction": [ { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Dysphagia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "MIWA T, YATA T, ARAKI K, KIDA T, TOYOOKA K, NISHINO I. A CASE OF SYSTEMIC AL AMYLOIDOSIS DIAGNOSED ON MUSCLE BIOPSY. CLINICAL NEUROLOGY. 2020?60(1):1?4.", "literaturereference_normalized": "a case of systemic al amyloidosis diagnosed on muscle biopsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210722", "receivedate": "20200106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17236438, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "JP-CELGENE-JPN-20200101172", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Capsule", "drugdosagetext": "UNKNOWN", "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "1", "drugtreatmentdurationunit": "802", "medicinalproduct": "REVLIMID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DEXAMETHASONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNKNOWN", "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": "1", "drugtreatmentdurationunit": "802", "medicinalproduct": "LENADEX" } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "66", "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yata T, Miwa T, Araki K, Kida T, Toyooka K, Nishino I. et al. A case of systemic AL amyloidosis diagnosed on muscle biopsy. Clinical neurology. 2020; 60(1): 1-4.", "literaturereference_normalized": "a case of systemic al amyloidosis diagnosed on muscle biopsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220501", "receivedate": "20220501", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20772052, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "Combination therapy using a BRAF and MEK inhibitor significantly improves both progression-free and overall survival in patients with BRAF V600-mutated stage IV melanoma. Dual MAPK inhibition achieves an objective response in the majority of patients. We present a case of a woman with BRAF V600E-mutated malignant melanoma and rapidly progressing liver, bone, and lymph node metastases. The patient commenced dabrafenib and trametinib with clinical and biochemical signs of response after 2 days. On day 3 she developed grade 3 liver hemorrhage, which was successfully embolized. Her anemia responded appropriately to transfusions and stabilized after interventional resolution of the hemorrhagic event. Subsequently she developed a pathological fracture of the right proximal humerus. MRI showed cystic bone metastases with stigmata of bleeding. To our knowledge, this is the first case report of a patient with hemorrhage of both liver and bone metastases of a melanoma. As the patient responded rapidly to dabrafenib and trametinib we hypothesize that the hemorrhage may be due to rapid tumor necrosis and bleeding of affected tumor supplying blood vessels. Our case demonstrates the importance of considering tumoral bleeding as a side effect of BRAF and MEK inhibition in responding melanoma patients. Mechanical intervention can be effective in resolving this treatment-related adverse event.", "affiliations": "Department of Medical Oncology, General Hospital Sint-Jozef Malle, Malle.;Department of General Medical Oncology, Leuven Cancer Institute.;Department of General Medical Oncology, Leuven Cancer Institute.;Department of Radiology, University Hospitals Leuven.;Department of Radiology, University Hospitals Leuven.;Department of General Medical Oncology, Leuven Cancer Institute.", "authors": "Loyson\|Tine\|T\|;Werbrouck\|Emilie\|E\|;Punie\|Kevin\|K\|;Bonne\|Lawrence\|L\|;Vandecaveye\|Vincent\|V\|;Bechter\|Oliver\|O\|", "chemical_list": "D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib", "country": "England", "delete": false, "doi": "10.1097/CMR.0000000000000419", "fulltext": null, "fulltext_license": null, "issn_linking": "0960-8931", "issue": "28(2)", "journal": "Melanoma research", "keywords": null, "medline_ta": "Melanoma Res", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007093:Imidazoles; D008113:Liver Neoplasms; D020930:MAP Kinase Kinase Kinases; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms", "nlm_unique_id": "9109623", "other_id": null, "pages": "147-150", "pmc": null, "pmid": "29215399", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hemorrhage of liver and bone metastases as a result of rapid response to dual BRAF/MEK inhibition in metastatic melanoma: a case report.", "title_normalized": "hemorrhage of liver and bone metastases as a result of rapid response to dual braf mek inhibition in metastatic melanoma a case report" }	[ { "companynumb": "PHHY2017BE200762", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABRAFENIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "202806", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABRAFENIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMETINIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRAMETINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteorrhagia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Humerus fracture", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LOYSON T, WERBROUCK E, PUNIE K, BONNE L, VANDECAVEYE V, BECHTER O. HEMORRHAGE OF LIVER AND BONE METASTASES AS A RESULT OF RAPID RESPONSE TO DUAL BRAF/MEK INHIBITION IN METASTATIC MELANOMA: A CASE REPORT. MELANOMA RESEARCH. 2017", "literaturereference_normalized": "hemorrhage of liver and bone metastases as a result of rapid response to dual braf mek inhibition in metastatic melanoma a case report", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20180223", "receivedate": "20180223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14568463, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]
{ "abstract": "A 19-year-old male with therapy-related myelodysplastic syndrome underwent allogeneic bone marrow transplantation with reduced-intensity conditioning from his HLA-identical sibling whose ABO blood type exhibited major incompatibility with the patient. After post-transplantation 1 month, chimerism analysis of the bone marrow revealed mixed chimerism with 30% of recipient cells, and after post-transplantation 3 months, complete remission was maintained; however, recipient granulocytes were elevated up to 50% per the chimerism analysis. Next, pancytopenia developed following the rapid discontinuation of the immunosuppressive agent. Although neutrophils and platelets spontaneously recovered, anemia progressed. Based on severe erythroid hypoplasia in the bone marrow and the elevation of anti-ABO isohemagglutinin against donor-derived red blood cells, the patient was diagnosed with pure red cell aplasia (PRCA) following hematopoietic cell transplantation. Because complete chimerism was attained at the PRCA onset even for B cells, we decided to conservatively manage PRCA with only red blood cell transfusion. Notably, after 2 months of the PRCA onset, anemia improved. This case suggests that the therapeutic strategy for PRCA following hematopoietic cell transplantation should be determined by considering the status of each patient, including chimerism.", "affiliations": "Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.", "authors": "Okamoto\|Kenji\|K\|;Osone\|Shinya\|S\|;Saito\|Taeko\|T\|;Imamura\|Toshihiko\|T\|;Hosoi\|Hajime\|H\|", "chemical_list": "D000017:ABO Blood-Group System; D016572:Cyclosporine", "country": "Japan", "delete": false, "doi": "10.11406/rinketsu.59.2408", "fulltext": null, "fulltext_license": null, "issn_linking": "0485-1439", "issue": "59(11)", "journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology", "keywords": "Chimerism; Cyclosporine; Hematopoietic cell transplantation; Pure red cell aplasia", "medline_ta": "Rinsho Ketsueki", "mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D001787:Blood Group Incompatibility; D016026:Bone Marrow Transplantation; D046528:Chimerism; D016572:Cyclosporine; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D012010:Red-Cell Aplasia, Pure; D014184:Transplantation, Homologous; D055815:Young Adult", "nlm_unique_id": "2984782R", "other_id": null, "pages": "2408-2412", "pmc": null, "pmid": "30531134", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation.", "title_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation" }	[ { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-213961", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysplasia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO K, OSONE S, SAITO T, IMAMURA T, HOSOI H. [PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION]. [JAPANESE]. RINSHO KETSUEKI. 2018?JUN? 59(11):2408-2412", "literaturereference_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190718", "receivedate": "20190718", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16589444, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "JP-TEVA-2019-JP-1073580", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZACITIDINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 COURSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYELODYSPLASTIC SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZACITIDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/M2 ON DAYS -8 TO -5", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74284", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77269", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G/M2 ON DAYS -8 TO -5", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO K, OSONE S, SAITO T, IMAMURA T, HOSOI H. [PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION]. RINSHO-KETSUEKI 2018?59(11):2408-2412.", "literaturereference_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190723", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16558762, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "JP-PFIZER INC-2018531012", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINBLASTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXAL [VINBLASTINE SULFATE]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, 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"activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONCOVIN" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO, K.. PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION. 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"drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MELPHALAN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINBLASTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINBLASTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO K, OSONE S, SAITO T, IMAMURA T, HOSOI H. [PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION]. RINSHO-KETSUEKI 2018?59(11):2408-2412.. 2018?59(11):2408-2412", "literaturereference_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190703", "receivedate": "20190703", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16526413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]
{ "abstract": "We report the case of a 59-year-old patient with Heartware (Framingham, MA, USA) biventricular assist device (BIVAD) implantation who had long-term sustained ventricular fibrillation and was managed on low-molecular-weight heparin for up to two years without any adverse events. The successful outcome in this case provides a clue that the long-term management of Heartware BIVADs with low-molecular-weight heparins could be a viable option even in patients with underlying malignant arrhythmias. <Learning objective: Long-term management of Heartware biventricular assist devices (BIVADs) using low-molecular-weight heparin is possible. This treatment strategy can serve as an alternative to oral anticoagulants in a select group of patients. This case report also suggests that BIVADs can potentially serve as a useful alternative to total artificial heart.>.", "affiliations": "Division of Cardiovascular Surgery, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.;Division of Cardiovascular Surgery, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.;Division of Cardiovascular Surgery, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.", "authors": "Chandola\|Rahul\|R\|;Buchholz\|Holger\|H\|;Macarthur\|Roderick\|R\|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1016/j.jccase.2016.08.002", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-5409", "issue": "14(6)", "journal": "Journal of cardiology cases", "keywords": "Heartware; Low-molecular-weight heparin; Unfractionated heparin", "medline_ta": "J Cardiol Cases", "mesh_terms": null, "nlm_unique_id": "101549579", "other_id": null, "pages": "171-173", "pmc": null, "pmid": "30546687", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": "17670627;2680160;17470211;16156320;14967716;17670482;11213859;20958827;17437746;10715251;8236105;24239003", "title": "Long-term use of low-molecular-weight heparin in a patient with Heartware BIVAD (HVAD) with underlying sustained ventricular fibrillation.", "title_normalized": "long term use of low molecular weight heparin in a patient with heartware bivad hvad with underlying sustained ventricular fibrillation" }	[ { "companynumb": "CA-VALIDUS PHARMACEUTICALS LLC-CA-2017VAL000248", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "VENTRICULAR FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOPROLOL TARTRATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "017963", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "VENTRICULAR FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOPROLOL TARTRATE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ventricular fibrillation", "reactionmeddraversionpt": "19.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "CHANDOLA R, BUCHHOLZ H, MACARTHUR R. LONG-TERM USE OF LOW-MOLECULAR-WEIGHT HEPARIN IN A PATIENT WITH HEARTWARE BIVAD (HVAD) WITH UNDERLYING SUSTAINED VENTRICULAR FIBRILLATION. JOURNAL OF CARDIOLOGY CASES. 2016;14:171-3", "literaturereference_normalized": "long term use of low molecular weight heparin in a patient with heartware bivad hvad with underlying sustained ventricular fibrillation", "qualification": "3", "reportercountry": "CA" }, "primarysourcecountry": "CA", "receiptdate": "20170223", "receivedate": "20170223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13264760, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170428" } ]
{ "abstract": "Diffuse alveolar hemorrhage (DAH) is a life-threatening condition requiring urgent treatment. There are many different treatment-relevant causes of DAH, making the diagnostic approach to these patients complex and necessitating a multidisciplinary team. We report the case of a kidney transplant recipient in whom all diagnostic efforts did not reveal the cause of DAH, and only autopsy was able to establish an unexpected diagnosis.", "affiliations": "Institute for Pathology, University Hospital Basel, Basel, Switzerland.", "authors": "Schlageter\|Manuel\|M\|;Jahn\|Kathleen D\|KD\|;Tzankov\|Alexandar\|A\|;Wiese\|Mark\|M\|;Bubendorf\|Lukas\|L\|;Tamm\|Michael\|M\|;Savic\|Spasenija\|S\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000358566", "fulltext": null, "fulltext_license": null, "issn_linking": "0025-7931", "issue": "87(6)", "journal": "Respiration; international review of thoracic diseases", "keywords": null, "medline_ta": "Respiration", "mesh_terms": "D001163:Arteriovenous Anastomosis; D017809:Fatal Outcome; D006394:Hemangiosarcoma; D006469:Hemoptysis; D006470:Hemorrhage; D006801:Humans; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008168:Lung; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0137356", "other_id": null, "pages": "504-7", "pmc": null, "pmid": "24732422", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "An unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient.", "title_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient" }	[ { "companynumb": "PHHY2015CH136675", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse alveolar damage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Bronchopulmonary aspergillosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "SCHLAGETER M, JAHN KD, TZANKOV A, WIESE M, BUBENDORF L, TAMM M, ET AL.. AN UNEXPECTED CAUSE OF DIFFUSE ALVEOLAR HEMORRHAGE IN A KIDNEY TRANSPLANT PATIENT.. RESPIRATION. 2014?87(6):504-7", "literaturereference_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20151028", "receivedate": "20151028", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11678087, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "CH-ASTELLAS-2014EU009650", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "050708", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation Unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CORTICOSTEROID NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation Unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CORTICOSTEROID NOS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Formulation Unknown", "drugdosagetext": "UNK UNK, UNKNOWN FREQ.", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary haemorrhage", "reactionmeddraversionpt": "17.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SCHLAGETER M, JAHN KD, TZANKOV A, WIESE M, BUBENDORF L, TAMM M, ET AL.. AN UNEXPECTED CAUSE OF DIFFUSE ALVEOLAR HEMORRHAGE IN A KIDNEY TRANSPLANT PATIENT. RESPIRATION. 2014;87 (6):504-7", "literaturereference_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20140723", "receivedate": "20140723", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10335867, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20150326" }, { "companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-105814", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH-DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ALVEOLAR HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ALVEOLAR HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary alveolar haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchopulmonary aspergillosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Angiosarcoma metastatic", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCHLAGETER M, JAHN KD, TZANKOV A, WIESE M, BUBENDORF L, TAMM M, ET AL. AN UNEXPECTED CAUSE OF DIFFUSE ALVEOLAR HEMORRHAGE IN A KIDNEY TRANSPLANT PATIENT. RESPIRATION. 2014?87 (6):504-7", "literaturereference_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20151110", "receivedate": "20151110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11717947, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]
{ "abstract": "Gorham-Stout disease (GSD) is a rare disorder characterised by massive painless osteolysis due to lymphangiomatous tissue progression. GSD's pathogenesis is still unclear, but osteoclasts' activation may play a role in its pathogenesis. There are multiple complications associated with GSD. One of the most severe and life-threatening complications is a chylothorax. Herein we discuss a case of a patient with a history of GSD who presented to the hospital with progressive dyspnoea secondary to a large left-sided pleural effusion, which was later confirmed to be a chylothorax. We will further discuss the current literature and treatment of chylothorax associated with GSD.", "affiliations": "Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA [email protected].;Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA.;Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA.;Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA.", "authors": "Olea-Mendoza\|Daniel\|D\|;Terrigno\|Vittorio Romeo\|VR\|;Balogun\|Ayobamidele\|A\|;Caprio\|Colleen\|C\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2020-239891", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(3)", "journal": "BMJ case reports", "keywords": "bronchopulmonary dysplasia; haematology (incl blood transfusion); oncology; respiratory medicine; vascular surgery", "medline_ta": "BMJ Case Rep", "mesh_terms": "D002916:Chylothorax; D006801:Humans; D010015:Osteolysis, Essential; D010996:Pleural Effusion", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33692056", "pubdate": "2021-03-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Gorham-Stout disease: interesting cause of pleural effusion.", "title_normalized": "gorham stout disease interesting cause of pleural effusion" }	[ { "companynumb": "US-PFIZER INC-2021375392", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "090621", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OLEA?MENDOZA, D.. GORHAM?STOUT DISEASE: INTERESTING CAUSE OF PLEURAL EFFUSION.. BMJ CASE REPORTS. 2021?14(3):ARTICLE NUMBER E239891", "literaturereference_normalized": "gorham stout disease interesting cause of pleural effusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210503", "receivedate": "20210419", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19152978, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TILLOMED LABORATORIES LTD.-2021-EPL-001125", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "201783", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OLEA?MENDOZA D, TERRIGNO VR, BALOGUN A, CAPRIO C.. GORHAM?STOUT DISEASE: INTERESTING CAUSE OF PLEURAL EFFUSION. BMJ CASE REPORTS.. 2021?14", "literaturereference_normalized": "gorham stout disease interesting cause of pleural effusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210414", "receivedate": "20210414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19133016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-ACCORD-222451", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "205279", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID" } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pain in jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OLEA?MENDOZA D, TERRIGNO VR, BALOGUN A, CAPRIO C. GORHAM?STOUT DISEASE: INTERESTING CAUSE OF PLEURAL EFFUSION. BMJ CASE REPORTS. 2021?14(3):ARTICLE NUMBER E239891. DOI: 10.1136/BCR?2020?239891.", "literaturereference_normalized": "gorham stout disease interesting cause of pleural effusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149846, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0134166", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091186", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201578", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USE IN UNAPPROVED INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pain in jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OLEA?MENDOZA D, TERRIGNO VR, BALOGUN A, CAPRIO C. GORHAM?STOUT DISEASE: INTERESTING CAUSE OF PLEURAL EFFUSION. BMJ CASE REPORTS. 2021?14(3):ARTICLE NUMBER E239891. DOI: 10.1136/BCR?2020?239891.", "literaturereference_normalized": "gorham stout disease interesting cause of pleural effusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210414", "receivedate": "20210414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19131892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "BACKGROUND\nAtrial fibrillation (AF) patients eligible for cardioversion tend to be younger and are at lower risk than 'general' AF clinic populations. We evaluated the incidence of major bleeding and death, as well as the predictive value of the HAS-BLED score in non-valvular AF patients who underwent electrical cardioversion (ECV).\n\n\nMETHODS\nConsecutive non-valvular AF patients who underwent ECV were recruited. Major bleeding episodes and mortality were recorded. Factors associated with both endpoints and the predictive value of the HAS-BLED score were analysed.\n\n\nRESULTS\n406 patients (281 males; age 66.9±10.9years) undergoing 571 ECV were included. After a follow-up of nearly 3years, 20 patients presented with major bleeding (1.9%/year;) and 26 patients died (2.4%/year). The HAS-BLED score predicted both major bleeding [c-statistics: 0.77; 95%CI: 0.71-0.83; p<0.001] and mortality [c-statistics: 0.83; 95%CI: 0.79-0.87; p<0.001]. Variables associated with bleeding were: renal impairment (HR: 4.35; 95%CI: 1.22-15.52; p=0.02), poor quality anticoagulation (HR: 3.21; 95%CI: 1.11-9.32; p=0.03), previous bleeding-predisposition (HR: 5.43; 95%CI: 1.76-16.75; p=0.003) and the HAS-BLED score (HR: 1.88; 95%CI: 1.34-2.64; p<0.001). Factors associated with mortality were: age (HR: 1.08; 95%CI: 1.03-1.14; p=0.004), poor quality anticoagulation (HR: 3.11; 95%CI: 1.15-8.36; p=0.02), previous bleeding-predisposition (HR: 5.90; 95%CI: 1.41-24.65; p=0.01), liver impairment (HR: 9.27; 95%CI:1.64-52.34; p=0.01), the CHA2DS2-VASc score (HR: 1.63; 95%CI: 1.18-2.26; p=0.003) and the HAS-BLED score (HR: 2.74; 95%CI: 1.86-4.04); p<0.001).\n\n\nCONCLUSIONS\nIn AF patients undergoing ECV, major bleeding episodes and mortality were independently associated with poor quality anticoagulation control and previous bleeding-predisposition. The HAS-BLED score successfully predicted major bleeding and mortality.", "affiliations": "Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;Department of Cardiology, Virgen de la Arrixaca University Hospital, University of Murcia, Spain. Electronic address: [email protected].;Hematology and Medical Oncology Unit, Morales Meseguer University Hospital, University of Murcia, Spain.;Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;Department of Cardiology, Virgen de la Arrixaca University Hospital, University of Murcia, Spain.;Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.", "authors": "García-Fernández\|Amaya\|A\|;Marín\|Francisco\|F\|;Roldán\|Vanessa\|V\|;Galcerá-Jornet\|Emilio\|E\|;Martínez-Martínez\|Juan Gabriel\|JG\|;Valdés\|Mariano\|M\|;Sogorb\|Francisco\|F\|;Lip\|Gregory Y H\|GY\|", "chemical_list": "D000925:Anticoagulants", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0167-5273", "issue": "217()", "journal": "International journal of cardiology", "keywords": "Atrial fibrillation; Electrical cardioversion; HAS-BLED; Haemorrhage; Mortality; Risk factors", "medline_ta": "Int J Cardiol", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D004554:Electric Countershock; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D015996:Survival Rate", "nlm_unique_id": "8200291", "other_id": null, "pages": "42-8", "pmc": null, "pmid": "27179207", "pubdate": "2016-08-15", "publication_types": "D016428:Journal Article", "references": null, "title": "The HAS-BLED score predicts long-term major bleeding and death in anticoagulated non-valvular atrial fibrillation patients undergoing electrical cardioversion.", "title_normalized": "the has bled score predicts long term major bleeding and death in anticoagulated non valvular atrial fibrillation patients undergoing electrical cardioversion" }	[ { "companynumb": "ES-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-35540BI", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ATRIAL FIBRILLATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "19.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "GARCIA-FERNANDEZ A,MARIN F,ROLDAN V,GALCERA-JORNET E,MARTINEZ-MARTINEZ J,VALDES M,ET AL. THE HAS-BLED SCORE PREDICTS LONG-TERM MAJOR BLEEDING AND DEATH IN ANTICOAGULATED NON-VALVULAR ATRIAL FIBRILLATION PATIENTS UNDERGOING ELECTRICAL CARDIOVERSION. INTERNATIONAL JOURNAL OF CARDIOLOGY 2016;217:42-48.", "literaturereference_normalized": "the has bled score predicts long term major bleeding and death in anticoagulated non valvular atrial fibrillation patients undergoing electrical cardioversion", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "ES", "receiptdate": "20160603", "receivedate": "20160603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 12433270, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160815" } ]
{ "abstract": "Thyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. First line treatment of thyroid storm is directed towards decreasing thyroid hormone production and peripheral conversion of T4 to T3, and treating adrenergic symptoms. When medical therapy fails, plasmapheresis is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis.\nA 50-year-old male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to another hospital with fever and altered mentation. He was found to have pneumonia on imaging and was started on antibiotics. He developed shock complicated by atrial fibrillation with rapid ventricular rate which was treated with amiodarone. He was transferred to our hospital for further management. On arrival, TSH was <0.01 mIU/L, free T4 was >7 ng/dL and total T3 was 358 ng/dL. The endocrinology team determined he was in thyroid storm. His medical treatment of thyroid storm was aggressively titrated to maximal therapy. His hospital course was complicated by transaminitis, respiratory failure requiring intubation, shock requiring vasopressor support, kidney failure requiring continuous renal replacement therapy, and heart failure. Despite maximal anti-thyroid therapy, he had not improved clinically and T4 and T3 remained markedly elevated. A 4-day course of plasmapheresis was initiated resulting in marked lowering of T4 and T3 and clinical stability.\nWhile current guidelines for plasmapheresis for thyroid storm recommend individualized decision making, no further clarification is provided on who would be a good candidate for the procedure. We present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis after failing maximal medical therapy. Given the significant improvement seen with plasmapheresis, endocrinologists should consider this mode of treatment earlier in the course of thyroid storm when patients are not improving with medical therapy alone.", "affiliations": "Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.", "authors": "Miller\|Ann\|A\|https://orcid.org/0000-0002-2098-3193;Silver\|Kristi D\|KD\|https://orcid.org/0000-0002-8320-517X", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2019/2475843", "fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2019/2475843Case ReportThyroid Storm with Multiorgan Failure Treated with Plasmapheresis https://orcid.org/0000-0002-2098-3193Miller Ann https://orcid.org/0000-0002-8320-517XSilver Kristi D. [email protected] of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USAAcademic Editor: Osamu Isozaki\n\n2019 9 10 2019 2019 24758439 5 2019 15 7 2019 29 7 2019 Copyright © 2019 Ann Miller and Kristi D. Silver.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Thyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. First line treatment of thyroid storm is directed towards decreasing thyroid hormone production and peripheral conversion of T4 to T3, and treating adrenergic symptoms. When medical therapy fails, plasmapheresis is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis. \n\nCase\nA 50-year-old male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to another hospital with fever and altered mentation. He was found to have pneumonia on imaging and was started on antibiotics. He developed shock complicated by atrial fibrillation with rapid ventricular rate which was treated with amiodarone. He was transferred to our hospital for further management. On arrival, TSH was <0.01 mIU/L, free T4 was >7 ng/dL and total T3 was 358 ng/dL. The endocrinology team determined he was in thyroid storm. His medical treatment of thyroid storm was aggressively titrated to maximal therapy. His hospital course was complicated by transaminitis, respiratory failure requiring intubation, shock requiring vasopressor support, kidney failure requiring continuous renal replacement therapy, and heart failure. Despite maximal anti-thyroid therapy, he had not improved clinically and T4 and T3 remained markedly elevated. A 4-day course of plasmapheresis was initiated resulting in marked lowering of T4 and T3 and clinical stability. \n\nConclusion\nWhile current guidelines for plasmapheresis for thyroid storm recommend individualized decision making, no further clarification is provided on who would be a good candidate for the procedure. We present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis after failing maximal medical therapy. Given the significant improvement seen with plasmapheresis, endocrinologists should consider this mode of treatment earlier in the course of thyroid storm when patients are not improving with medical therapy alone.\n==== Body\n1. Background\nThyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. Thyroid storm has an estimated mortality rate of 20%–30% [1]. First line treatment of thyroid storm is directed at decreasing thyroid hormone production and peripheral conversion of thyroxine (T4) to triiodothyronine (T3), and treating adrenergic symptoms. When medical therapy fails, therapeutic plasma exchange (TPE), also called therapeutic plasmapheresis, is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was successfully treated with TPE.\n\n2. Case\nA 50-year-old African American male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to an outside hospital with fever and an altered mental status. He was diagnosed with hyperthyroidism about three months prior to hospitalization. He was started on methimazole (MMI), but compliance taking the medication was low. His primary care provider had recommended thyroidectomy; however, he was unable to have the procedure due to lack of health insurance. On presentation to the outside hospital, imaging revealed right lower lobe pneumonia with an effusion and he was started on antibiotics. His clinical status deteriorated, and he developed shock complicated by atrial fibrillation with rapid ventricular rate with documented rates in the 140–190 beats per minute. His arrhythmia was refractory to digoxin, diltiazem, and two attempts at cardioversion with 200 Joules. He was initiated on an amiodarone infusion which stabilized his arrhythmia. His TSH documented at the outside hospital was 0.01 mIU/L and free T4 was 8 ng/dL.\n\nHe was transferred to our hospital for further management. Prior to transfer, he was started on hydrocortisone 50 mg every 6 hours and MMI 10 mg three times daily. MMI was used instead of propylthiouracil (PTU) due to elevated liver function tests. On the day of arrival to our hospital, the inpatient endocrinology team was consulted for assistance with thyroid management. He was intubated for respiratory distress at the time of the endocrinology team's initial assessment. His blood pressure, supported by two pressors, was 90/63 mmHg. His temperature was 36.9˚C and his pulse ranged from 88 to 134 beats per minute on the amiodarone infusion. Physical examination was significant for scleral icterus and left neck fullness. No thyroid bruit or discrete nodules were identified; however, the neck exam was limited due to multiple central lines. His heart beat was irregular consistent with atrial fibrillation and a cardiac murmur was also detected. Lower extremities were notable for edema and hyperreflexia. The endocrinology team was unable to assess his mental status due to the patient being sedated. Thyroid labs on admission to our hospital included TSH <0.01 mIU/L (0.47–4.68 mIU/L), total T3 358 ng/dL (97–169 ng/dL), free T4 > 7 ng/dL (0.6–2.5 ng/dL) and thyroid stimulating antibodies >500% (normal ≤122%). Additional laboratory studies (Table 1) showed acute kidney injury and elevated liver function tests, troponin, and white blood cell count. Thyroid ultrasound with doppler showed an enlarged, heterogeneous thyroid gland, more pronounced on the right than the left without any nodules, although the view of the left side was limited due to the endotracheal tube and central line.\n\nHis Burch–Wartofsky score [2] for hyperthyroid storm was 100 which was highly concerning for thyroid storm. As the Burch–Wartofsky score can sometimes be misleading with elevated scores in critically ill patients without thyroidal illness, the Japan Thyroid Association thyroid storm criteria, a diagnostic criterion less likely to incorrectly diagnose thyroid storm in critically ill patients, was also utilized to assess for thyroid storm in our patient [3]. Employing this second diagnostic criterion, our patient again met criteria for thyroid storm based on the family report of altered mental status, tachycardia with documented rates of 140–190 per minute, heart failure with an estimated ejection fraction of 30%, and thyrotoxicosis with suppressed TSH and elevated free T4 and total T3 levels.\n\nThe endocrine consult team recommended increasing MMI to 20 mg three times daily and starting cholestyramine 4 g three times daily. Over the ensuing days, his renal function worsened such that he required continuous renal replacement therapy. On day 2, saturated potassium iodide solution (SSKI) 250 mg three times daily was initiated and cholestyramine was increased to 4 g four times daily. Liver function tests improved by day 3; therefore, he was switched from MMI to PTU 200 mg three times daily to take advantage of the decreased conversion of T4 to T3 seen with PTU. On day 4, TSH remained undetectable and free T4 was unchanged at >7 ng/dL. Total T3 began to decrease, but remained >200 ng/dL. Despite maximal medical therapy for thyroid storm, his clinical status continued to worsen with evidence of multiorgan failure. The endocrinology team consulted the hematology physicians for initiation of TPE.\n\nHe was started on daily TPE on hospital day 4. Replacement fluid contained half fresh frozen plasma (FFP) and half 5% albumin and was equal in volume to his total plasma volume (about 4L). His TPE treatment lasted about two hours each day and he received plasmapheresis daily for four days. After the first day of TPE, his free T4 and total T3 decreased to 5.3 ng/dL and 139 ng/dL, respectively. After 4 sessions of daily TPE, his free T4 was 1.9 ng/dL and total T3 was 77 ng/dL (Figure 1). With TPE, his clinical course significantly improved to the point where he was weaned off of pressors and extubated. Over the following 2 weeks, he was safely titrated off of SSKI and hydrocortisone, and switched from PTU to MMI. For definitive treatment of hyperthyroidism, the endocrine surgery team was consulted to evaluate the patient for total thyroidectomy. At the time of their evaluation, the patient was clinically euthyroid. Given his recent critical illness, the surgeons considered him to be a high-risk surgical candidate. Therefore, they recommended performing an elective thyroidectomy once the patient was further out from his critical illness and had undergone outpatient cardiac optimization. He was discharged home three weeks later on MMI 30 mg twice daily and cholestyramine 4 g twice daily. At time of discharge, he did not require any supplemental oxygen and his left ventricular ejection fraction improved to 48% as measured on positron emission tomography myocardial perfusion scan. He was no longer in atrial fibrillation as he had converted back to sinus rhythm and amiodarone had been discontinued. With the exception of total bilirubin, his liver function tests had normalized before discharge. By 2 months post discharge, his total bilirubin had also normalized. He was discharged with intermittent dialysis needs, though two weeks after leaving the hospital, dialysis was discontinued because his kidney function recovered.\n\n3. Discussion\nPlasmapheresis is an extracorporeal blood purification technique that helps remove larger molecular weight substances from blood. Plasmapheresis is a general term that refers to removing plasma from blood. TPE is a type of plasmapheresis that involves removal of patient plasma and replacing it with something else (either donor plasma, colloid, or crystalloid). TPE is most often used to treat conditions, where a pathogenic substance or component is in the blood and needs to be rapidly removed. Examples of pathogenic substances include auto-antibodies, immunocomplexes, cryoglobulins, myeloma light chains, endotoxins, cholesterol containing lipoproteins, and as with our patient, plasma protein-bound thyroid hormones. The necessary tools for TPE include vascular access, either using large-bore needles in the limb veins or an implanted catheter in the large veins of the neck, chest, or groin, and a plasmapheresis machine. The machine separates the patient's plasma from the rest of the blood components and exchanges plasma with a replacement fluid. TPE is effective for treatment of thyroid storm as thyroid hormone is almost entirely bound to plasma proteins (99.97% of total serum T4 and 99.7% of total serum T3). The three main plasma proteins that bind T4 and T3 are thyroxine binding globulin (TBG), transthyretin, and albumin. TBG binds 75% of T4 and T3. Transthyretin binds 20% of T4 and <5% of T3. Albumin binds 5% of T4 and 20% of T3. TBG and transthyretin are relatively similar in size, 54 kDa and 55 kDa, respectively. Albumin is larger with a molecular mass of 66.5 kDa [4]. Because of the size of thyroid binding proteins, conventional dialysis cannot remove these proteins from blood. In contrast, TPE removes larger proteins, and thus can be used to reduce circulating thyroid hormone and treat refractory thyroid storm. TPE can also remove TSH receptor autoantibody (also referred to as thyroid stimulating immunoglobulin) and its removal has been predicted mathematically to result in rapid lowering of the free thyroxine levels [5].\n\nRandomized placebo-controlled studies of TPE with medical management resistant thyroid storm have not been performed due to the rarity of the disorder. Therefore, guidelines for the use of TPE for thyroid storm are based on case reports, retrospective studies, and expert opinion. According to The American Society for Apheresis 2016 clinical practice guidelines, treatment of thyroid storm with plasmapheresis is a category III indication [6] meaning that the optimal role of TPE in thyroid storm is not established and the decision to use TPE for this indication should be individualized. Per these guidelines, when plasmapheresis is used to treat thyroid storm, FFP or albumin should be used as the replacement fluid. FFP has the benefit of increasing the concentration of TBG, which binds specifically to thyroxine and triiodothyronine, while albumin provides greater capacity for binding thyroid hormone. The recommended volume of replacement fluid is 1–1.5 times the total plasma volume. TPE treatment should be daily to every 3 days until clinical improvement is noted. TPE should be reserved for patients with severe symptoms of thyroid storm in whom first line medical therapies have failed or have had detrimental side effects that outweigh the benefits of treatment. These guidelines are similar to the guidelines set forth by The Japan Thyroid Association and Japan Endocrine Society in 2016 [7]. The Japanese guidelines recommend the use of TPE for treatment of thyroid storm if there is acute liver failure or no clinical improvement after 24–48 hours on optimized medical management. The Japanese guidelines recommend FFP over albumin as the replacement fluid due to its higher levels of TBG and specificity to bind thyroid hormone.\n\nThe effectiveness of TPE is dependent on multiple variables and is not a procedure without risk. The successful removal of pathogenic substances from blood through plasmapheresis depends on the volume of blood processed and plasma exchanged in each procedure, number of procedures performed, frequency of exchange, and rate of mobilization, stabilization, and re-synthesis of the cells or plasma components. Complications of plasmapheresis include bleeding, infection, disseminated intravascular coagulation (DIC), coagulation factor depletion leading to hypocoagulability, hypocalcemia, hypotension, and transfusion reactions such as transfusion associated infections, pulmonary edema, and pulmonary embolism. Despite these potential complications, the mortality rate of plasmapheresis is <1% [8].\n\nAshkar et al. first described thyrotoxicosis treated with plasmapheresis in 1970 in a case report of three thyrotoxic patients [9]. All three patients had deteriorating clinical status despite maximal medical treatment of thyrotoxicosis. The first patient underwent true TPE as his plasma was replaced with his red blood cells and lactate ringers. The other two patients were treated with plasmapheresis with removal of plasma with only their red blood cells returned to them. All three patients had significant clinical improvement. Since this initial description, case reports have described successful treatment with TPE in a variety of hyperthyroid scenarios ranging from post-operative thyroid storm complicated by pneumonia and septic shock [10] to MMI induced agranulocytosis [11] to amiodarone induced thyrotoxicosis [12]. While patients previously described as receiving plasmapheresis for thyroid storm were often critically ill, few have had multisystem organ failure similar to our patient. Of the few with multiorgan failure, one with a history of Graves' and medication noncompliance developed symptomatic thyrotoxicosis including palpitations, nausea, and vomiting. He was treated with medical therapy, but had to be switched from PTU to MMI due to liver dysfunction. He clinically decompensated despite medical therapy and developed DIC. He was treated with plasmapheresis and after two treatments, his free T4 and free T3 normalized. The same paper discusses a male with Graves' disease who also presented with thyrotoxicosis symptoms and medication noncompliance. This patient was started on oral medical therapy with MMI 20 mg daily and propranolol 40 mg twice daily. Shortly after admission, he became febrile with a temperature of 38.1°C and was found unresponsive and pulseless. He underwent cardiopulmonary resuscitation. He developed ventricular fibrillation and required electrical cardioversion. His clinical status further worsened with development of transaminitis and acute kidney injury with continued tachyarrhythmia. Neurologically, he was unresponsive off of sedation. After one day of plasmapheresis, his free T4 declined from 10.9 ng/dL to 8.57 ng/dL. He received two more treatments of plasmapheresis daily over the next two days. His free T4 continued to trend downwards as he continued to receive methimazole, SSKI, and steroids. While the paper does not talk about his neurological status after TPE, it did say that he became clinically and biochemically euthyroid and underwent definitive treatment with a total thyroidectomy [13]. Similarly, in a case reported by Baena et al., a 36-year-old woman with Graves' disease and multiorgan failure including acute liver and heart failure, acute kidney injury, cytopenia, rhabdomyolysis and coagulopathy improved with the use of medical management plus plasmapheresis [14].\n\nBecause of the infrequent use of TPE for treatment of thyroid storm/thyrotoxicosis, randomized controlled studies on its efficacy versus continuing with only maximal medical therapy have not yet been performed. Few retrospective reviews on TPE with thyroid storm involving more than one or two patients have been published. In a review by Ezer et al., 11 thyrotoxicosis patients successfully responded to pre-operative plasmapheresis treatment [15]. The etiologies of thyrotoxicosis (7-Graves' Disease, 3-toxic multinodular goiters, 1-iodine induced thyrotoxicosis) and the indications for plasmapheresis varied (7-poor response to medical therapy, 2-agranulocytosis, 1-iodine induced thyrotoxicosis and 1-urgent need for operation). All patients underwent plasmapheresis prior to surgery (10 patients underwent total thyroidectomy and 1 patient underwent an open reduction and internal fixation for femur fracture). The majority of patients required 1 to 3 plasmapheresis sessions to see clinical improvement and reductions in free T4 levels. Only one patient experienced a complication from plasmapheresis, a non-life threatening allergic reaction. Another patient had intraoperative bleeding from operative sites assumed to be secondary to the coagulopathy that can develop from TPE. Additionally, 50% of patients who underwent total thyroidectomy developed transient postoperative hypocalcemia. Hypocalcemia was presumed to be the result of long-term exposure to thyroid hormones with severe untreated hyperthyroidism, though postoperative hypocalcemia may have been due to parathyroid injury during surgery. Hyperthyroidism increases bone turnover which over time can lead to thyrotoxic osteodystrophy. After total thyroidectomy for hyperthyroidism, hypocalcemia can result from rapid recalcification of bones after loss of thyroid hormone stimulation [16].\n\nIn the largest retrospective study to date, 46 patients with thyrotoxicosis who were either unable to use anti-thyroid medications due to side effects, did not improve with standard thyrotoxicosis treatment or needed rapid improvement in thyroid function due to thyroid storm were treated with TPE [17]. Plasmapheresis was performed daily with sessions lasting 2.5–3 hours. The replacement fluid was FFP and the volume of replacement fluid was 1–1.5 times the calculated total plasma volume of the patient. The underlying etiology for the majority of the patients' thyrotoxicosis was Graves' disease with smaller numbers having amiodarone induced thyrotoxicosis or toxic nodular goiter. A significant improvement in free T4 levels from before to after plasmapheresis (free T4 2.9 ng/dL vs. 1.6 ng/dL, P ≤ 0.001) was found in all patients. When stratified by hyperthyroid diagnosis, only the patients with Graves' disease had a statistically significant reduction in free T4 levels with TPE (free T4 2.9 ng/dL vs. 1.6 ng/dL, P ≤ 0.001). While not statistically significant, possibly due to smaller numbers of subjects, the median free T4 did decrease after TPE in the patients with non-Graves' hyperthyroidism (free T4 3.1 ng/dL vs. 1.8 ng/dL, P = NS). In this study, complications related to TPE comprised of a deep vein thrombosis in a pregnant female and 2 catheter infections.\n\n4. Conclusion\nWhile current recommendations regarding TPE for treatment of thyroid storm recommend individualized decision making, little clarification regarding who would be a good candidate is available. In our case report, we present a patient with thyroid storm and multiorgan failure who was ineffectively treated with maximal medical anti-thyroid therapy alone, but was rapidly and successfully treated once plasmapheresis was added to medical anti-thyroid therapy. Our case is one of the first to show that a patient with severe critical multiorgan failure can benefit from TPE. Given our patient's extraordinary recovery and the remarkable improvements in other patients with thyroid storm treated with TPE, endocrinologists should have a lower threshold to pursue treatment of thyroid storm with plasmapheresis if patients are not improving with medical antithyroid therapy alone. Future research is needed to answer questions regarding optimal replacement fluid and volume, frequency, and duration at which TPE should proceed for thyroid storm.\n\nAbbreviations\nMMI:Methimazole\n\nPTU:Propylthiouracil\n\nSSKI:Saturated potassium iodide solution\n\nTPE:Therapeutic plasma exchange\n\nT4:Thyroxine\n\nTBG:Thyroxine binding globulin\n\nT3:Triiodothyronine.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Free T4 and total T3 Levels during hospitalization. ∗Values were >7 ng/dL, → first day of plasmapheresis.\n\nTable 1 Admission laboratory studies.\n\nLab\tResult\tReference range\t\nWBC\t29.7\t4.5–11.0 K/µL\t\nHemoglobin\t10.3\t12.6–17.4 g/dL\t\nPlatelets\t149\t153–367 K/µL\t\nCreatinine\t1.43\t0.66–1.25 mg/dL\t\nAST\t177\t17–59 units/L\t\nALT\t44\t21–72 units/L\t\nTotal bilirubin\t3.8\t0.3–1.2 mg/dL\t\nLactate\t2.8\t0.5–1.6 mmol/L\t\nTroponin\t7.05\t≤0.06 ng/mL\n==== Refs\n1 Tietgens S. T. Leinung M. C. Thyroid storm Medical Clinics of North America 1995 79 1 169 184 10.1016/S0025-7125(16)30090-6 2-s2.0-0028861298 7808090 \n2 Burch H. B. Wartofsky L. Life-threatening thyrotoxicosis. thyroid storm Endocrinology and Metabolism Clinics of North America 1993 22 2 263 277 10.1016/S0889-8529(18)30165-8 8325286 \n3 Akamizu T. Satoh T. Isozaki O. Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys Thyroid 2012 22 7 661 679 10.1089/thy.2011.0334 2-s2.0-84863428154 22690898 \n4 Pappa T. Ferrara A. M. Refetoff S. Inherited defects of thyroxine-binding proteins Best Practice & Research Clinical Endocrinology & Metabolism 2015 29 5 735 747 10.1016/j.beem.2015.09.002 2-s2.0-84945974045 26522458 \n5 Leow M. K.-S. A mathematical model of pituitary–thyroid interaction to provide an insight into the nature of the thyrotropin–thyroid hormone relationship Journal of Theoretical Biology 2007 248 2 275 287 10.1016/j.jtbi.2007.05.016 2-s2.0-34548039279 17602707 \n6 Schwartz J. Padmanabhan A. Aqui N. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the american society for apheresis: the seventh special issue Journal of Clinical Apheresis 2016 31 3 149 162 10.1002/jca.21470 2-s2.0-84975795988 27322218 \n7 Satoh T. Isozaki O. Suzuki A. Guidelines for the management of thyroid storm from the Japan thyroid association and Japan endocrine society (first edition) Endocrine Journal 2016 63 12 1025 1064 10.1507/endocrj.EJ16-0336 2-s2.0-85007618830 27746415 \n8 Huestis D. W. Mortality in therapeutic haemapheresis The Lancet 1983 321 8332 p. 1043 10.1016/S0140-6736(83)92664-8 2-s2.0-0021096795 \n9 Ashkar F. S. Katims R. B. Smoak W. M. Thyroid storm treatment with blood exchange and plasmapheresis JAMA: The Journal of the American Medical Association 1970 214 7 1275 1279 10.1001/jama.214.7.1275 5536311 \n10 Petry J. Van Schil P. E. Y. Abrams P. Jorens P. G. Plasmapheresis as effective treatment for thyrotoxic storm after sleeve pneumonectomy The Annals of Thoracic Surgery 2004 77 5 1839 1841 10.1016/S0003-4975(03)01246-3 2-s2.0-1942532740 15111206 \n11 Vyas A. A. Vyas P. Fillipon N. L. Vijayakrishnan R. Trivedi N. Successful treatment of thyroid storm with plasmapheresis in a patient with methimazole-induced agranulocytosis Endocrine Practice 2010 16 4 673 676 10.4158/EP09265.CR 2-s2.0-79952020460 20439250 \n12 Diamond T. H. Rajagopal R. Ganda K. Manoharan A. Luk A. Plasmapheresis as a potential treatment option for amiodarone-induced thyrotoxicosis Internal Medicine Journal 2004 34 6 369 370 10.1111/j.1444-0903.2004.00600.x 2-s2.0-3242812001 15228405 \n13 Carhill A. Gutierrez A. Lakhia R. Nalini R. Surviving the storm: two cases of thyroid storm successfully treated with plasmapheresis BMJ Case Reports 2012 2012 10.1136/bcr2012-006696 \n14 Baena J. C. Padilla J. Guzman G. Thyroid storm associated with multiorganic dysfunction Medicina (B Aires) 2017 77 4 337 440 28825582 \n15 Ezer A. Caliskan K. Parlakgumus A. Belli S. Kozanoglu I. Yildirim S. Preoperative therapeutic plasma exchange in patients with thyrotoxicosis Journal of Clinical Apheresis 2009 24 3 111 114 10.1002/jca.20200 2-s2.0-67449168623 19484727 \n16 Karunakaran P. Maharajan C. Ramalingam S. Rachmadugu S. V. Is hungry bone syndrome a cause of postoperative hypocalcemia after total thyroidectomy in thyrotoxicosis? a prospective study with bone mineral density correlation Surgery 2018 163 2 367 372 10.1016/j.surg.2017.09.008 2-s2.0-85035103440 29146231 \n17 Simsir I. Y. Ozdemir M. Duman S. Erdogan M. Donmez A. Ozgen A. G. Therapeutic plasmapheresis in thyrotoxic patients Endocrine 2018 62 1 144 148 10.1007/s12020-018-1661-x 2-s2.0-85049573906 29968224\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-651X", "issue": "2019()", "journal": "Case reports in endocrinology", "keywords": null, "medline_ta": "Case Rep Endocrinol", "mesh_terms": null, "nlm_unique_id": "101576457", "other_id": null, "pages": "2475843", "pmc": null, "pmid": "31687222", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "20439250;15228405;5536311;15111206;27322218;26522458;7808090;23087271;6133078;28825582;8325286;22690898;19484727;17602707;29146231;27746415;29968224", "title": "Thyroid Storm with Multiorgan Failure Treated with Plasmapheresis.", "title_normalized": "thyroid storm with multiorgan failure treated with plasmapheresis" }	[ { "companynumb": "US-TEVA-2021-US-1994480", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74079", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Arrhythmia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIGOXIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Arrhythmia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIGOXIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHIMAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM DAILY; 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{ "abstract": "The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is life-threatening. It associates a skin condition with hematological and visceral disorders. The DRESS syndrome diagnosis in the intensive care unit (ICU) is difficult as clinical features are nonspecific. Furthermore, the need to treat patients with multiple drugs usually prevents the identification of the causative drug. We report the case of a patient who developed two bouts of DRESS caused by piperacillin-tazobactam, the first being complicated with a distributive shock. Cases of DRESS occurring inside ICU are seldom reported. However, any intensivist may encounter this situation during his career and should be aware of its diagnostic and management specific aspects.", "affiliations": "Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département de Néonatologie et de Réanimation Néonatale, Hôpital Femme Mère Enfant, 32 Avenue Doyen Jean Lépine, 69500 Bron, France.;Département d'Allergologie et d'Immunologie Clinique, Centre Hospitalier de Lyon-Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France; Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France.", "authors": "Moriceau\|Florent\|F\|0000-0003-1699-6757;Prothet\|Johanne\|J\|;Blaise\|Benjamin J\|BJ\|;Ben Said\|Benoit\|B\|;Page\|Mathieu\|M\|;Ber\|Charles-Eric\|CE\|;Crozon\|Jullien\|J\|;Rimmelé\|Thomas\|T\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/9453286", "fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2016/9453286Case ReportDRESS Syndrome in the ICU: When a Patient Is Treated with Multiple Drugs http://orcid.org/0000-0003-1699-6757Moriceau Florent \n1\n\n\nProthet Johanne \n1\nBlaise Benjamin J. \n2\nBen Said Benoit \n3\nPage Mathieu \n1\nBer Charles-Eric \n1\nCrozon Jullien \n1\nRimmelé Thomas \n1\n\n4\n1Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France2Département de Néonatologie et de Réanimation Néonatale, Hôpital Femme Mère Enfant, 32 Avenue Doyen Jean Lépine, 69500 Bron, France3Département d'Allergologie et d'Immunologie Clinique, Centre Hospitalier de Lyon-Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France4Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, FranceFlorent Moriceau: [email protected] Editor: Caterina Mammina\n\n2016 24 1 2016 2016 945328622 11 2015 4 1 2016 Copyright © 2016 Florent Moriceau et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is life-threatening. It associates a skin condition with hematological and visceral disorders. The DRESS syndrome diagnosis in the intensive care unit (ICU) is difficult as clinical features are nonspecific. Furthermore, the need to treat patients with multiple drugs usually prevents the identification of the causative drug. We report the case of a patient who developed two bouts of DRESS caused by piperacillin-tazobactam, the first being complicated with a distributive shock. Cases of DRESS occurring inside ICU are seldom reported. However, any intensivist may encounter this situation during his career and should be aware of its diagnostic and management specific aspects.\n==== Body\n1. Introduction\nThe DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome is a severe drug hypersensitivity reaction. Although it is less known than Lyell or Stevens-Johnson syndromes and less striking than anaphylactic shock, it can result in a dreadful prognosis, with a mortality rate of 2 to 45% [1–3]. DRESS occurring in an intensive care unit (ICU) is a complex situation. It can mimic more usual causes of shock and organ failure, such as sepsis. Furthermore, identifying the responsible treatment may not be straightforward due to the multiple drugs use in the intensive care unit. Finally, the necessity to remove any suspected treatment will make the patient's management more complicated. We report the case of DRESS induced by piperacillin-tazobactam initially identified as a septic shock and reoccurring after the inappropriate reintroduction of a suspected treatment. The patient's family gave a written consent to report this case.\n\n2. Case Report\nA 53-year-old woman was admitted to the ICU due to angiocholitis complicated by a septic shock. She had a medical history of high blood pressure and, despite two episodes of kidney transplantation, she had recently reached end-stage renal disease. She was under antihypertensive therapy and immunosuppressant drugs (prednisolone, mycophenolate, and cyclosporine).\n\nThe early evolution was positive with a probabilistic antibiotherapy associating piperacillin-tazobactam and amikacin. It was decreased to ceftriaxone alone on the fifth day, after the identification of a biliary Klebsiella pneumoniæ pneumoniæ (Figure 1). On the 21st day after the ICU admission, the patient developed another septic shock due to angiocholitis, forcing the reintroduction of the initial probabilistic antibiotherapy. On the 23rd day, the antibiotherapy was modified again to ceftriaxone and vancomycin, after the bloodstream identification of a Pantoea agglomerans and a coagulase-negative Staphylococcus. A third round of septic shock occurred on the 26th day leading us to widen the antibiotherapy, associating piperacillin-tazobactam and amikacin to the already administered vancomycin (Figure 1).\n\nFollowing this last modification, a benign-looking rash appeared on the patient's chest on the 29th day. After 48 h of hemodynamic stability, a high fever and a distributive shock requiring consequent norepinephrine infusion (1 μg/kg/min) emerged. The procalcitonin measurement reached a high level (2.98 μg/L), which was compatible with sepsis. However, the rash evolved into erythrodermia (Figure 2), associated with enlarged cervical and inguinal lymph nodes, eosinophilia (absolute eosinophil count of 1.0 × 109/L), agranulocytosis (absolute neutrophil count of 0.4 × 109/L), and activated circulating T-lymphocytes. These elements led to the diagnosis of DRESS syndrome.\n\nAll drugs introduced at least ten days before the rash were interrupted, except for vasopressors. Vancomycin was replaced by linezolid. A systemic corticotherapy with methylprednisolone (1 mg/kg/d) was initiated, along with the use of granulocyte colony-stimulating factors (G-CSF).\n\nEosinophilia reached a maximum of 4.2 × 109/L on the 32nd day, associated with a thrombocytopenia and a nonregenerative anemia. A myelogram revealed a hypoplastic bone marrow, mostly composed of eosinophils (30%) without hemophagocytic lymphohistiocytosis. A skin biopsy showed basal membrane vacuoles, spongiosis, and an inflammatory infiltration of dermis, described as activated lymphocytes and eosinophils. The Epstein-Barr Virus (EBV) load was found elevated at 700 copies/mL. No differential diagnosis was identified.\n\nThe cutaneous condition improved within 10 days, from the chest to the limbs, with a reepithelialization following a desquamation and blisters. Eosinophilia and agranulocytosis normalized within five days. However, the nonregenerative anemia and the thrombocytopenia remained.\n\nVancomycin was initially suspected. Therefore, piperacillin-tazobactam was used again during another bout of sepsis, after the identification of a sensitive Klebsiella pneumoniæ pneumoniæ (Figure 1). Erythrodermia reoccurred immediately following this reintroduction, with early eosinophilia (absolute eosinophil count of 1.0 × 109/L), deep agranulocytosis (undetectable neutrophils), and hyperlactatemia (3.2 mmol/L), but without hemodynamic instability. This new DRESS was associated with EBV reactivation (viral load of 5,200 copies/mL). A new myelogram reported a highly hypoplastic bone marrow, with more eosinophils (40%) than previously counted, and the noticeable absence of neutrophilic cells. We thus interrupted the piperacillin-tazobactam administration and increased methylprednisolone up to 2 mg/kg/d. Cutaneous and hematological conditions improved within two weeks. This recurrence clearly incriminated piperacillin-tazobactam.\n\nLater evolution was unfortunately negative, with numerous ICU-associated adverse events (ventilator-associated pneumonia, neuromyopathy, and severe malnutrition). The patient died of septic shock complications triggered by pneumonia, on day 102 after ICU admission.\n\n3. Discussion\nAn occurrence of DRESS inside the ICU is difficult to diagnose, and its management is not obvious. In addition, the intensive care specific aspects are seldom mentioned in the literature.\n\nThe DRESS syndrome is a delayed hypersensitivity reaction. Its clinical features include a cutaneous reaction (almost 100% of cases, usually maculopapular, often itchy and extensive to the whole body), a facial edema (76%), a polyadenopathy (54%), a fever (90%), and an organ involvement (91%, either liver, lung, brain, kidney, or heart) [2, 4, 5]. Mortality ranges from 2 to 45% depending on the severity of the organ involvement [1–3, 6]. Few cases of shock have recently been reported, highlighting the need to mention the DRESS syndrome in the diagnosis algorithm of a distributive shock [6]. Hematological abnormalities include a possible eosinophilia (95%) which can be delayed, with either lymphopenia (5%) or lymphocytosis, and often circulating activated T-lymphocytes (67%), as observed in infectious mononucleosis [2]. A hemophagocytic lymphohistiocytosis is not uncommon. It is associated with a worse prognosis and sometimes preceded by biological marker raises (hyperferritinemia, hypertriglyceridemia, and elevated lactate dehydrogenase levels). Procalcitonin can rise regardless of any sepsis [5].\n\nThe pathophysiology of the organ involvement is multifactorial and still not fully understood. Human herpes-virus family reactivations, their local proliferation, and the cytotoxic immune response they induce may be involved. Indeed, viral DNAs have been identified in affected organs, but no causal link has yet been established [3, 7, 8]. The viral load is a diagnosis criterion in some countries [9]. Descamps and Ranger-Rogez also reported a genetic predisposition that influences cytotoxic T-lymphocytes response [5].\n\nThe list of medications that may potentially induce DRESS keeps growing and includes more than 40 drugs. The most frequent triggers are (in descending order) anticonvulsants (carbamazepine, lamotrigine, phenobarbital, phenytoin, and sodium valproate), allopurinol, psychotropic drugs, sulfonamides (dapsone, sulfasalazine, and sulfamethoxazole), antiviral therapies, and antibiotics (mostly vancomycin and beta-lactam antibiotics) [2, 4, 10, 11]. The DRESS syndrome is a relatively rare drug reaction with an incidence of 1/5000 for anticonvulsants [12]. It occurs with a median delay of 22 days after the administration of the causal treatment [2]. Any drug initiated one to four weeks before the rash must be suspected. In the intensive care unit, the use of multiple medications may prevent the identification of the responsible drug. This is usually achieved after full recovery, through further allergological investigations such as skin or immunobiological tests (lymphocytes proliferation and cytokine production assays). In this case, the antibiotic changes increased the number of potential causal drugs. Vancomycin was the initial main suspect as it is the most common trigger for DRESS among antibiotics [2], and as the 10-day delay between introduction and symptoms was compatible with the pathophysiology of the DRESS. Furthermore, piperacillin-tazobactam had seldom been related to DRESS at that time, with only three cases reported [13–15]. Since then, Cabañas et al. have added 8 more [16]. Interestingly, piperacillin-tazobactam had been used only 24 hours before the last onset of symptoms. The delay of the symptoms onset can indeed be dramatically shortened in the case of a previous exposure, as the sensitized antigen-specific T-lymphocytes can remain activated for years [17, 18]. Thus, we observed a shortened delay and an intensified reaction when DRESS reoccurred.\n\nRuling out the differential diagnoses is an additional difficulty in the ICU. DRESS can indeed complicate an underlying condition, such as sepsis with which it shares many clinical features. Kardaun et al. [4] suggested a score that classifies cases as definite, probable, possible, or no case. Relevant clinical features were fever, enlarged lymph nodes, a skin condition, and a late resolution (more than 15 days). Additional criteria were hematological abnormalities (eosinophilia, activated circulating lymphocytes), a compatible skin biopsy, and organ involvement. They also considered the unfruitful research of differential diagnoses, after ruling out autoimmune diseases (lupus, Kawasaki disease), infectious diseases (mononucleosis or other viral exanthems, toxic shock syndrome), and hematological diseases (angioimmunoblastic lymphoma, hypereosinophilic syndrome), to be relevant. In the present case, Kardaun's score reached 8 points, making the diagnosis of DRESS syndrome certain.\n\nThe key element in the management of a patient with DRESS is the early and permanent withdrawal of every suspected medication. The use of strong topical steroids is sufficient for mild cases. Severe cases will require the use of a systemic corticotherapy (methylprednisolone 1-2 mg/kg/d). In our case, the early corticotherapy initiated with 1 mg/kg/d of methylprednisolone allowed a general improvement but did not prevent the recurrence. Full recovery will generally be obtained after weeks, even with an early and optimal management [5]. Intravenous immunoglobulins are no longer recommended due to their frequent secondary effects and lack of benefit compared to corticotherapy [19]. A granulopoietic stimulant (G-CSF) can be discussed. On one hand, it may shorten the duration of agranulocytosis. On the other hand, it may redirect the immune response of T4 lymphocytes from the hyperactivated T helper 1 (Th-1) response to the Th-2 response [20, 21]. Viral reactivations may benefit from a specific treatment.\n\n4. Conclusion\nAny intensivist may encounter or may have to manage a patient with DRESS syndrome. In the ICU, clinical features and organ involvement have a poor specificity. The suspicious drugs are often numerous due to the many treatments used. The prognosis relies on organ failure and delay to the treatment initiation. The early and permanent withdrawal of every suspected causal agent is of primary importance. Any reintroduction of a drug exposes the patient to the risk of a more severe recurrence.\n\nDisclosure\nAll the authors have approved the final paper.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 The chronology of events and drugs use related to DRESS occurrences. D: day; TZP: piperacillin-tazobactam; AMK: amikacin; CTX: ceftriaxone; VA: vancomycin; IMP: imipenem; LIN: linezolid; MP: methylprednisolone. Day 1: admission to the ICU.\n\nFigure 2 Erythrodermia in ICU ventilated patient. Focus on the chest showing a maculopapular rash.\n==== Refs\n1 Bocquet H. Bagot M. Roujeau J. C. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Seminars in Cutaneous Medicine and Surgery 1996 15 4 250 257 10.1016/S1085-5629(96)80038-1 2-s2.0-0030441359 9069593 \n2 Kardaun S. H. Sekula P. Valeyrie-Allanore L. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study British Journal of Dermatology 2013 169 5 1071 1080 10.1111/bjd.12501 2-s2.0-84887102194 23855313 \n3 Eshki M. Allanore L. Musette P. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure Archives of Dermatology 2009 145 1 67 72 10.1001/archderm.145.1.67 2-s2.0-58849091724 19153346 \n4 Kardaun S. H. Sidoroff A. Valeyrie-Allanore L. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? British Journal of Dermatology 2007 156 3 609 611 10.1111/j.1365-2133.2006.07704.x 2-s2.0-33846997845 17300272 \n5 Descamps V. Ranger-Rogez S. DRESS syndrome Joint Bone Spine 2014 81 1 15 21 10.1016/j.jbspin.2013.05.002 2-s2.0-84893747138 23816504 \n6 Kimmoun A. Dubois E. Perez P. Barbaud A. Levy B. Shock state: an unrecognized and underestimated presentation of drug reaction with eosinophilia and systemic symptoms Shock 2013 40 5 387 391 10.1097/shk.0000000000000041 2-s2.0-84887101009 24088996 \n7 Mardivirin L. Descamps V. Lacroix A. Delebassée S. Ranger-Rogez S. Early effects of drugs responsible for DRESS on HHV-6 replication in vitro \n Journal of Clinical Virology 2009 46 3 300 302 10.1016/j.jcv.2009.08.006 2-s2.0-72149134631 19758840 \n8 Mardivirin L. Valeyrie-Allanore L. Branlant-Redon E. Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on human herpesvirus 6 replication in vitro European Journal of Dermatology 2010 20 1 68 73 10.1684/ejd.2010.0821 2-s2.0-76749119336 19822481 \n9 Shiohara T. Iijima M. Ikezawa Z. Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations British Journal of Dermatology 2007 156 5 1083 1084 10.1111/j.1365-2133.2007.07807.x 2-s2.0-34247329801 17381452 \n10 Cacoub P. Musette P. Descamps V. The DRESS syndrome: a literature review American Journal of Medicine 2011 124 7 588 597 10.1016/j.amjmed.2011.01.017 2-s2.0-79959337439 21592453 \n11 Um S. J. Lee S. K. Kim Y. H. Clinical features of drug-induced hypersensitivity syndrome in 38 patients Journal of Investigational Allergology and Clinical Immunology 2010 20 7 556 562 2-s2.0-79251486696 21313995 \n12 Tennis P. Stern R. S. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study Neurology 1997 49 2 542 546 10.1212/wnl.49.2.542 2-s2.0-0030749007 9270593 \n13 Jurado-Palomo J. Cabañas R. Prior N. Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillintazobactam: two case reports Journal of Investigational Allergology and Clinical Immunology 2010 20 5 433 436 2-s2.0-78649363676 20945612 \n14 Cabañas R. Muñoz L. López-Serrano C. Hypersensitivity to piperacillin Allergy 1998 53 8 819 820 2-s2.0-0031878164 9722239 \n15 Fahim S. Jain V. Victor G. Pierscianowski T. Piperacillin-tazobactam-induced drug hypersensitivity syndrome Cutis 2006 77 6 353 357 2-s2.0-33745844489 16838767 \n16 Cabañas R. Calderón O. Ramírez E. Piperacillin-induced DRESS: distinguishing features observed in a clinical and allergy study of 8 patients Journal of Investigational Allergology and Clinical Immunology 2014 24 6 425 430 2-s2.0-84918812712 25668894 \n17 Wu Y. Farrell J. Pirmohamed M. Park B. K. Naisbitt D. J. Generation and characterization of antigen-specific CD4+ , CD8+ , and CD4+ CD8+ T-cell clones from patients with carbamazepine hypersensitivity Journal of Allergy and Clinical Immunology 2007 119 4 973 981 10.1016/j.jaci.2006.12.617 2-s2.0-34047103842 17320939 \n18 Rozieres A. Vocanson M. Saïd B. B. Nosbaum A. Nicolas J.-F. Role of T cells in nonimmediate allergic drug reactions Current Opinion in Allergy and Clinical Immunology 2009 9 4 305 310 10.1097/ACI.0b013e32832d565c 2-s2.0-68649096857 19474707 \n19 Joly P. Janela B. Tetart F. Poor benefit/risk balance of intravenous immunoglobulins in DRESS Archives of Dermatology 2012 148 4 543 544 10.1001/archderm.148.4.dlt120002-c 2-s2.0-84859958072 22508885 \n20 Nishio D. Izu K. Kabashima K. Tokura Y. T cell populations propagating in the peripheral blood of patients with drug eruptions Journal of Dermatological Science 2007 48 1 25 33 10.1016/j.jdermsci.2007.05.013 2-s2.0-34548031382 17601705 \n21 Franzke A. Piao W. Lauber J. G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases Blood 2003 102 2 734 739 10.1182/blood-2002-04-1200 2-s2.0-0037818348 12676791\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2016()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "9453286", "pmc": null, "pmid": "26904309", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "19758840;19474707;17320939;17300272;25668894;21313995;17601705;22508885;9722239;12676791;23816504;20945612;21592453;19822481;17381452;16838767;23855313;9069593;9270593;24088996;19153346", "title": "DRESS Syndrome in the ICU: When a Patient Is Treated with Multiple Drugs.", "title_normalized": "dress syndrome in the icu when a patient is treated with multiple drugs" }	[ { "companynumb": "FR-PFIZER 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Cholangitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Pantoea agglomerans infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Hyperlactacidaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neuromyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Distributive shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20120502" } }, "primarysource": { "literaturereference": "MORICEAU, F.. DRESS SYNDROME IN THE ICU: WHEN A PATIENT IS TREATED WITH MULTIPLE DRUGS. CASE REPORTS IN CRITICAL CARE (ONLINE). 2016;9453286", "literaturereference_normalized": "dress syndrome in the icu when a patient is treated with multiple drugs", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160427", "receivedate": "20160325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12211272, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "During the coronavirus disease 2019 (COVID-19) pandemic, a rapid screening method for COVID-19 detection is needed to decide the appropriate strategy to treat stroke patients. In acute ischemic stroke treatment, the efficacy and safety of emergent carotid artery stenting (eCAS) for hyperacute ischemic stroke (hAIS) due to internal carotid artery stenosis (ICS) have not been sufficiently established.\n\n\n\nA 71-year-old man with hAIS caused by severe ICS was treated via intravenous alteplase infusion. The patient underwent screening for COVID-19 by the loop-mediated isothermal amplification (LAMP) assay shortly after arrival at our institution. The LAMP result was obtained within 90 minutes, during intravenous alteplase infusion, and turned out to be negative. The symptom of hemiplegia worsened during alteplase infusion, and he, therefore, underwent eCAS after administration of aspirin (200 mg). Recanalization was achieved successfully by eCAS, and dual antiplatelet therapy and argatroban were administrated following eCAS. Hemorrhagic complications or restenosis/occlusion of the carotid artery were not observed. He was discharged without neurologic deficits 15 days following eCAS. Because of the rapid negative diagnosis for COVID-19 using the LAMP method, eCAS could be performed following standard procedures, along with infectious defense, without delay.\n\n\n\nThis case report suggests that eCAS for hAIS due to ICS following intravenous alteplase can be an effective treatment, along with appropriate antiplatelet medication and management in select patients. During the COVID-19 pandemic, the LAMP assay for COVID-19 detection might be a suitable diagnostic strategy preceding stroke treatment because of the rapid turnaround time.", "affiliations": "Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan. Electronic address: [email protected].;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.", "authors": "Michiwaki\|Yuhei\|Y\|;Tanaka\|Tatsuya\|T\|;Wakamiya\|Tomihiro\|T\|;Tabei\|Yusuke\|Y\|;Samura\|Kazuhiro\|K\|;Suehiro\|Eiichi\|E\|;Kawashima\|Masatou\|M\|", "chemical_list": "D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban", "country": "United States", "delete": false, "doi": "10.1016/j.wneu.2020.09.166", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-8750", "issue": "145()", "journal": "World neurosurgery", "keywords": "Acute ischemic stroke; Alteplase; COVID-19; Carotid artery stenting; Emergency; LAMP assay", "medline_ta": "World Neurosurg", "mesh_terms": "D000368:Aged; D001120:Arginine; D000086382:COVID-19; D016893:Carotid Stenosis; D003131:Combined Modality Therapy; D005343:Fibrinolytic Agents; D006429:Hemiplegia; D006801:Humans; D000083242:Ischemic Stroke; D008279:Magnetic Resonance Imaging; D008297:Male; D025202:Molecular Diagnostic Techniques; D021141:Nucleic Acid Amplification Techniques; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D015607:Stents; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "101528275", "other_id": null, "pages": "356-359", "pmc": null, "pmid": "33045450", "pubdate": "2021-01", "publication_types": "D002363:Case Reports", "references": "32295835;31978945;32228369;32333644;25517348;25671798;25671797;18403765;22170821;25882510;27725550;32277754;26898852;32361529;25882376;22115640;32387786;15891193;7477192;32276116;32253352;32233980;18815396", "title": "Emergent Carotid Artery Stenting Following Intravenous Alteplase Infusion After Rapid Negative Diagnosis for COVID-19 by Loop-Mediated Isothermal Amplification Assay.", "title_normalized": "emergent carotid artery stenting following intravenous alteplase infusion after rapid negative diagnosis for covid 19 by loop mediated isothermal amplification assay" }	[ { "companynumb": "JP-ROCHE-2714241", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC STROKE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": ".6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTILYSE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "103172", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CAROTID ARTERY STENOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTILYSE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DABIGATRAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hemiplegia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "MICHIWAKI Y, TANAKA T, WAKAMIYA T, TABEI Y, SAMURA K, SUEHIRO E, ET AL. EMERGENT CAROTID ARTERY STENTING FOLLOWING INTRAVENOUS ALTEPLASE INFUSION AFTER RAPID NEGATIVE DIAGNOSIS FOR COVID-19 BY LOOP-MEDIATED ISOTHERMAL AMPLIFICATION ASSAY.. WORLD NEUROSURGERY. ?145:356-359.", "literaturereference_normalized": "emergent carotid artery stenting following intravenous alteplase infusion after rapid negative diagnosis for covid 19 by loop mediated isothermal amplification assay", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201117", "receivedate": "20201117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18511451, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]
{ "abstract": "OBJECTIVE\nTricyclic antidepressants (TCAs) are still widely used and are available to purchase without prescription in some countries. Awareness of adverse cutaneous drug reactions is essential.\n\n\nMETHODS\nWe reported a case of photo-distributed hyperpigmentation due to imipramine and carried out a systematic search of the related articles using the search terms \"tricyclic antidepressants\" or \"tricyclic antidepressive agents\", and \"hyperpigmentation\" or \"photosensitivity disorder\". Fifty non-duplicate citations were identified of which 28 articles which were independently assessed in full. The review was registered in PROSPERO, CRD42018107338.\n\n\nRESULTS\nThe remaining 25 articles met our inclusion criteria. Photo-distributed hyperpigmentation tricyclic antidepressant-induced photosensitivity reactions (TIPs) was the most common presentation. In 21 cases, this presented as an asymptomatic discolouration of exposed sites. Imipramine (81%), amitriptyline (9.5%), desipramine hydrochloride (4.8%) and mirtazapine (4.8%) were reported to be the culprit drugs. Nineteen were female with a mean age at presentation of 55 years. Mean duration from commencing the culprit drug until the development of discolouration was 10.4 years. Mean daily dose was 222.7 mg for imipramine. Histology was characteristic with golden-brown or brownish granules deposited in dermis. Staining for Masson-Fontana and MEL-5 was positive in all cases. Phototesting had not been done in cases prior to ours (negative 3 months after discontinuation of imipramine). Three further reports of suspected TIP presented with non-specific and eczematous eruption. The two presentations were reported along with systemic problems (thrombocytopenia and hepatic injury).\n\n\nCONCLUSIONS\nThis systematic review highlights the characteristic features of exposed site hyperpigmentation of TCA-induced photosensitivity occurring after prolonged drug exposure in many cases.", "affiliations": "Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Dermatopathology Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.", "authors": "Boontaveeyuwat\|Einapak\|E\|;Steyn\|Mia\|M\|;Rickaby\|William\|W\|;Mcfadden\|John P\|JP\|;Sarkany\|Robert P E\|RPE\|;Fityan\|Adam\|A\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/phpp.12724", "fulltext": null, "fulltext_license": null, "issn_linking": "0905-4383", "issue": null, "journal": "Photodermatology, photoimmunology & photomedicine", "keywords": "hyperpigmentation; imipramine; photocontact allergy; phototoxicity; tricyclic antidepressants", "medline_ta": "Photodermatol Photoimmunol Photomed", "mesh_terms": null, "nlm_unique_id": "9013641", "other_id": null, "pages": null, "pmc": null, "pmid": "34358364", "pubdate": "2021-08-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Tricyclic antidepressant-induced photosensitivity; A case report and systematic review.", "title_normalized": "tricyclic antidepressant induced photosensitivity a case report and systematic review" }	[ { "companynumb": "GB-LUPIN PHARMACEUTICALS INC.-2022-05648", "fulfillexpeditecriteria": "2", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMIPRAMINE PAMOATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090444", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMIPRAMINE PAMOATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCUSATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCUSATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Depression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CHOLECALCIFEROL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Photosensitivity reaction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Skin hyperpigmentation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Boontaveeyuwat E, Steyn M, Rickaby W, Mcfadden JP, Sarkany RPE, Fityan A. Tricyclic antidepressant-induced photosensitivity; a case report and systematic review. Photodermatology Photoimmunology and Photomedicine. 2022;38(2):112-122", "literaturereference_normalized": "tricyclic antidepressant induced photosensitivity a case report and systematic review", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20220430", "receivedate": "20220418", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20720100, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]
{ "abstract": "The mortality associated with unresectable or metastatic melanoma remains high despite of the emergence of new anti-tumor agents. In this case report, we present two metastatic melanoma patients with copy number variations (CNVs) of cyclin dependent kinase 4 (CDK4) pathway-related genes, who had failed in previous chemotherapy or immunotherapy, were treated with CDK4/6 inhibitor palbociclib and achieved tumor control for over 6 months. The copy number of CDK4, CCND1 and P16INK4a of one patient was 3.6, 3, 2 copies, and for the other patient, the copy number was 3, 2, 1 respectively. It indicates that CDK4 may be a potential target for melanoma.", "affiliations": "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China. [email protected].", "authors": "Tang\|Bixia\|B\|;Sheng\|Xinan\|X\|;Kong\|Yan\|Y\|;Chi\|Zhihong\|Z\|;Si\|Lu\|L\|;Cui\|Chuanliang\|C\|;Yan\|Xieqiao\|X\|;Mao\|Lili\|L\|;Lian\|Bin\|B\|;Li\|Siming\|S\|;Wang\|Xuan\|X\|;Dai\|Jie\|J\|;Bai\|Xue\|X\|;Zhou\|Li\|L\|;Guo\|Jun\|J\|", "chemical_list": "D010879:Piperazines; D011725:Pyridines; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib", "country": "China", "delete": false, "doi": "10.21037/cco.2018.06.08", "fulltext": null, "fulltext_license": null, "issn_linking": "2304-3865", "issue": "7(6)", "journal": "Chinese clinical oncology", "keywords": "Metastatic; cyclin dependent kinase 4 (CDK4); melanoma; mutation; palbociclib", "medline_ta": "Chin Clin Oncol", "mesh_terms": "D000328:Adult; D051358:Cyclin-Dependent Kinase 4; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008545:Melanoma; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines; D011725:Pyridines", "nlm_unique_id": "101608375", "other_id": null, "pages": "62", "pmc": null, "pmid": "30180747", "pubdate": "2018-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Palbociclib for treatment of metastatic melanoma with copy number variations of CDK4 pathway: case report.", "title_normalized": "palbociclib for treatment of metastatic melanoma with copy number variations of cdk4 pathway case report" }	[ { "companynumb": "CN-MYLANLABS-2019M1001482", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205227", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENDOSTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENDOSTAR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC MALIGNANT MELANOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TANG B, SHENG X, KONG Y, CHI Z, SI L, CUI C, ET AL. PALBOCICLIB FOR TREATMENT OF METASTATIC MELANOMA WITH COPY NUMBER VARIATIONS OF CDK4 PATHWAY: CASE REPORT. CHIN-CLIN-ONCOL 2018?7:NO. 6.", "literaturereference_normalized": "palbociclib for treatment of metastatic melanoma with copy number variations of cdk4 pathway case report", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190110", "receivedate": "20190110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15807392, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" } ]
{ "abstract": "BACKGROUND\nINI1-deficient undifferentiated rhabdoid carcinoma is a rare pancreatic carcinoma for which the optimal treatment is unknown. Pancreatic ductal adenocarcinoma, the most common histology of pancreas cancer, is treated with combination chemotherapy in the advanced setting, a strategy supported by strong evidence in well powered studies. In patients with excellent performance status, first-line treatment usually consists of the three-drug regimen FOLFIRINOX, with the combination of gemcitabine with nab-paclitaxel, typically less toxic than the three-drug regimen, reserved for second-line therapy. Given the lack of published reports describing treatment outcomes for patients with rare forms of pancreatic cancer, the same treatment approach used for pancreatic ductal adenocarcinoma is typically employed.\n\n\nMETHODS\nThis case describes a patient with metastatic pancreatic INI1-deficient undifferentiated rhabdoid carcinoma who was primarily resistant to FOLFIRINOX therapy but who then achieved an immediate, marked and sustained response to gemcitabine with nab-paclitaxel.\n\n\nCONCLUSIONS\nGiven the lack of data informing on optimal management of INI1-deficient pancreatic undifferentiated rhabdoid carcinoma, and the exceptional response achieved by gemcitabine with nab-paclitaxel, this case report highlights a surprising and potentially informative anecdote. Additional studies are needed to confirm responses observed in this report which when taken together may strongly influence first-line therapy choice for this rare malignancy. Given the difficult in acquiring sufficient numbers of these rare histologies in any one institution, multi-institution collaboration in studying outcomes of rare pancreatic malignancies is likely essential.", "affiliations": "Department of Medicine, Stanford University, Stanford, CA, USA.;Department of Medicine, Stanford University, Stanford, CA, USA.;Department of Pathology, Stanford University, Stanford, CA, USA.;Department of Medicine, Stanford University, Stanford, CA, USA.", "authors": "King\|Daniel A\|DA\|;Rahalkar\|Smruti\|S\|;Bingham\|David B\|DB\|;Fisher\|George A\|GA\|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/jgo-20-478", "fulltext": null, "fulltext_license": null, "issn_linking": "2078-6891", "issue": "12(2)", "journal": "Journal of gastrointestinal oncology", "keywords": "INI1-deficient undifferentiated rhabdoid carcinoma; case report; pancreatic cancer; sarcomatoid undifferentiated carcinoma", "medline_ta": "J Gastrointest Oncol", "mesh_terms": null, "nlm_unique_id": "101557751", "other_id": null, "pages": "874-879", "pmc": null, "pmid": "34012674", "pubdate": "2021-04", "publication_types": "D002363:Case Reports", "references": "20195681;31433515;26372701;22409864;26151040;21345145;30980040;31146420;25103069;27811314;11420713;21934399;20979179;27528705;26941181;21561347", "title": "Pancreatic INI1-deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab-paclitaxel following immediate progression on FOLFIRINOX: a case report.", "title_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report" }	[ { "companynumb": "US-CELGENEUS-USA-20210505777", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "041", "drugauthorizationnumb": "021660", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABRAXANE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201911" } }, "primarysource": { "literaturereference": "DANIEL A K. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. JOURNAL OF GASTROINTESTINAL ONCOLOGY. 2021 APR 01?12(2): 874?879:.", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210529", "receivedate": "20210529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19333074, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "NVSC2021US116990", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUCOVORIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLINIC ACID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "78817", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, 3 DOSES", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancreatic carcinoma metastatic", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KING DA, RAHALKAR S, BINGHAM DB, FISHER GA. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. JOURNAL OF GASTROINTESTINAL ONCOLOGY. 2021?12(2):874?9", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210804", "receivedate": "20210804", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19657698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0135960", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091365", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201907" } }, "primarysource": { "literaturereference": "KING D, RAHALKAR S, BINGHAM B, FISHER A. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. J GASTROINTEST ONCOL. 2021?12(2):874?9. 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METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FREQUENCY WAS REDUCED TO EVERY OTHER WEEK AFTER 2 MONTHS OF THERAPY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", 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"drugdosageform": null, "drugdosagetext": "100 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FREQUENCY WAS REDUCED TO EVERY OTHER WEEK AFTER 2 MONTHS OF THERAPY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201906" } }, "primarysource": { "literaturereference": "KING DA, RAHALKAR S, BINGHAM DB, FISHER GA. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. J?GASTROINTEST?ONCOL 2021?12(2):874?879.", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210602", "receivedate": "20210602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19367270, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1920111", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "079160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078589", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAB?PACLITAXEL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "079160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201906" } }, "primarysource": { "literaturereference": "KING DA, RAHALKAR S, BINGHAM DB, FISHER GA. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. J?GASTROINTEST?ONCOL 2021?12(2):874?879.", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210621", "receivedate": "20210610", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19399945, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Hyponatraemia is the commonest electrolyte abnormality and has major clinical implications. However, few studies of hyponatraemia in the primary care setting has been published to date.\n\n\n\nTo determine the prevalence, potential causes and management of hyponatraemia and to identify factors associated with severity of hyponatraemia among older persons in a primary care setting.\n\n\n\nElectronic records were searched to identify all cases aged ≥60 years with a serum sodium <135mmol/l, attending outpatient clinic in 2014. Patients' medical records with the available blood test results of glucose, potassium, urea and creatinine were reviewed.\n\n\n\nOf the 21,544 elderly, 5873 patients (27.3%) had electrolyte profile tests. 403 (6.9%) had hyponatraemia in at least one blood test. Medical records were available for 253, mean age 72.9±7.3 years, 178 (70.4%) had mild hyponatraemia, 75 (29.6%) had moderate to severe hyponatraemia. Potential causes were documented in 101 (40%). Patients with moderate to severe hyponatraemia were five times more likely to have a cause of hyponatraemia documented (p<0.01). Medications were the commonest documented cause of hyponatraemia (31.7%). Hydrochlorothiazide use was attributed in 25 (78.1%) of 32 with medication-associated hyponatraemia. Repeat renal profile (89%) was the commonest management of hypotonic hyponatraemia.\n\n\n\nWhilst hyponatraemia was common in the clinic setting, many cases were not acknowledged and had no clear management strategies. In view of mild hyponatraemia has deleterious consequences, future studies should determine whether appropriate management of mild hyponatraemia will lead to clinical improvement.", "affiliations": "Simpang Health Clinic, Taiping, Perak, Malaysia. [email protected].;Institute of Applied Health Sciences, School of Medicine, Medical Sciences & Nutrition College of Life Sciences & Medicine, University of Aberdeen, United Kingdom.;University of Malaya Medical Centre, Department of Primary Care Medicine, Kuala Lumpur, Malaysia.;Aberdeen Royal Infirmary Foresterhill, Department of Geriatric Medicine, Aberdeen, United Kingdom.;University of Malaya Medical Centre, Department of Medicine, Geriatric Unit, Kuala Lumpur, Malaysia.", "authors": "Tay\|C L\|CL\|;Myint\|P K\|PK\|;Mohazmi\|M\|M\|;Soiza\|R L\|RL\|;Tan\|M P\|MP\|", "chemical_list": null, "country": "Malaysia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-5283", "issue": "74(2)", "journal": "The Medical journal of Malaysia", "keywords": null, "medline_ta": "Med J Malaysia", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D007010:Hyponatremia; D015994:Incidence; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011320:Primary Health Care; D012720:Severity of Illness Index", "nlm_unique_id": "0361547", "other_id": null, "pages": "121-127", "pmc": null, "pmid": "31079122", "pubdate": "2019-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic.", "title_normalized": "prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic" }	[ { "companynumb": "MY-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-251389", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "070043", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAY CL, MYINT PK, MOHAMED M, SOIZA RL, TAN MP. PREVALENCE AND DOCUMENTED CAUSES OF HYPONATRAEMIA AMONG GERIATRIC PATIENTS ATTENDING A PRIMARY CARE CLINIC. MED J MALAYSIA. 2019?74(2):121?127", "literaturereference_normalized": "prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17982842, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "MY-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-214220", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40810", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAY CL, MYINT PK, MOHAMED M, SOIZA RL, TAN MP. PREVALENCE AND DOCUMENTED CAUSES OF HYPONATRAEMIA AMONG GERIATRIC PATIENTS ATTENDING A PRIMARY CARE CLINIC. MED J MALAYSIA. 2019?74(2):121?127", "literaturereference_normalized": "prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17982271, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Mycobacterium chelonae is a rapidly growing mycobacterium that has the potential to cause refractory infections in humans. Mycobacteremia resulting from the organism is extremely rare, and its clinical features are yet to be uncovered. We herein present a case of M. chelonae bloodstream infection involving an immunocompromised older patient. A 79-year-old woman, on a long-term treatment with prednisolone plus tacrolimus for rheumatoid arthritis, visited our outpatient department complaining of deteriorating pain and swelling at her right 1st toe. Laboratory parameters showed elevated C-reactive protein and leukocytosis, and magnetic resonance imaging indicated osteomyelitis at the proximal phalanx of her right 1st toe. Considering the refractory course, the infected toe was immediately amputated. M. chelonae was isolated from bacterial cultures of the resected tissue and blood (BD BACTEC™ FX blood culture system, Becton Dickinson, Sparks, MD, USA), leading to a diagnosis of disseminated M. chelonae infection. We treated the patient with an antibiotic combination of clarithromycin, minocycline, and imipenem (2 weeks), which was converted to oral therapy of clarithromycin, doxycycline, and levofloxacin. This case highlighted the potential pathogenesis of M. chelonae to cause mycobacteremia in an immunocompromised patient.", "affiliations": "Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address: [email protected].;Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.", "authors": "Ueda\|Yayoi\|Y\|;Tokumasu\|Kazuki\|K\|;Hagiya\|Hideharu\|H\|;Iio\|Koji\|K\|;Fujimori\|Takumi\|T\|;Kakehi\|Ayaka\|A\|;Okura\|Mami\|M\|;Minabe\|Hiroshi\|H\|;Otsuka\|Fumio\|F\|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jiac.2020.03.004", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": "26(8)", "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": "Mycobacteremia; Mycobacterium chelonae; Non-tuberculous mycobacteria; Osteomyelitis; Rapidly growing mycobacteria; Rheumatoid arthritis", "medline_ta": "J Infect Chemother", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008279:Magnetic Resonance Imaging; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D010019:Osteomyelitis; D014034:Toes; D016896:Treatment Outcome", "nlm_unique_id": "9608375", "other_id": null, "pages": "843-846", "pmc": null, "pmid": "32402735", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe: A case report.", "title_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report" }	[ { "companynumb": "JP-PBT-000359", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090802", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Osteomyelitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, IIO K, FUJIMORI T, KAKEHI A, ET AL. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. J INFECT CHEMOTHER. 2020 MAY 10:S1341-321X(20)30082-9. DOI: 10.1016/J.JIAC.2020.03.004.", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200601", "receivedate": "20200601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17845745, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "JP-TEVA-2020-JP-1824693", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM DAILY; LONG?TERM THERAPY, HAD BEEN RECEIVING FOR 3 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM DAILY; 250MG TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN?CLAVULANATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM DAILY; LONG?TERM THERAPY, HAD BEEN RECEIVING FOR 2 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "26.5", "reaction": [ { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteomyelitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, IIO K, FUJIMORI T, KAKEHI A, ET AL. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. J?INFECT?CHEMOTHER 2020?26(8):843?846.", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200915", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18239995, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "JP-ACCORD-183152", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LONG-TERM TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LONG-TERM TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "26.5", "reaction": [ { "reactionmeddrapt": "Osteomyelitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, IIO K, FUJIMORI T, KAKEHI A, ET AL. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. J INFECT CHEMOTHER. 2020 MAY 10:S1341-321X(20)30082-9.", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200604", "receivedate": "20200528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17833241, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "JP-BAUSCH-BL-2020-014862", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "26.5", "reaction": [ { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, LIO K, FUJIMORI T, KAKEHI A, OKURA M, MINABE H, OTSUKA F. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. JOURNAL OF INFECTION AND CHEMOTHERAPY. 2020 MAY 10?1-4. DOI:10.1016/J.JIAC.2020.03.004", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200526", "receivedate": "20200526", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17826593, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]

{ "abstract": "Subglottic hemangioma is a potentially life-threatening manifestation of the PHACES syndrome. The disease process has been treated with corticosteroids, oral chemotherapeutic agents, endoscopic airway interventions, tracheostomy, and even laryngotracheal reconstruction. Oral propranolol has emerged as an effective therapy and in many cases has led to complete regression of hemangioma during the proliferative phase. There have been several reports of patients showing signs of reproliferation after discontinuing propranolol therapy. This article illustrates a patient who has had multiple episodes of reproliferation of subglottic hemangioma after weaning from propranolol therapy.", "affiliations": "Division of Otolaryngology, Department of Surgery, Texas A&M College of Medicine/Scott and White Memorial Hospital Program, Temple, Texas.;Division of Otolaryngology, Department of Surgery, Baylor Scott and White McLane Children's Hospital, Temple, Texas.", "authors": "Holdgraf|Randall W|RW|;Kress|Melissa|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1080/08998280.2017.1415547", "fulltext": null, "fulltext_license": null, "issn_linking": "0899-8280", "issue": "31(2)", "journal": "Proceedings (Baylor University. Medical Center)", "keywords": "PHACES syndrome; propranolol; subglottic hemangioma", "medline_ta": "Proc (Bayl Univ Med Cent)", "mesh_terms": null, "nlm_unique_id": "9302033", "other_id": null, "pages": "194-196", "pmc": null, "pmid": "29706817", "pubdate": "2018-04", "publication_types": "D002363:Case Reports", "references": "19858157;20674045;25721095;20643720;22082463;18676554;16172341;15510009", "title": "The PHACES syndrome: Multiple episodes of reproliferation of subglottic hemangioma.", "title_normalized": "the phaces syndrome multiple episodes of reproliferation of subglottic hemangioma" }

[ { "companynumb": "US-PFM-2019-06245", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile haemangioma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.25", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.6 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.0 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.67 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.67", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "4", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile haemangioma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "3", "patientonsetageunit": "803", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Stridor", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug titration error", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Holdgraf RW, Kress M. The PHACES syndrome: multiple episodes of reproliferation of subglottic hemangioma. Bayl Univ Med Cent Proc. 2018;31:194-6", "literaturereference_normalized": "the phaces syndrome multiple episodes of reproliferation of subglottic hemangioma", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220614", "receivedate": "20220614", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20955276, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "The objective of this manuscript is to describe the challenges of Cardio-Cerebral Infarction (CCI) treatment and to highlight the variable approaches in management. CCI is a rare clinical presentation of simultaneous acute ischemic stroke (AIS) and acute myocardial infarction (AMI) and poses a therapeutic challenge for practitioners. Each disease requires timely intervention to prevent irreversible damage; however, optimal management remains unclear. We describe three cases of CCI. All three patients presented with symptomatic left MCA (M1) occlusion, with ST elevation myocardial infarction (STEMI) and left ventricular apical thrombus. Fibrinolysis and mechanical thrombectomy (MT) were discussed in all cases, but only one patient received alteplase (0.9 mg/kg) and none underwent MT. Percutaneous intervention (PCI) was done in only one case. The two patients that did not receive thrombolysis were treated with modified therapeutic heparin (no bolus), and all received antiplatelet therapy. Ultimately, all three patients passed away. CCI poses a clinical challenge for physicians including (1) optimal strategies to enable swift mechanical reperfusion to both the brain and myocardium; (2) difference in dosage of thrombolytics for AIS versus AMI; (3) risk of symptomatic intracerebral hemorrhage following administration of anticoagulation and/or antiplatelet therapy; and (4) caution with use of thrombolytics in the setting of acute STEMI due to the risk of myocardial rupture. In the absence of high quality evidence and clinical guidelines, treatment of CCI is highly individualized.", "affiliations": "Department of Neurology and Neurocritical Care, The Ohio State University, 395 West 12th Avenue, 7th Floor, Columbus, OH, 43210, USA. [email protected].;Department of Neurology and Neurocritical Care, The Ohio State University, 395 West 12th Avenue, 7th Floor, Columbus, OH, 43210, USA.;Department of Neurology and Neurocritical Care, The Ohio State University, 395 West 12th Avenue, 7th Floor, Columbus, OH, 43210, USA.", "authors": "Ibekwe|Elochukwu|E|http://orcid.org/0000-0002-0339-6384;Kamdar|Hera A|HA|;Strohm|Tamara|T|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.1007/s10072-021-05628-x", "fulltext": null, "fulltext_license": null, "issn_linking": "1590-1874", "issue": null, "journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology", "keywords": "Acute ischemic stroke; Alteplase; Cardio-cerebral infarct; Cerebral ischemia; Myocardial infarct", "medline_ta": "Neurol Sci", "mesh_terms": null, "nlm_unique_id": "100959175", "other_id": null, "pages": null, "pmc": null, "pmid": "34590206", "pubdate": "2021-09-29", "publication_types": "D016428:Journal Article", "references": "32281601;23247304;24495655;11023929;24703066;27105568;28220330;31555206;20977759;31318627;15769776;31662037;31893142;22552166;16974058;29018137;28886621;842403;31277605;10475182;24363753;31327296;25692111;31971093;15956123;25306124;30484009;23151669;32829200;18715661;28302386;16505298;28450663;6465861;29270151;33530272;31436141;33045929;27333833;33446625;19608993", "title": "Cardio-cerebral infarction in left MCA strokes: a case series and literature review.", "title_normalized": "cardio cerebral infarction in left mca strokes a case series and literature review" }

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}, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "Unknown,ASKED BUT UNKNOWN,ASKED BUT", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "WITH INFUSION AT 28.7 MG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ischaemic stroke", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "Unknown,ASKED BUT UNKNOWN,ASKED BUT", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.9 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".9", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALTEPLASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Cerebrovascular accident", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.9%", "drugenddate": null, "drugenddateformat": null, "drugindication": "Oedema", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Prophylaxis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM CHLORIDE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Ibekwe E, Kamdar H, Strohm T. Cardio-cerebral infarction in left MCA strokes: a case series and literature review. Neurological Sciences. 2021;:-.", "literaturereference_normalized": "cardio cerebral infarction in left mca strokes a case series and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211006", "receivedate": "20211006", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19925099, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" } ]

{ "abstract": "ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT.\n\n\n\nTwenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 ≤ age < 18; n = 10).\n\n\n\nThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection.\n\n\n\nABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases.", "affiliations": "Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.;Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.", "authors": "Honda|Masaki|M|;Sugawara|Yasuhiko|Y|;Kadohisa|Masashi|M|;Shimata|Keita|K|;Sakisaka|Masataka|M|;Yoshii|Daiki|D|;Uto|Keiichi|K|;Hayashida|Shintaro|S|;Ohya|Yuki|Y|;Yamamoto|Hidekazu|H|;Yamamoto|Hirotoshi|H|;Inomata|Yukihiro|Y|;Hibi|Taizo|T|", "chemical_list": "D000017:ABO Blood-Group System; D005938:Glucocorticoids; D007518:Isoantibodies; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.1097/TP.0000000000002197", "fulltext": "\n==== Front\nTransplantationTransplantationTPTransplantation0041-13371534-6080Lippincott Williams & Wilkins TP50148210.1097/TP.000000000000219700025Original Clinical Science—LiverLong-term Outcomes of ABO-incompatible Pediatric Living Donor Liver Transplantation Honda Masaki MD, PhD1Sugawara Yasuhiko MD, PhD1Kadohisa Masashi MD1Shimata Keita MD1Sakisaka Masataka MD, PhD1Yoshii Daiki MD, PhD1Uto Keiichi MD1Hayashida Shintaro MD1Ohya Yuki MD, PhD1Yamamoto Hidekazu MD, PhD1Yamamoto Hirotoshi MD, PhD1Inomata Yukihiro MD, PhD1Hibi Taizo MD, PhD11 Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.Correspondence: Yasuhiko Sugawara, MD, PhD, Department of Transplantation and Pediatric Surgery, Postgraduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan. ([email protected]).10 2018 24 9 2018 102 10 1702 1709 2 10 2017 14 2 2018 17 2 2018 Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc.2018Wolters Kluwer Health, Inc. All rights reserved.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Background\nABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT.\n\nMethods\nTwenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 ≤ age < 18; n = 10).\n\nResults\nThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection.\n\nConclusions\nABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases.\n\nThe authors of this single-center retrospective study demonstrate that ABO incompatible (ABOi) LDLT is a feasible option for pediatric end-stage liver disease patients by comparing the clinical outcomes between ABOi and non-ABOi pediatric LDLT recipients as well as assessing the safety and efficacy of a rituximab-based desensitization protocol. Supplemental digital content is available in the text.\n\n OPEN-ACCESSTRUESDCT\n==== Body\nLiver transplantation has been established as an effective treatment for end-stage liver disease. Although considerable progress of perioperative care and the refinement of surgical techniques have been achieved, chronic donor shortage has been a serious problem globally. In several countries, living donor liver transplantation (LDLT) remains a major modality because of the limited availability of deceased donor organs for sociocultural reasons. Furthermore, liver grafts from ABO-incompatible (ABOi) donors have been used to increase the possibilities of transplantation.1,2 Pediatric patients who suffer from liver disease are no exception to this issue.\n\nAdvanced strategies in ABOi LDLT through innovation of B-cell desensitization using intravenous immunoglobulin, intrahepatic portal and/or arterial infusion therapy, plasma exchange (PE), splenectomy, and anti-CD20 monoclonal antibody, rituximab have expanded the donor pool effectively over the last 2 decades.3-7 Indeed, recent studies using the induction of rituximab have demonstrated the dramatically improved survival rate in ABOi pediatric and adult LDLT.1,8-11 However, the incidence of antibody-mediated rejection (AMR) remains an issue that has not yet been completely resolved. In addition, several reports showed that concerns still remain in the incidence of high prevalence rates, such as biliary stricture and infectious complications.1,8,12\n\nTo date, few studies have reported the detailed B-cell desensitization protocol and long-term outcomes of ABOi pediatric LDLT in rituximab era. Therefore, safety and efficacy of the rituximab based protocol for ABOi pediatric LDLT are unclear. The aims of our single-center study are to analyze the long-term outcomes of pediatric patients who underwent ABOi LDLT and to assess the adequacy of the immunosuppressive protocol against the ABO-barrier.\n\nMATERIALS AND METHODS\nStudy Population\nBetween December 1998 and March 2016, 444 patients underwent 463 LDLT at Kumamoto University Hospital. Of these, 160 pediatric LDLT recipients younger than 18 years were analyzed retrospectively by reviewing the clinical records. Data were collected and analyzed in December 2016. All patients were of Asian ethnic origin. In the study population, 29 recipients underwent ABOi LDLT. The characteristics of study population are shown in Table 1. All our LDLT protocol received an approval from the institutional review committee. This study was performed according to the Ethical Guidelines for Clinical Research published on April 1, 2009, by the Ministry of Health, Labour and Welfare of Japan.\n\nTABLE 1 Patients characteristics (n = 160)\n\nSurgical Procedure\nThe transplant procedures in our institution have been described previously.13,14 Briefly, hepatic and portal veins were reconstructed under a surgical loupe, and hepatic arteries were reconstructed under a microscope. Duct-to-duct biliary reconstruction was a routine procedure except for the recipients with biliary atresia. Absolute indication of graft size reduction was that the estimated graft-to-recipient weight ratio (GRWR) was greater than 4.0%. Even if the preoperative GRWR was less than 4.0%, the reduction was considered to ensure a size match.\n\nBasic Immunosuppressive Regimen\nThe immunosuppressive regimen consisted of tacrolimus combined with low-dose steroids. The target trough levels of tacrolimus were between 10 and 15 ng/mL in the first 2 weeks, around 10 ng/mL in the next 2 weeks, and between 5 and 10 ng/mL thereafter. Steroids were initiated with an injection of 10 mg/kg of methylprednisolone before graft perfusion during surgery. Recipients received the intravenous injection of 1 mg/kg of methylprednisolone during postoperative day (POD) 1-3, 0.5 mg/kg during POD 4-6, and 0.3 mg/kg at POD 7. Subsequently, they were changed to oral administration of prednisolone and were tapered off until around 3 to 6 months. When acute cellular rejection (ACR) was suspected by a liver function test, patients were initially treated by increasing the dose of tacrolimus. If a liver function test showed no improvement or ACR as proven by liver biopsy, high-dose methylprednisolone (10 mg/kg) was administered at 3 days as a steroid pulse therapy and then the dose was tapered (over 7-10 days totally).\n\nImmunosuppressive Protocol for ABOi Pediatric LDLT\nWe have performed a total of 29 cases of ABOi pediatric LDLT, of which 10 cases were 2 years or older. A target trough level of tacrolimus was the same as that of non-ABOi cases as described above. Steroids were administered as same as non-ABOi cases until 1 month after LDLT, and tapered off taking twice as much time. Oral administration of mycophenolate mofetil (MMF) (10 mg/kg twice a day) was started POD 1. In patients younger than 2 years, preoperative PE was performed in 6 of 8 cases by 2010 to decrease the antidonor blood group antibody to less than 16, and in 11 cases since 2010, additional prophylaxis protocol was not performed (Figure 1). All of patients who were 2 years or older received single dose of rituximab 2 weeks before LDLT (3 of them received at different timings). The dose of rituximab was 300 mg/m2 for 1 patient, 375 mg/m2 for 6 patients, and 500 mg/body for 3 patients. Of these, the first consecutive three patients received additional B-cell desensitization using preoperative PE, infusion therapy, and splenectomy. From 2010, we have used a protocol without additional B-cell desensitization except for rituximab. Acetaminophen (10 mg/kg) and d chlorpheniramine maleate (0.04 mg/kg) were orally administered before administration of rituximab to prevent adverse events. The diagnosis of AMR was made based on the clinical course, immunological assays, and histopathological findings.15,16 C4d immunostaining was performed case by case if AMR was suspected.17\n\nFIGURE 1 Protocol of the pediatric ABOi LDLT at Kumamoto University Hospital.\n\nEvaluated Factors\nAs patient characteristics, clinical data including age at transplant, sex, primary disease, donor age, donor sex, graft type, GRWR, blood loss, cold ischemia time (CIT), warm ischemia time (WIT), and operation time were assessed. Moreover, incidence for bacterial infection, cytomegalovirus infection, fungal infection, vascular complication, biliary complication, ACR, AMR, and graft survival were compared between ABOi and non-ABOi LDLT group. Bacterial infection was defined as elevated inflammatory parameters accompanied by infected foci, and cytomegalovirus infection was evaluated by the antigenemia test. Fungal infection was diagnosed with identification in culture or image findings accompanied by the increase of β-d glucan. Vascular and biliary complications were defined as those requiring some intervention. Rituximab-treated group was further evaluated in detail including pediatric end-stage liver disease (PELD) score (under 12 years of age) or model for end-stage liver disease score, blood type combination, lymphocyte crossmatch test (flow cytometry), peak titer of Immunoglobulin M (IgM) and G (IgG) isoagglutinin against donor erythrocyte antigens at admission, at LDLT, and after transplantation, proportion of CD19+ lymphocyte cells (%) before rituximab treatment and at LDLT, and adverse events of rituximab treatment. The clinical course before and after AMR onset was described separately in detail.\n\nStatistical Analysis\nContinuous variables were expressed as mean values ± standard deviations. Statistical analysis was performed using the Mann-Whitney U test or Wilcoxon signed-rank test as appropriate for continuous data, whereas categorical variables were compared using either the χ2 test (without the Yates correction) or Fisher exact test as appropriate. The cumulative graft survival was estimated using the Kaplan-Meier product limit method. The log-rank (Mantel-Cox) test was used for comparison of the curves. A P value less than 0.05 was considered statistically significant; all tests were 2-tailed. All statistical analyses were performed using the GraphPad Prism 7 (GraphPad Software).\n\nRESULTS\nClinical Characteristics\nAmong 160 pediatric LDLT recipients, 29 recipients underwent ABOi LDLT (Table 1). The mean age at transplant was significantly lower in ABOi group (3.0 ± 5.2 years vs 4.6 ± 5.6 years, P = 0.040). The mean follow-up period was 60.6 ± 45.4 months in ABOi group and was 83.8 ± 55.6 months in non-ABOi group. The most common indication for ABOi LDLT was biliary atresia (51.7%). There were no significant differences in donor-related factors including donor age and sex between ABOi and non-ABOi groups. The most used graft type was left lateral (75.9%), and mean GRWR was 3.2 ± 3.9 in ABOi group. Operation-related factors including graft type, GRWR, CIT, WIT, operation time, and blood loss also showed no significant differences.\n\nPostoperative Outcomes and Graft Survivals\nThere were no significant differences in the incidence of infection, vascular complications, biliary complications, and ACR between ABOi and non-ABOi group (Table 2). Meanwhile, 2 (6.9%) patients developed AMR in ABOi group but not in non-ABOi group (P = 0.036). Next, to elucidate the impact of rituximab treatment, we compared the clinical outcomes between rituximab-treated and non–rituximab-treated ABOi group. Rituximab-treated 10 patients were classified into 2 groups based on the additional B-cell desensitization protocol as described. Reflecting excessive immunosuppression, rituximab-treated ABOi group (until 2010, n = 3) showed a higher incidence of bacterial and fungal infection compared with rituximab-treated ABOi group (from 2010, n = 7) and non–rituximab-treated ABOi group (n = 19) (Table 3). The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, respectively, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively (P = 0.375, Figure 2A). Rituximab-treated ABOi group showed comparable graft survival rate (80.0%, 80.0%, 66.7% at 1, 3, and 5 years with a mean follow-up of 40.7 ± 27.4 months) compared with the non-ABOi and non–rituximab-treated ABOi group (P = 0.328, Figure 2B). During the study period, mortality rate in non–rituximab-treated ABOi group was 15.8%, and in rituximab-treated ABOi group was 30.0%. The cause of death in the former group was heart failure (in related to the primary disease, glycogen storage disease type IV), pulmonary hypertension (in related to the primary disease, mitochondrial DNA depletion syndrome), and interstitial pneumonia (Table S1, SDC,\nhttp://links.lww.com/TP/B555). The cause of death in the latter group was AMR in 2 patients and the other was multiple organ failure related to complications of the primary disease (progressive familial intrahepatic cholestasis type 1 [PFIC1]) including bleeding from the ileostomy, severe malnutrition, and chronic renal failure.18\n\nTABLE 2 Clinical outcomes between ABOi and non-ABOi group\n\nTABLE 3 Clinical outcomes between rituximab-treated and non–rituximab-treated ABOi group\n\nFIGURE 2 Cumulative graft survival rate of pediatric LDLT recipients. (A) Comparison between ABOi and non-ABOi group. Log-rank test, P = 0.375. (B) Comparison between ABOi (age < 2), ABOi (2 ≤ age < 18), and non-ABOi group. Log-rank test, P = 0.328.\n\nSafety and Efficacy of Rituximab for ABOi Pediatric LDLT\nTo analyze the detailed clinical course in related to the rituximab administration for pediatric patients, we reviewed the 10 rituximab-treated ABOi LDLT recipients whose age was 2 years or older (Table 4). Mean age at LDLT was 8.6 ± 5.5 and male-female ratio was equivalent. The most common indication for rituximab-treated ABOi LDLT was graft failure (40.0%). The original disease was PFIC1 in case 2 (104 months from first LDLT), acute liver failure in case 3 (36 months from first LDLT), and biliary atresia in cases 8 and 10 (163 and 192 months from first LDLT, respectively). The cause of graft failure was chronic rejection in cases 2, 3, 8, and unknown in case 10. Cases 1 to 3 had received PE and splenectomy and/or infusion therapy during the perioperative period. The lymphocyte crossmatch test was positive for T and B cells in case 1, and for B cells in cases 5 and 10. The median titers of IgM and IgG isoagglutinin at LDLT were 1:16 (1:1–1:256), 1:8 (1:1–1:256), respectively. CD19+ lymphocyte counts were decreased significantly after rituximab administration (24.9 ± 9.8% to 0.49 ± 0.46%, P < 0.001). Case 2 experienced rebound elevation of the CD19+ lymphocyte counts (19.4%) and received 375 mg/m2 rituximab 10 days after LDLT. When rituximab was administered, 1 case of headache, rash, cough was observed, but both of symptoms were mild, and it was not necessary to stop the treatment. In addition, although significant elevation of body temperature was observed after rituximab treatment (36.7 ± 0.4°C to 37.6 ± 0.4°C, P < 0.001), which improved promptly within 1 day.\n\nTABLE 4 Detailed outcomes of rituximab-treated ABOi pediatric LDLT patients\n\nIn rituximab-treated group, 2 patients (cases 1 and 9) developed AMR. In case 1, both T and B were positive in the preoperative lymphocyte crossmatch test. Although the elevation of antidonor type IgM and IgG could not be observed after LDLT, the patient repeated cholangitis from the early stage of posttransplant and showed the distinctive AMR phenotype with intrahepatic biliary complications. The patient received high-dose intravenous immunoglobulin administration and percutaneous transhepatic biliary drainage against multiple biloma, however eventually died of graft failure 5 months after LDLT. As previously reported, case 9 developed streptococcal infection 13 days after rituximab, and LDLT was postponed.19 CD19+ lymphocyte count decreased to 0.1% at 9 days after rituximab administration, but the number just before LDLT increased to 1.2%. The patient showed an increased ascites, a marked increase of hepatic enzyme levels, and decreased platelet levels on POD 5. Both of the IgM and IgG antidonor antibody titers increased to 1:1024, and the CD19+ lymphocyte count increased to 4.1%. The liver histology showed hepatocyte ballooning, portal inflammation, sinusoidal congestion, and complement component 4d positivity in the vascular endothelium. Therefore, in this case, it was speculated that streptococcal infection resulted in reactivation of B cells, which might make a foothold to trigger AMR. Despite treatment with PE, intravenous immunoglobulin, steroid pulse therapy, and readministration of rituximab, the patient died with graft failure accompanied by renal failure and acute respiratory distress syndrome 1 month after LDLT.\n\nDISCUSSION\nIn Japan, ABOi grafts have been used in 13.8% of pediatric LDLT from 1989 to 2013.20 Thus, even in pediatric patients, ABOi LDLT has been implemented as an important option to compensate for the shortage of donors. In our institution, 18.1% of pediatric LDLT was performed using ABOi grafts and their clinical outcomes and graft survival were comparable to non-ABOi grafts. We evaluated the clinical outcomes and the adequacy of the immunosuppressive protocol in ABOi pediatric LDLT.\n\nPrevious literatures have reported that infants show better outcomes in ABOi LT.2,21 One possible reason is the different immune responses of infants to ABOi graft. Infants do not produce isohemagglutinins, therefore, their anti-A and -B antibody titers remain low levels in early childhood.22 Additionally, the activation of complement system is suppressed in infants.23 Taken together, infants have less mediators in related to the AMR. In accordance with these mechanisms, ABOi pediatric LDLT recipients who are younger than 2 years in our study cohort did not develop AMR. Therefore, we believe that it is unnecessary to use rituximab in ABOi pediatric LDLT younger than 2 years.\n\nWe have used the rituximab-based protocol in 10 pediatric ABOi LDLT recipients for B-cell desensitization. The pretransplant therapy could be performed safely without severe adverse events and reduced their CD19+ lymphocyte counts effectively just before LT. However, regardless of the desensitization, we experienced 2 cases (cases 1 and 9) of AMR. Case 1 developed the distinctive AMR phenotype with intrahepatic biliary complications without the elevation of anti-donor type IgM and IgG. Characteristically, case 1 had shown positive lymphocyte crossmatch for T and B cells before LDLT. Importantly, Hori et al24 have shown that a positive lymphocyte crossmatch has a negative impact on LDLT possibly because of the wide expression of HLA antigens. As such background might affect clinical course of case 1, advanced immunological strategies must be considered for lymphocyte crossmatch-positive recipients. Case 9 showed specific clinical course suggesting the streptococcal infection after rituximab administration resulted in reactivation of B cells, which might trigger AMR.19 In the light of experience, we think that additional desensitization therapy should be considered if the reactivation of B cells is suspected before ABOi LDLT.\n\nPlasmapheresis is a standard procedure to reduce donor specific antibody titers, but the titer required to prevent AMR is not defined. Egawa et al1 observed no significant relationships between plasmapheresis and clinical outcomes after ABOi adult LDLT from a Japanese multicenter study. The study also revealed that local infusion, splenectomy, antilymphocyte antibody, and intravenous immunoglobulin had no significant impact on overall survival or AMR incidence in rituximab-treated ABOi LDLT recipients. As these results indicate, we believe that the most important key to prevent AMR in ABOi LT is inhibition of new antibody production. Additionally, the procedure, such as catheter insertion for local infusion, or splenectomy increases the risk of bleeding and infection. Based on this policy, we have used a protocol based on the administration of rituximab (patients who were 2 years or older), tacrolimus, steroids, and MMF without PE, local infusion, and splenectomy since 2010 in ABOi LDLT.25\n\nFrom the viewpoint of rituximab dose, it is widely accepted that a single maximum dose of rituximab with efficacy and safety is 375 mg/m2 for the B-cell lymphoma treatment.26 Recently, Egawa et al27 suggested that the dose in 300 mg/m2 or less of rituximab single administration would be insufficient for prevention of AMR in ABOi adult LDLT. Indeed, 1 patient who had received 300 mg/m2 of rituximab showed rebound elevation of the CD19+ lymphocyte counts after LDLT in our study cohort. Thus, the use of rituximab at sufficient dose is recommended, whereas it is worth mentioning that careful attention must be paid to the prevention of infectious diseases.\n\nThe optimal treatment strategy for AMR after LDLT remains unclear so far. Based on a combination of calcineurin inhibitor, corticosteroid, plasmapheresis, and B cell–modulating therapies, use of thymoglobulin is also considered as an option to disrupt key T-cell and B-cell interactions.28 In addition, in some cases, AMR can be induced by isohemagglutinin production from plasma cells which do not express CD20. In such a case, treatment with bortezomib, which is a proteasome inhibitor, can be considered as another option.29,30 Recently, eculizumab, which is a monoclonal antibody that blocks the complement pathway, is successfully used for the treatment of AMR after pediatric LT.31 In this report, eculizumab was used for recipient showing refractory AMR associated with C1q-binding donor specific antibody. Of course, retransplantation that does not miss the time should always be considered.\n\nThe precise role of donor-specific antibodies (DSA) after LT is unclear, whereas evidence is increasing that DSA, especially those with higher mean fluorescence intensity, are associated with both acute and chronic liver allograft rejections.32-35 In our study cohort, case 1 in rituximab-treated ABOi group developed AMR which did not seem to be involved in antiblood type antibodies, therefore, involvement of DSA should be taken into consideration as the cause of AMR. For the impact of DSA on humoral immunity in post-LT follow-up, more detailed investigation will be needed, including intervention of immunosuppressive protocols. It is also worth noting that detrimental aspect of DSA might differ between deceased donor LT and LDLT.36\n\nIt has been well accepted that hypogammaglobulinemia is a crucial risk factor for development of infection.37 As a reminder, rituximab and immunosuppressive drugs, such as steroids and MMF, are known to induce iatrogenic hypogammaglobulinemia. Although ABOi pediatric LDLT recipients did not develop the recurrent infections related low IgG levels in our cohort, serum IgG levels, in particular, rituximab-treated ABOi LDLT recipients, should be monitored at least until the recovery of B cells. Proper IgG supplementation has to be done in case a serum IgG level is below 500 mg/dL with recurrent or severe infections.\n\nOur study has some limitations. First, it was a retrospective single-center cohort study of a relatively small patient population. However, we believe that the data from our cohort are reliable because the treatment practices, immunosuppressive strategy, and surgical techniques are standardized. Prospective and multicenter studies are needed to clarify the feasibility of our protocol. Second, the observation period in ABOi group, in particular in rituximab-treated group, is shorter compared with the non-ABOi group. This difference is affected by the time of approval of rituximab, but we believe that an observation period of over 40 months on average is sufficient to evaluate the long-term posttransplant outcomes. Third, our study population does not contain acute liver failure patients in rituximab-treated group. The timing of rituximab administration is known to be related to the rebound elevation of isohemagglutinin titers,38 therefore, further investigation will be needed to detect the minimal time interval from rituximab administration to ABOi LDLT.\n\nIn conclusion, ABOi LDLT is a feasible option for PELD patients. Rituximab-based protocol is a promising procedure for preventing AMR in ABOi pediatric LDLT recipients who are 2 years or older. However, we need to keep in mind that the current protocol does not completely prevent the onset of AMR in several cases, and further research is required in the future.\n\nSupplementary Material\nSUPPLEMENTARY MATERIAL\n The authors declare no funding or conflicts of interest.\n\nM.H., Y.S., H.Y, and Y.I. participated in the study concept and design, analysis and interpretation of data, and critical revision of the article. M.H., M.K., S.K., M.S., D.Y., K.U., S.H., Y.O., H.Y., and H.Y. participated in data collection. M.H., T.H., and Y.S. participated in the writing of the article.\n\nSupplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).\n==== Refs\nREFERENCES\n1 Egawa H Teramukai S Haga H \nImpact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study . Am J Transplant . 2014 ;14 :102 –114 .24279828 \n2 Stewart ZA Locke JE Montgomery RA \nABO-incompatible deceased donor liver transplantation in the United States: a national registry analysis . Liver Transpl . 2009 ;15 :883 –893 .19642117 \n3 Tanabe M Shimazu M Wakabayashi G \nIntraportal infusion therapy as a novel approach to adult ABO-incompatible liver transplantation . 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Front Immunol . 2014 ;5 :626 .25538710 \n38 Egawa H Ohmori K Haga H \nB-cell surface marker analysis for improvement of rituximab prophylaxis in ABO-incompatible adult living donor liver transplantation . Liver Transpl . 2007 ;13 :579 –588 .17394164\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0041-1337", "issue": "102(10)", "journal": "Transplantation", "keywords": null, "medline_ta": "Transplantation", "mesh_terms": "D000017:ABO Blood-Group System; D000293:Adolescent; D001402:B-Lymphocytes; D001787:Blood Group Incompatibility; D002648:Child; D002675:Child, Preschool; D058625:End Stage Liver Disease; D005240:Feasibility Studies; D005260:Female; D005938:Glucocorticoids; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D015994:Incidence; D007518:Isoantibodies; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D011183:Postoperative Complications; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "0132144", "other_id": null, "pages": "1702-1709", "pmc": null, "pmid": "29620615", "pubdate": "2018-10", "publication_types": "D016428:Journal Article", "references": "24279828;28002655;20096431;26887781;26372830;14966415;22410063;25538710;17929298;28938311;28583540;16048608;16498648;10071029;19642117;26896194;23293980;28060025;4432260;2333747;21672151;25689881;17394164;12131697;26038872;27273869;22681986;24801413;14755773;27597379;23928408;27436684;27016995;11133748;19667930;21342448;20477975;27570428", "title": "Long-term Outcomes of ABO-incompatible Pediatric Living Donor Liver Transplantation.", "title_normalized": "long term outcomes of abo incompatible pediatric living donor liver transplantation" }

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LONG-TERM OUTCOMES OF ABO-INCOMPATIBLE PEDIATRIC LIVING DONOR LIVER TRANSPLANTATION. 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{ "abstract": "A 42-year-old woman underwent renal transplantation in 200X. After the transplant, she received tacrolimus as immunosuppressant therapy. Eleven years after the transplant, diffuse large B-cell lymphomas were detected in the duodenum and terminal ileum. Wireless capsule endoscopy (WCE) revealed multiple lymphoma lesions in the entire small intestine. The patient achieved complete response through the administration of R-CHOP therapy and discontinuation of immunosuppressant therapy. Post-transplant lymphoproliferative disorder (PTLD) is a rare complication and WCE may be useful for diagnosing PTLD of the small intestine.", "affiliations": "Department of Gastroenterology, Oita University Hospital.", "authors": "Sonoda|Akira|A|;Katsuta|Makoto|M|;Yada|Mika|M|;Mizukami|Kazuhiro|K|;Okamoto|Kazuhisa|K|;Ogawa|Ryo|R|;Okimoto|Tadayoshi|T|;Kodama|Masaaki|M|;Murakami|Kazunari|K|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.11405/nisshoshi.112.729", "fulltext": null, "fulltext_license": null, "issn_linking": "0446-6586", "issue": "112(4)", "journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology", "keywords": null, "medline_ta": "Nihon Shokakibyo Gakkai Zasshi", "mesh_terms": "D000328:Adult; D053704:Capsule Endoscopy; D005260:Female; D006801:Humans; D007410:Intestinal Diseases; D007421:Intestine, Small; D016030:Kidney Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D011183:Postoperative Complications", "nlm_unique_id": "2984683R", "other_id": null, "pages": "729-35", "pmc": null, "pmid": "25843462", "pubdate": "2015-04", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "A case of lymphoproliferative disorder in the entire small intestine after renal transplantation detected by wireless capsule endoscopy.", "title_normalized": "a case of lymphoproliferative disorder in the entire small intestine after renal transplantation detected by wireless capsule endoscopy" }

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{ "abstract": "BACKGROUND\nRadioactive iodine-131 (RAI) is an established treatment for patients with Graves' hyperthyroidism. RAI is reported to be associated with a 20-30% incidence of development or exacerbation of Graves' ophthalmopathy (GO). This study compares the progression of GO in patients who had evidence or no evidence of GO before RAI therapy.\n\n\nMETHODS\nForty-eight patients were studied. One group had no evidence whereas the other group had evidence of GO before RAI treatment. All underwent RAI therapy. Group A (27 patients, 18 women, nine men, age: 19-68 with a mean of 49 years) had pre-existing exophthalmos. Group B consisted of 21 patients (13 women, eight men, age: 30-63 with a mean of 43 years) developed exophthalmos after treatment. All patients underwent RAI therapy and followed by ophthalmologists.\n\n\nRESULTS\nThe average administered dose in group A was 24.3 mCi (range: 10-36.2 mCi) compared with group B: 25.4 mCi (range: 13-35.9 mCi), P=0.60. Ten (37%) of the 27 patients in group A experienced worsening of symptoms post-treatment. There was no significant difference between the administered dose of RAI in patients with worsening symptoms, 25.1 mCi versus patients with stable symptoms, 24.5 mCi (P=0.82). However, group A developed GO symptoms earlier than group B (4.5 vs. 9.5 months), P=0.02.\n\n\nCONCLUSIONS\nRAI is known to exacerbate ophthalmopathy. Our study showed it was not dose-dependent. Patients without a previous history of GO were observed to have a significantly delayed period for the development of symptoms.", "affiliations": "Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.;Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.;Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.;Department of Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA.;Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Temple University Health System.", "authors": "Khiyani|Neeraj|N|;Dadparvar|Simin|S|;Gish|Aaron|A|;Intenzo|Charles M|CM|;Malmud|Leon S|LS|", "chemical_list": "D007457:Iodine Radioisotopes; C000614965:Iodine-131", "country": "England", "delete": false, "doi": "10.1097/MNM.0000000000001008", "fulltext": null, "fulltext_license": null, "issn_linking": "0143-3636", "issue": "40(5)", "journal": "Nuclear medicine communications", "keywords": null, "medline_ta": "Nucl Med Commun", "mesh_terms": "D000328:Adult; D000368:Aged; D004307:Dose-Response Relationship, Radiation; D005260:Female; D049970:Graves Ophthalmopathy; D006801:Humans; D006980:Hyperthyroidism; D015994:Incidence; D007457:Iodine Radioisotopes; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "8201017", "other_id": null, "pages": "455-460", "pmc": null, "pmid": "30855542", "pubdate": "2019-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Does the dose of iodine-131 influence the incidence of Graves' ophthalmopathy?", "title_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy" }

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DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. 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DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-CURIUM-201900183", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-CURIUM-201900188", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338091, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-CURIUM-201900191", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338101, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-CURIUM-201900189", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "016515", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADIOACTIVE IODINE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM IODIDE I 131" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Endocrine ophthalmopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHIYANI N, DADPARVAR S, GISH A, INTENZO CM, MALMUD LS. DOES THE DOSE OF IODINE-131 INFLUENCE THE INCIDENCE OF GRAVES^ OPHTHALMOPATHY? NUCL MED COMMUN. 2019 MAY?40(5):455-460. DOI: 10.1097/MNM.0000000000001008.", "literaturereference_normalized": "does the dose of iodine 131 influence the incidence of graves ophthalmopathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190521", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16338093, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "Long-term outcome of ustekinumab in Crohn's disease (CD) has not been evaluated.\n\n\n\nTo evaluate the long-term efficacy and safety of ustekinumab and identify the predictive factors of ustekinumab failure-free persistence in a cohort of anti-TNF refractory CD patients.\n\n\n\nWe performed a retrospective multicentre cohort study including all consecutive CD patients who began subcutaneous ustekinumab and presented a clinical response (defined as a significant improvement of CD-related clinical symptoms assessed by the patient's physician leading to continued ustekinumab) during the first year of treatment. Primary outcome was treatment failure defined as withdrawal of treatment due to loss of response, intolerance or need for surgery.\n\n\n\nEighty-eight of the 122 (72%) CD patients beginning ustekinumab from March 2011 to December 2014, responded to ustekinumab and were followed up until November 2016. Median time on ustekinumab was 26.6 (13.4-34.4) months. Forty-seven patients (54%) continued ustekinumab with a clinical response and 38 (43%) stopped treatment (32 for failure, five for remission and one for pregnancy). Endoscopic response was observed in 82% of patients with endoscopic evaluation and mucosal healing in 39%. Ustekinumab failure-free persistence rates were 78% at 12 months, 66% at 24 months and 55% at 36 months. No predictive factor of ustekinumab failure-free persistence was identified. One severe adverse event was observed (anal adenocarcinoma).\n\n\n\nIn this cohort of refractory CD patients receiving long-term ustekinumab therapy, more than 50% of patients continued ustekinumab treatment with no loss of response, intolerance or surgery and with a good safety profile.", "affiliations": "Lille, France.;Clichy, France.;Lausanne, Switzerland.;Lyon, France.;Reims, France.;Paris, France.;Paris, France.;Strasbourg, France.;Marseille, France.;Clermont-Ferrand, France.;Créteil, France.;Amiens, France.;Saint Etienne, France.;Nancy, France.;Nice, France.;Rennes, France.;Paris, France.;Colombes, France.;Paris, France.;Bordeaux, France.;Lille, France.", "authors": "Wils|P|P|;Bouhnik|Y|Y|;Michetti|P|P|0000-0003-4982-7327;Flourie|B|B|;Brixi|H|H|;Bourrier|A|A|;Allez|M|M|;Duclos|B|B|;Serrero|M|M|;Buisson|A|A|0000-0002-6347-409X;Amiot|A|A|0000-0001-6676-1222;Fumery|M|M|;Roblin|X|X|0000-0002-7929-4878;Peyrin-Biroulet|L|L|0000-0003-2536-6618;Filippi|J|J|;Bouguen|G|G|0000-0002-7444-5905;Abitbol|V|V|;Coffin|B|B|;Simon|M|M|;Laharie|D|D|0000-0002-4753-6676;Pariente|B|B|0000-0003-1442-0244;|||", "chemical_list": "D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab", "country": "England", "delete": false, "doi": "10.1111/apt.14487", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "47(5)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000328:Adult; D015331:Cohort Studies; D003424:Crohn Disease; D004351:Drug Resistance; D004724:Endoscopy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D011247:Pregnancy; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab", "nlm_unique_id": "8707234", "other_id": null, "pages": "588-595", "pmc": null, "pmid": "29315694", "pubdate": "2018-03", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Long-term efficacy and safety of ustekinumab in 122 refractory Crohn's disease patients: a multicentre experience.", "title_normalized": "long term efficacy and safety of ustekinumab in 122 refractory crohn s disease patients a multicentre experience" }

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{ "abstract": "BACKGROUND\nThe antiphospholipid syndrome is an acquired autoimmune thrombophilia, characterized by arterial and/or venous thrombosis. Rarely, this condition can have a catastrophic presenta tion, with high mortality, and presence of microangiopathy and involvement of three or more organs.\n\n\nOBJECTIVE\nTo describe the clinical presentation and evolution of a pediatric patient with catastrophic antiphospholipid syndrome, with a seronegative onset form, whose response to aggressive therapy was favorable.\n\n\nMETHODS\nAdolescent female, with a one-week history of pain, increased abdo minal volume and edema in the lower extremities. Generalized lupus erythematosus was diagnosed and the neoplastic process was ruled out. During its evolution, she presented various thrombotic events, initially with the presence of negative antiphospholipid antibodies, which were subsequently positive. The patient presented multisystemic failure secondary to multiorgan thrombosis, required hemodynamic and ventilatory support. It was managed with low molecular weight heparin, plas mapheresis, anticoagulation, immunosuppression and boluses of rituximab with excellent response.\n\n\nCONCLUSIONS\nWe consider this case interesting because it is an infrequent diagnosis in the pediatric age and whose suspicion, timely and aggressive intensive management, can change the poor progno sis and high mortality of these patients.", "affiliations": "Servicio de Medicina Interna Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Medicina Interna Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Banco de Sangre, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Hematología Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.;Servicio de Medicina Interna Pediátrica, Centro Médico Nacional 20 de Noviembre, Ciudad de México, México.", "authors": "Vargas-Quevedo|Ericka|E|;Ordoñez-Gutiérrez|Eduardo|E|;Trejo-Gómora|Jorge Enrique|JE|;Chávez-Aguilar|Lénica Anahí|LA|;Peña-Vélez|Rubén|R|", "chemical_list": "D017152:Antibodies, Antiphospholipid; D015415:Biomarkers", "country": "Chile", "delete": false, "doi": "10.4067/S0370-41062018000200236", "fulltext": null, "fulltext_license": null, "issn_linking": "0370-4106", "issue": "89(2)", "journal": "Revista chilena de pediatria", "keywords": null, "medline_ta": "Rev Chil Pediatr", "mesh_terms": "D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D015415:Biomarkers; D002648:Child; D005260:Female; D006801:Humans", "nlm_unique_id": "0404261", "other_id": null, "pages": "236-240", "pmc": null, "pmid": "29799892", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "\"Seronegative\" catastrophic antiphospholipid syndrome in pediatrics: Clinical case.", "title_normalized": "seronegative catastrophic antiphospholipid syndrome in pediatrics clinical case" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VARGAS?QUEVEDO E, ORDONEZ?GUTIERREZ E, TREJO?GOMORA JE, CHAVEZ?AGUILAR LA, PENA?VELEZ R.. ^SERONEGATIVE^ CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME IN PEDIATRICS: CLINICAL CASE. REV?CHILE?PED. 2018?89(2):236?240", "literaturereference_normalized": "seronegative catastrophic antiphospholipid syndrome in pediatrics clinical case", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180807", "receivedate": "20180807", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15249069, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "MX-TEVA-2018-MX-909382", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", 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null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": 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null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPHOSPHOLIPID SYNDROME", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ONE BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": "LUPUS NEPHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "750", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ENOXAPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENOXAPARIN" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastritis erosive", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Volume blood decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cystitis haemorrhagic", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lower gastrointestinal haemorrhage", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "VARGAS?QUEVEDO E, ORDONEZ?GUTIERREZ E, TREJO?GOMORA JE, CHAVEZ?AGUILAR LA, PENA?VELEZ R. ^SERONEGATIVE^ CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME IN PEDIATRICS: CLINICAL CASE. REV?CHILE?PED 2018?89(2):236?240.", "literaturereference_normalized": "seronegative catastrophic antiphospholipid syndrome in pediatrics clinical case", "qualification": "1", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180704", "receivedate": "20180620", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15036291, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "MX-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-175762", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG/KG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "040", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MG/KG/ DOSAGE (THREE BOLUSES)", "drugenddate": null, "drugenddateformat": null, "drugindication": "CUTANEOUS LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ENOXAPARIN SODIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", 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"activesubstance": { "activesubstancename": "DABIGATRAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUBCLAVIAN VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGAS-QUEVEDO E, ORDONEZ-GUTIERREZ E, TREJO-GOMORA JE, CHAVEZ-AGUILAR LA, PENA-VELEZ R. ^SERONEGATIVE^ CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME IN PEDIATRICS: CLINICAL CASE. REV CHILE PED. 2018?DEC? 89(2):236-240", "literaturereference_normalized": "seronegative catastrophic antiphospholipid syndrome in pediatrics clinical case", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20180615", "receivedate": "20180615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15014571, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "BACKGROUND\nPsoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors.\n\n\nMETHODS\nA 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis.\n\n\nCONCLUSIONS\nPatients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.", "affiliations": "Department of Neurology, University of California, San Francisco, California, USA. [email protected].;Division of Neuropathology, Department of Pathology, University of California, San Francisco, California, USA.;Division of Neuropathology, Department of Pathology, Duke University, Durham, North Carolina, USA.;Division of Neuropathology, Department of Pathology, University of California, San Francisco, California, USA.;Department of Neurology, Salinas Valley Memorial Healthcare System, Salinas, California, USA.;Department of Neurology, University of California, San Francisco, California, USA.;Department of Neurology, University of California, San Francisco, California, USA.;Department of Neurology, University of California, San Francisco, California, USA.", "authors": "Fan|Joline M|JM|;Solomon|David A|DA|;López|Giselle Y|GY|;Hofmann|Jeffrey W|JW|;Colorado|Rene A|RA|;Kim|Anthony S|AS|;Meisel|Karl|K|;Halabi|Cathra|C|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12883-020-01681-9", "fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377 BioMed Central London \n\n1681\n10.1186/s12883-020-01681-9\nCase Report\nCatastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report\nFan Joline M. [email protected] 1 Solomon David A. 2 López Giselle Y. 3 Hofmann Jeffrey W. 2 Colorado Rene A. 4 Kim Anthony S. 1 Meisel Karl 1 Halabi Cathra 15 1 grid.266102.10000 0001 2297 6811Department of Neurology, University of California, San Francisco, California USA \n2 grid.266102.10000 0001 2297 6811Division of Neuropathology, Department of Pathology, University of California, San Francisco, California USA \n3 grid.26009.3d0000 0004 1936 7961Division of Neuropathology, Department of Pathology, Duke University, Durham, North Carolina USA \n4 grid.430059.bDepartment of Neurology, Salinas Valley Memorial Healthcare System, Salinas, California USA \n5 grid.266102.10000 0001 2297 6811Weill Institute for Neurosciences, University of California, San Francisco, California USA \n21 3 2020 \n21 3 2020 \n2020 \n20 1062 9 2019 10 3 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nPsoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors.\n\nCase presentation\nA 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis.\n\nConclusion\nPatients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.\n\nKeywords\nAtherosclerosisStrokePsoriasisPsoriatic arthritisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPsoriasis is a common chronic inflammatory disorder affecting approximately 1.5–3% of the adult population [1, 2]. An additional 6–30% of patients with psoriasis also have psoriatic arthritis, which may reflect a more pronounced systemic disease [3–5]. Population cohort studies have identified both psoriasis and psoriatic arthritis to be individual risk factors for vascular disease [4–7]; however, the contribution of comorbid inflammatory diseases for clinical screening and management guidelines remains unknown. Here, we present an illustrative report of a fatal stroke in a young patient with severe psoriasis, psoriatic arthritis, and metabolic syndrome.\n\nCase presentation\nA 49 year-old Caucasian woman with psoriasis, psoriatic arthritis, multivessel coronary artery disease, hypertension, subclinical hypothyroidism, and diabetes mellitus presented with bilateral lower extremity weakness and severe anemia. Regarding her history of psoriasis, she initially developed diffuse psoriatic plaques and axial psoriatic arthritis at age 19. Her first severe psoriasis flare occurred at age 29. Chart review did not reveal recorded Psoriasis Area and Severity Index (PASI) scores but there was documentation of erythema and pustular psoriasis measured over 70% of her body surface area with elevated white blood cell count. Despite treatment with prednisone and acitretin, after 1 year she developed severe cutaneous flares of pustular psoriasis measuring up to 90% of total body surface area with spared regions in her legs, necessitating multiple hospitalizations. Her treatment was escalated to Geockerman therapy, methotrexate, and topical steroids, in addition to prednisone and acitretin. In subsequent years, her chronic psoriatic skin manifestations involved roughly 30% of her total body surface area, meeting criteria for severe psoriasis, and these skin manifestations were managed primarily with topical steroids. Plain films ultimately revealed active inflammatory spondylitis. Despite recommendations to start disease modifying therapy, the patient declined further treatment.\n\nSix years prior to the most recent presentation, the patient was diagnosed with metabolic syndrome. Risk factors measured at the time of diagnosis included a peak hemoglobin A1c level of 11.6%, body mass index of 36, triglycerides of 310, high density lipoprotein (HDL) of 34, and systolic blood pressures routinely measured between 140 and 160. For her modifiable risk factors of diabetes, dyslipidemia, and hypertension, she was prescribed insulin, statins, and antihypertensive agents, respectively. Her family history was notable for ischemic stroke in her mother though of unknown etiology and age. There were no known inflammatory disorders in the family. Three months prior to the most recent presentation, the patient was hospitalized for a non-ST elevation myocardial infarction (NSTEMI). Cardiac catheterization revealed severe right coronary artery (RCA) disease and in-stent thrombosis of a pre-existing stent within the left circumflex artery placed 6 years prior. She underwent re-stenting for her left circumflex artery and RCA and was subsequently treated with a dual antiplatelet therapy regimen with aspirin and clopidogrel.\n\nSubsequently, she presented with subacute bilateral lower extremity weakness and confusion. Her brain MRI revealed acute bilateral watershed infarcts, in addition to subacute left parietal and frontal gyrus infarcts. CT angiography of the head and neck revealed diffuse atherosclerotic plaques in the aortic arch and carotid bulbs, occlusion of the left internal carotid artery (ICA), and narrowing of the bilateral M1 segments of the middle cerebral artery (MCA). (Fig. 1a-c). There was reconstitution of flow in the left cavernous and supraclinoid segments of the ICA via an intact Circle of Willis. In addition to the bilateral MCA narrowing, there was mild narrowing of the right carotid artery and a single diminutive A1 segment which perfused bilateral anterior cerebral arteries (ACA) vessels.\nFig. 1 a Diffusion-weighted axial MRI showing bilateral anterior cerebral artery (ACA) and middle cerebral artery (MCA) distribution infarcts. b CTA axial MIP demonstrating mild irregular luminal narrowing of the right M1 segment and severe focal narrowing of the distal left M1 segment. c CTA sagittal MIP demonstrating calcified atherosclerotic plaque of the left carotid bulb and complete occlusion of the proximal cervical left internal carotid artery. d Diffusion-weighted axial MRI showing marked interval progression of infarcts involving the bilateral ACA and left MCA distributions\n\n\n\nThere were no known preceding hemodynamic changes or systemic illnesses. Possible etiologies of her multifocal infarcts included severe atherosclerosis and related artery-artery thromboembolic events, cardioembolic events, hypercoagulable state, infection, or vasculitis. Cardiac rhythm telemetry did not reveal atrial fibrillation. Transthoracic echocardiogram revealed normal left ventricular function, normal left and right atrial size, no thrombus, and no intra- or extra-cardiac shunt. Subsequent transesophageal echocardiogram (TEE) again did not reveal thrombus or valvular lesions. The TEE also demonstrated atheromatous plaque in the proximal descending aorta greater than 4 mm in thickness. Laboratory studies included hemoglobin (Hg) of 4.2 g/dL, an elevated erythrocyte sedimentation rate > 100 mm/hr. (normal 0–15 mm/hr) and lipoprotein (a) 133 nmol/L (normal < 75 nmol/L) but were otherwise unrevealing (Table 1). The cerebral spinal fluid (CSF) did not have infectious or inflammatory properties. Workup of anemia was consistent with alpha thalassemia and severe iron deficiency, also supported by peripheral blood smear.\nTable 1 Summary of serum and CSF studies obtained on present hospitalization\n\n\tData\tReference\t\nLipid profile\t\n Cholesterol, Total\t179\t< 200 mg/dL\t\n Triglycerides\t253\t< 200 mg/dL\t\n LDL\t114\t< 130 mg/dL\t\n Lipoprotein a\t133\t< 75 nmol/L\t\nHypercoagulation\t\n Beta-2-glycoprotein Antibody, IgG\t< 10.0\t< 20.1 CU\t\n Beta-2-glycoprotein Antibody, IgM\t< 5.0\t< 20.1 CU\t\n Protein C, Activity\t99\t76–146%\t\n Anti-Cardiolipin Antibody, IgG\t15.8\t< 20.1 CU\t\n Anti-Cardiolipin Antibody, IgM\t< 10.0\t< 20.1 CU\t\n Lupus Anticoagulant by HEXA\tNeg\tNeg\t\n RVVT Seconds\t30.9\t29.0–44.0 s\t\nCSF studies\t\n WBC\t1\t< 6 x10E6/L\t\n RBC\t44\t0 x10E6/L\t\n Glucose\t76\t40–70 mg/dL\t\n Protein\t13\t15–50 mg/dL\t\n IgG Index\t0.6\t0.3–0.6 Ratio\t\n Serum glucose\t164\t< 200\t\n Rapid HSV-1 PCR\tNeg\tNeg\t\n Rapid HSV-2 PCR\tNeg\tNeg\t\n VZV PCR\tNeg\tNeg\t\n VZV IgM\t0.03\t< 0.9\t\nAutoimmune/Endocrine\t\n Hemoglobin A1c\t6.4\t4.3–5.6%\t\n TSH\t0.64\t0.45–4.12 mlU/L\t\n Free T4\t13\t10–18 pmol/L\t\n CRP\t5.4 - > 36.9\t< 6.3\t\n ESR\t> 100\t0–15 mm/h\t\n Anti-Nuclear Antibodies\t< 40\t< 40\t\n Anti Proteinase 3 Ab\t< 10.0\t< 20.0 CU\t\n Anti Myeloperoxidase\t< 10.0\t< 20.0 CU\t\n GAD-65 Autoantibodies\t< 1.0\t< 1.0 U/mL\t\n Insulin Autoantibody\t< 0.4\t< 0.4 U/mL\t\n Islet Cell Antigen 512 Antibody\t< 0.8\t< 0.8 U/mL\t\n Rheumatoid Factor, serum\t< 40\t< 40 IU/mL\t\n Complement C3, serum\t101\t71–159 mg/dL\t\n Complement C4, serum\t26.4\t13–30 mg/dL\t\n Cryoglobulin\t< 0.12\t< 0.12 g/L\t\n Heterophile Agglutination\tNeg\tNeg\t\nInfectious\t\n Hepatitis B sAb\t< 5\tmIU/mL\t\n Hepatitis B cAb\tNeg\tNeg\t\n Hepatitis B sAg\tNeg\tNeg\t\n Hepatitis C Antibody\tNeg\tNeg\t\n HIV Ag/Ab\tNeg\tNeg\t\n\n\nDespite aggressive medical management, the patient clinically deteriorated. Repeat imaging revealed marked interval infarct progression involving multiple vascular territories (Fig. 1d). She underwent a left-sided decompressive hemicraniectomy as a life sustaining maneuver, and concomitant brain biopsy did not demonstrate evidence of vasculitis or infection. Clinical course was further complicated by sepsis, renal failure, and an acute generalized exanthematous pustulosis drug reaction to iodine contrast. In accordance with the patient’s prior wishes, she was transitioned to comfort-focused care and her family agreed to an autopsy.\n\nThe autopsy revealed eccentric, firm, yellow plaques involving all proximal intracranial vessels, consistent with severe atherosclerosis. There was an occlusive thrombus of the right ACA as well as diffuse arteriolar microthrombi. Elements of acute and chronic ischemic changes were seen on histology, including extensive ischemic neuronal necrosis. Diffuse, severe atherosclerosis was determined to be the cause of fatal burden of ischemic stroke (Fig. 2).\nFig. 2 Gross and microscopic pathology. a Gross pathology of aortic arch revealing extensive atheromas (black arrows). b Histopathology of the anterior cerebral artery. There is intimal thickening underlying the internal elastic lamina (blue arrow); the media and adventitia are distorted by fibrosis (blue dashed arrow). A recently-formed fibrin thrombus (black arrow) is adherent to a chronic and organized atherosclerotic plaque (red arrow). c Cross-sectional view of the left anterior descending coronary artery containing an intramural calcified nodule (black arrow). d Cross-sectional view of the basilar artery wall, demonstrating architectural distortion with cholesterol clefts (black arrow) and microcalcifications. e Left anterior descending artery with thickening of the intima and inflammatory infiltrate including T lymphocytes (red arrows) and macrophages (black arrows)\n\n\n\nDiscussion and conclusions\nWe present a case of a young patient with psoriasis and psoriatic arthritis, severe and diffuse atherosclerosis, and ultimately a fatal burden of ischemic infarcts of the brain. While the definitive contributions of the patient’s individual inflammatory conditions and anemia are unknown, we suggest that severe psoriasis and psoriatic arthritis enhance and accelerate progression of early presence of vascular risk factors and that recognition of this relationship provides another opportunity for risk factor stratification and treatment. Psoriasis and psoriatic arthritis have each been associated with cardiovascular risk factors and metabolic syndrome. This report illustrates that the burden and severity of comorbid inflammatory conditions and metabolic syndrome should prompt aggressive screening and management of vascular risk factors.\n\nPathophysiology\nThe pathophysiology of psoriasis involves the activation of effector T lymphocytes, including T helper cell type 1 and 17. Skin infiltration of activated T cells promotes antigen presentation and propagation of inflammatory cytokines [3]. A dysregulated Th1 system within the vessel wall intimal layer is implicated in the development of atherosclerosis and is a biologically plausible explanation for accelerated atherosclerosis in a chronic inflammatory state [8, 9]. The initial lesion responsible for atherogenesis is the fatty-streak, which is pathologically composed of monocytes and T lymphocytes [8, 10]. Endothelial cell activation leads to an enhanced local inflammatory response with upregulation of leukocyte adhesion molecules, increased of leukocyte recruitment, and expansion of the subendothelial fatty streak, leading to plaque formation [10, 11]. Progressive focal narrowing of vessels is punctuated by exposure of thrombogenic material when there is intimal layer plaque rupture or endothelial cell layer disruption. Thrombosis then leads to conditions such as unstable angina, myocardial infarction, or stroke [11, 12]. Fig. 2 illustrates extensive atheromas (2a) and chronic changes to the vessel wall layers (2c-d). Figure 2e illustrates the presence of T lymphocytes and macrophages within the thickened intima, which can be seen within the natural process of atherosclerosis [8, 10]. There is no evidence of excessive or patterned presence of inflammatory cells in pathology specimens, suggesting a chronic, cumulative process, and highlighting indirect and potentially synergistic roles of systemic inflammation in accelerating atherosclerosis.\n\nCirculation of inflammatory substances including low density lipoprotein (LDL) and lipoprotein (a) have also been directly implicated in vessel wall reactivity and plaque formation [3]. Studies have shown increased subclinical atherosclerosis and increased intima-medial thickness in patients with psoriatic arthritis, but without otherwise clear cardiovascular risk factors [13, 14], illustrating a more direct effect of systemic inflammation on the arterial wall. More severe subclinical atherosclerosis has also been seen in patients with psoriatic arthritis as compared to control populations and patients with cutaneous psoriasis alone [12]. The severity of atherosclerosis may increase with the added burden of inflammatory joint disease in patients with psoriasis.\n\nPsoriasis\nPopulation studies have demonstrated that patients with psoriasis have increased cardiovascular risk factors, including diabetes, hypertension, hyperlipidemia, and obesity, which are all features of metabolic syndrome [15–18]. Across observational studies, meta-analyses describe a 1.4–2.2 fold increased risk of developing metabolic syndrome in patients with psoriasis as compared to controls [18, 19]. In addition, the risk of developing metabolic syndrome has been shown to increase with psoriasis severity, with odds ratios (OR) of 1.22, 1.56, 1.98 for mild, moderate, and severe psoriasis, respectively [18]. Other studies have noted specific risk factors that are more prevalent in severe versus mild psoriasis, including diabetes (OR 1.39, 95% CI 1.22–1.58) and obesity (OR 1.47, 95% CI 1.32–1.63) [20]. These studies illustrate the relationship between the degree of systemic inflammation and development of metabolic syndrome.\n\nIn addition to the added risk conferred from elevated cardiovascular risk factors, population studies have also demonstrated that psoriasis independently leads to an increased risk of myocardial infarction or stroke [7, 18, 21, 22]. After adjusting for cardiovascular risk factors, studies demonstrate that mild and severe psoriasis confer a 1.29-fold risk (95% CI 1.02–1.63) and a 1.7-fold risk (CI 1.32–2.18) of myocardial infarction, as well as a 1.12-fold risk (95% CI, 1.08–1.16) and a 1.56-fold risk (95% CI 1.32–1.84) of stroke [23], respectively. These findings suggest a shared inflammatory pathway involved in the pathogenesis of psoriasis and atherogenesis [24].\n\nThe risk of cardiovascular risk factors and adverse events has also been noted to correlate with age of onset [22, 25]. The risk of incident myocardial infarction (MI) was found to be higher in younger patients with severe psoriasis as compared to older patients with late-onset psoriasis (HR 3.10 in a 30 year-old vs 1.36 in a 60 year-old) [25]. The difference in the disease activity of psoriasis is dependent on both genetic and environmental factors. Detection of specific human leukocyte antigens (HLA), such as type Cw6, has been differentially found in patients with early onset psoriasis as compared to late onset psoriasis, as one example of biological differences that contribute towards disease activity [26].\n\nPsoriatic arthritis\nOther studies have looked at the contribution of psoriatic arthritis as an independent risk factor for metabolic syndrome and adverse cardiovascular events. Patients with psoriatic arthritis have increased prevalence of hypertension (OR 1.31, 95% CI 1.26–1.47), hyperlipidemia (OR 1.23, 95% CI 1.18–1.29), diabetes (OR, 1.38, 95% CI 1.31–1.45), and obesity (OR 1.69, 95% CI 1.62–1.75) [4]. The prevalence of MI (OR 1.36-fold, 95% 1.04–1.77) and stroke (OR 1.26-fold, 95% CI 1.03–1.71) was also higher in patients with psoriatic arthritis as compared to controls [7, 27]. Notably, diagnosis of psoriatic arthritis did not confer a statistically significant elevation in mortality, as compared to controls [5]. Fewer studies have looked at the additive risk of accruing vascular risk factors in patients that have psoriatic arthritis in addition to cutaneous psoriasis. One study reports the elevated risk of vascular risk factors for patients with psoriatic arthritis to be 2.59-fold (95% CI 1.43–4.67) for cardiovascular disease, 2.42-fold (95% CI, 1.82–3.22) for hypertension, 1.9-fold (95% CI, 1.22–2.96) for diabetes, and 1.58-fold (95% CI, 1.19–2.09) for obesity [28, 29]. The presence of multiple inflammatory conditions may imply presence of multiple vascular risk factors.\n\nThere are many contributing factors toward atherosclerosis and vascular events, including conventional risk factors of dyslipidemia and hypertension, family history, ethnicity, and lifestyle [30]. The potential impact of anemia [31] and hemoglobinopathy [32] is also acknowledged but not definitive. In this report, however, we have focused on addressing the direct and indirect contributions of psoriasis and psoriatic arthritis.\n\nImmunosuppressive therapy\nMethotrexate and tumor necrosis factor inhibitors lead to 0.72-fold (95% CI 0.57–0.91) and 0.7-fold (95% CI 0.54–0.9) respective reduction of incident vascular events including MI and stroke in rheumatic diseases while agents such as cyclosporine, oral retinoids, steroids, and non-steroidal anti-inflammatory agents may confer increased risk [33, 34]. While fewer studies have been performed in patients with psoriasis and psoriatic arthritis, data suggests that disease modifying therapies, biologics, and anti-inflammatory agents may also lead to a reduced rate of cerebrovascular risk factors and events [35–39].\n\nIn conclusion, psoriasis and psoriatic arthritis have both indirect and direct causative roles in increasing the risk of vascular disease. Younger patients or those with multisystem disease need aggressive screening and treatment for active inflammatory disease along with vascular risk factor stratification. In patients with inflammatory conditions, we suggest screening for modifiable vascular risk factors and treating the risk factors in accordance with contemporary guidelines. Similarly, in young patients with vascular risk factors, we suggest reviewing systems for undiagnosed inflammatory disease in the appropriate clinical context. Studies are needed to help identify appropriate immunosuppressive therapy selection for synergistic risk factor reduction. Studies are also needed to help identify timing, cost-effectiveness, and patient selection for screening and treatment strategies.\n\nAbbreviations\nACAAnterior cerebral artery\n\nCIConfidence interval\n\nCTAComputerized tomography angiogram\n\nHDLHigh-density lipoprotein\n\nHgHemoglobin\n\nHLAHuman leukocyte antigens\n\nHRHazard ratio\n\nICAInternal carotid artery\n\nLDLLow density lipoprotein\n\nMCAMiddle cerebral artery\n\nMIMyocardial infarction\n\nNSTEMINon-ST elevation myocardial infarction\n\nOROdds ratios\n\nPASIPsoriasis Area and Severity Index\n\nRCARight coronary artery\n\nTEETransesophageal echocardiogram\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone.\n\nAuthors’ contributions\nJF, CH performed the data acquisition, analysis, and drafting of the manuscript. DS, GL, JH assisted with the analysis and interpretation of the pathology-specific data and the review of the manuscript. RC assisted with the data acquisition of the radiology images, figure creation, and the review of the manuscript. AK, KM, and CH assisted with the overall interpretation of the data and the review of the manuscript. All authors reviewed and approved of this manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nEthics approval and consent to participate\nNot applicable; see consent for publication.\n\nConsent for publication\nWritten informed consent was obtained from the next of kin for the publication of this case report, patient images, and lab data.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Tardif J-C Efficacy and safety of low-dose colchicine after myocardial infarction N Engl J Med 2019 381 26 2497 10.1056/NEJMoa1912388 31733140\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2377", "issue": "20(1)", "journal": "BMC neurology", "keywords": "Atherosclerosis; Psoriasis; Psoriatic arthritis; Stroke", "medline_ta": "BMC Neurol", "mesh_terms": "D015535:Arthritis, Psoriatic; D050197:Atherosclerosis; D015897:Comorbidity; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D024821:Metabolic Syndrome; D008875:Middle Aged; D011565:Psoriasis; D012307:Risk Factors; D020521:Stroke", "nlm_unique_id": "100968555", "other_id": null, "pages": "106", "pmc": null, "pmid": "32199449", "pubdate": "2020-03-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23360868;31733140;29295598;9887164;27696731;19022533;22736087;15843671;28917453;22392612;18697777;23557749;21173301;25303139;17553036;25814357;25351522;24642015;22161801;4056119;17330278;17032986;21600738;21905258;23221331;26425147;21777216;17665475;18294316;17052489;25561362;22897416;16365254;21098427;30150978;23845149;19458634;8181179;11955534", "title": "Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report.", "title_normalized": "catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis a case report" }

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{ "abstract": "BACKGROUND Myocardial bridging, although frequent, is often a forgotten cause of angina. It is a congenital anomaly in which the coronary artery tunnels through the myocardium with the overlying muscle, termed a myocardial bridge. The tunneled artery is prone to increased myocardial compression, mechanical load, endothelial damage, and vascular remodeling. During myocardial systole, the tunneled artery undergoes narrowing caused by myocardial compression, which leads to disruption of blood flow, thereby precipitating angina, arrhythmias, infarction, and sudden cardiac death. CASE REPORT Here, we present a case of a 29-year-old white woman who presented with atypical left-sided achy chest pain, occurring primarily at rest. Further evaluation showed mildly elevated troponins, with normal electrocardiogram, chest x-ray, and CTA chest. She subsequently underwent coronary angiography and was found to have myocardial bridging of her left anterior descending artery, with compression of up to 40% during systole. She was initially treated with diltiazem, but due to adverse effects was transitioned to metoprolol succinate, which she has tolerated well. CONCLUSIONS Myocardial bridging, although benign in nature, carries a vast array of complications requiring these patients to undergo prompt diagnosis and treatment. Vascular spasm, wall stress of the tunneled artery, and intensity of systolic constriction coupled with any delay in management can lead to ischemia, infarction, dysrhythmias, and death. Therefore, it is imperative that patients who have low clinical suspicion for atherosclerosis but who are presenting with anginal equivalents undergo coronary angiography to assess for myocardial bridging and receive immediate treatment.", "affiliations": "Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.;Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, USA.", "authors": "Duymun|Shahnaz|S|;Misodi|Emmanuel|E|", "chemical_list": "D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D014336:Troponin; D008790:Metoprolol", "country": "United States", "delete": false, "doi": "10.12659/AJCR.923075", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32683394\n10.12659/AJCR.923075\n923075\nArtilces\nMyocardial Bridging: A Case Presentation of Atypical Chest Pain Syndrome in a Young Woman\nDuymun Shahnaz EF Misodi Emmanuel E Department of Medicine, Arnot Ogden Medical Center, Elmira, NY, U.S.A.\nCorresponding Author: Shahnaz Duymun, e-mail: [email protected]’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n19 7 2020 \n21 e923075-1 e923075-5\n25 1 2020 30 4 2020 20 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 29-year-old\n\nFinal Diagnosis: Myocardial bridging\n\nSymptoms: Chest pain\n\nMedication: —\n\nClinical Procedure: Coronary angiography • CT scan • echocardiography\n\nSpecialty: Cardiology • General and Internal Medicine\n\nObjective:\nRare disease\n\nBackground:\nMyocardial bridging, although frequent, is often a forgotten cause of angina. It is a congenital anomaly in which the coronary artery tunnels through the myocardium with the overlying muscle, termed a myocardial bridge. The tunneled artery is prone to increased myocardial compression, mechanical load, endothelial damage, and vascular remodeling. During myocardial systole, the tunneled artery undergoes narrowing caused by myocardial compression, which leads to disruption of blood flow, thereby precipitating angina, arrhythmias, infarction, and sudden cardiac death.\n\nCase Report:\nHere, we present a case of a 29-year-old white woman who presented with atypical left-sided achy chest pain, occurring primarily at rest. Further evaluation showed mildly elevated troponins, with normal electrocardiogram, chest x-ray, and CTA chest. She subsequently underwent coronary angiography and was found to have myocardial bridging of her left anterior descending artery, with compression of up to 40% during systole. She was initially treated with diltiazem, but due to adverse effects was transitioned to metoprolol succinate, which she has tolerated well.\n\nConclusions:\nMyocardial bridging, although benign in nature, carries a vast array of complications requiring these patients to undergo prompt diagnosis and treatment. Vascular spasm, wall stress of the tunneled artery, and intensity of systolic constriction coupled with any delay in management can lead to ischemia, infarction, dysrhythmias, and death. Therefore, it is imperative that patients who have low clinical suspicion for atherosclerosis but who are presenting with anginal equivalents undergo coronary angiography to assess for myocardial bridging and receive immediate treatment.\n\nMeSH Keywords:\nCoronary AngiographyCoronary Vessel AnomaliesMyocardial Bridging\n==== Body\nBackground\nMyocardial bridging is a congenital variant of the coronary artery vasculature in which the vessel tunnels through the myocardium rather than running a typical epicardial course. The prevalence ranges anywhere from 0.5% to 85%, noted mostly on coronary angiography and autopsy [1]. It is primarily believed to be a benign finding, but it has been reported to cause myocardial ischemia, infarction, arrhythmias, and even sudden cardiac death [2]. These complications arise when the tunneled artery becomes compressed during systole and the stress and damage the vessel undergoes from the overlying muscle fibers and increased flow velocity. Treatment is therefore targeted towards decreasing the length and force of the contraction these arteries undergo. First-line therapy includes negative inotropic and chronotropic agents such as beta-blockers and calcium-channel blockers. Ivabradine and anti-platelet therapy could also be used if needed. If medical therapy fails to control symptoms, surgical intervention is warranted.\n\nCase Report\nWe present the case of a 29-year-old white woman with no significant past medical history who developed a sudden achy non-radiating pain in her left chest. It occurred while at rest and lasted approximately 30 minutes, with resolution after aspirin administration. She had associated left-hand pain and numbness but did not experience diaphoresis, dyspnea, nausea, lightheadedness, or headaches.\n\nShe had a Mirena IUD in place and had no known drug allergies. She had smoked one-half to one pack per day for 11 years but quit intermittently during her pregnancies. She drank alcohol occasionally but does not use any illicit drugs. Her family history was significant for a father with early coronary artery disease and stent placement in his early 40s.\n\nUpon admission, she was found to have an elevated troponin of 0.36, which remained relatively stable throughout her hospital stay. A urine drug screen was negative, minimizing the suspicion of drug-induced ischemia. D-dimer was obtained out of concern for a pulmonary embolus, but it was negative. Vasculitic pathology was considered; therefore, ESR and ANA were obtained, both of which were negative. CK and CK-MMB were both within normal limits, at 64 and 0.9, respectively, and a lipid panel was unremarkable. She was observed on a telemetry unit during her stay, without any major arrhythmias identified or worsening of symptoms.\n\nEKG revealed normal sinus rhythm and did not exhibit any acute ischemic changes (Figure 1). Chest radiography showed clear lungs without pleural effusions or consolidations. A CTA chest was obtained, which revealed clear lungs and no pulmonary embolus. The heart was normal in shape and size. No pericardial effusion or pulmonary vascular congestion were noted. An echocardiogram was performed, revealing a hyper-dynamic myocardium with an ejection fraction of 60–65%. Otherwise, echocardiography was unremarkable. She subsequently underwent a cardiac catheterization, which revealed a tubular zone of myocardial bridging of the left anterior descending artery with a mid-vessel lesion of 40% (Figure 2). She was started on aspirin and diltiazem and discharged home.\n\nUpon outpatient follow-up with cardiology, there was concern regarding diltiazem as she experienced episodes of lightheadedness and restless legs while taking the medication. Thus, she was switched to metoprolol succinate for therapy, which she has been tolerating well.\n\nDiscussion\nMyocardial bridging is a congenital anomaly described as tunneling of a coronary artery through the myocardium rather than running a typical epicardial course. Its prevalence ranges from 0.5% to 29.4% when detected by angiographic procedures; however, by autopsy, occurrences are noted to range from 5.4% to 85% [1]. Myocardial bridging most commonly involves the left anterior descending artery, as demonstrated in our patient, but there have been a few case reports of involvement of the right coronary artery. Typically a benign feature, symptoms usually do not appear until the third decade of life. Symptoms may include anginal equivalents, arrhythmias, and sudden cardiac death. The mechanism behind these symptoms lies in the disturbance of blood flow through the tunneled artery. There is enhanced myocardial compression in which the vessel enters into the myocardium, leading to a disturbance of blood flow to the rest of the myocardium. This disturbance mainly occurs during systole and is resolved in the diastolic phase. This transient hypoperfusion is thought to be the cause of presenting symptoms, myocardial ischemia, infarction, and sudden cardiac death. Our patient only described symptoms during rest; however, they can also occur with exertion.\n\nDuring rest, there is vasospasm of the tunneled artery, as well as mechanical trauma to the vessel wall. The inherent nature of the tunneled artery, coursing through the myocardium, causes the arterial wall to undergo an increased amount of oscillatory wall shear stress, prompting increased vascular cell adhesion molecule expression, reactive oxygen species production, and the development of pro-atherogenic endothelial cells. Together, the overexpression of these molecules and cells stimulate endothelial injury and plaque formation, leading to chest pain syndromes, dysrhythmias, ischemia, and death [3]. During exercise, ischemia is mediated by effort-induced tachycardia, which increases myocardial oxygen demand, contractility, and flow velocity, and reduces the coronary flow [4,5]. Symptoms and complications of myocardial bridging are associated with the degree of systolic narrowing, depth of tunneled artery, number of tunneled segments, and high heart rate [5,6].\n\nResting electrocardiograms rarely show any abnormalities in these patients; therefore, other modalities are needed to identify myocardial bridging. Coronary angiography remains the criterion standard of diagnosing the presence of myocardial bridging. The systolic compression of the tunneled artery is portrayed as a “milking effect” on coronary angiography, demonstrated as retrograde blood flow and subsequent antegrade flow with expansion of the vessel diameter during diastole. Other invasive studies such as intravascular ultra-sound and intracoronary Doppler sonography can be used for diagnosis. Intravascular ultrasound characterizes the length, thickness, and location of the myocardial bridge. It is seen as a “half-moon” sign, demonstrated by an echolucent area between the bridged artery and the epicardial tissue that persists throughout the cardiac cycle [3]. Intracoronary Doppler demonstrates a diastolic fingertip phenomenon specific for myocardial bridging, characterized by rapid diastolic blood flow followed by a plateau in the bridged segment [7].\n\nNoninvasive studies such as cardiac CT, cardiac MRI, and transthoracic echocardiography can also be used to diagnose myocardial bridging, but these are not the modalities of choice. Cardiac CT is a currently evolving method as an alternative to diagnosing coronary anomalies. It provides information regarding the lumen and walls of the coronary arteries and is effective in evaluating coronary anomalies, as well as atherosclerosis, stent patency, bypass grafts, and myocardial irregularities [8]. It offers the advantage of being noninvasive, using lower doses of radiation, and usefulness in treatment planning. Although is not the criterion standard for diagnosis, cardiac CT would have been a great option to diagnose myocardial bridging in our patient, given the low pretest probability of discovering significant coronary atherosclerosis on angiography as the cause of her presentation in light of her young age and minimal risk factors.\n\nOur patient, without any significant cardiac history or risk factors, was found to have a 40% lesion of the mid-LAD from myocardial bridging, likely due to the effects of shear stress of the tunneled artery from repetitive compression. It is unclear if her family history of early coronary disease had an impact on her coronary anomaly. Cerit found that patients with myocardial bridging have increased levels of inflammatory markers, neutrophil-to-lymphocyte ratio, and platelet activity [9]. It is well known that increased platelet activity and increased neutrophils play a key role in the development and destabilization of atherosclerotic plaques in cardiovascular disease. Although she did not exhibit any atherosclerosis on angiography, there may have been a genetic component of platelet and neutrophil activity contributing to her symptoms, especially given the history of early cardiovascular disease in her father.\n\nGiven the pathophysiology underlying myocardial bridging, treatment is focused on decreasing the compression of intramyocardial arteries via decreasing systolic contraction and prolonging the diastolic phase. First-line therapy includes negative inotropic and chronotropic agents such as beta-blockers and calcium-channel blockers, both of which were used in our patient. These agents lower transmural pressures, reducing the compression of the tunneled artery and prolonging diastole, thus mitigating symptoms. They have the added benefit of reducing heart rates, thus decreasing the frequency of systolic compression and increasing the diastolic period. Ivabradine has also been shown to have an effect on myocardial bridges by inhibiting the pacemaker current, thus decreasing heart rates and subsequently prolonging diastole [1]. If atherosclerosis is present, anti-platelet therapy can be used as an adjunct. Drugs to avoid include pure vasodilating agents such as nitrates, as they intensify systolic compression of the tunneled segment, leading to retrograde flow and thus worsening symptoms [3]. Intracoronary injection of dobutamine, epinephrine, and isoprotenerol was also shown to exacerbate vessel narrowing during systole and delay diastolic relaxation [5]. If symptoms persist despite medical therapy, intracoronary stenting or surgical myotomy can be considered, as these measures also counteract transmural pressures [10]. Minimally invasive coronary artery bypass grafting has also been reported as an option for the management of myocardial bridges [11].\n\nIn evaluating the cause of atypical chest pain syndromes in patients with low risk for atherosclerosis, as in this case, it is also important to consider other nonatherosclerotic causes of myocardial injury such as MINOCA (myocardial infarction with nonobstructive coronary arteries), microvascular angina, vascular spasm, coronary dissection, and coagulation disorders, as they can present similarly. MINOCA occurs in patients presenting with an acute myocardial infarction but in the absence of obstructing coronary disease, with no lesion greater than 50% and without another explanation for the presentation [12]. It is mostly seen in younger female patients presenting with NSTEMI, similar to our patient [13]. MINOCA was considered in this case, but with the angiographic findings of the existing myocardial bridge, we postulated that our patient’s presentation was due to the bridge. Microvascular angina, vascular spasms, and coronary dissection could also be considered; however, with no change in electrocardiography and the findings of myocardial bridging on angiography, our suspicion for other causes remained low. Nonetheless, it is imperative to perform complete imaging studies for diagnosing coronary anomalies in patients that have low pretest probability of atherosclerosis but who are presenting with anginal equivalents, as these anomalies can cause significant complications.\n\nConclusions\nMyocardial bridging is a frequent but often forgotten cause of angina and can be present in up to 25% of the population. Patients can present with a variety of symptoms, including angina and dysrhythmias, but the vast array of complications arising from myocardial bridging require these patients to undergo prompt coronary angiography. Vascular spasm, wall stress of the tunneled artery, and intensity of systolic constriction coupled with any delay in management can lead to ischemia, infarction, and sudden cardiac death. Therefore, it is imperative that patients for whom there is low clinical suspicion for atherosclerosis but who are presenting with anginal equivalents undergo coronary angiography to assess for myocardial bridging and receive immediate treatment for this coronary anomaly.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Electrocardiogram of our patient with myocardial bridging demonstrating normal sinus rhythm without any acute ischemic changes.\n\nFigure 2. Coronary angiography of our patient, demonstrating compression of the left anterior descending artery during systole (red circle).\n==== Refs\nReferences:\n1. Tarantini G Migliore F Cademartiri F Left anterior descending artery myocardial bridging J Am Coll Cardiol 2016 68 2887 99 28007148 \n2. Hostiuc S Rusu MC Hostiuc M Cardiovascular consequences of myocardial bridging: A meta-analysis and meta-regression Sci Rep 2017 7 1 14644 29116137 \n3. Corban M Hung OY Eshtehardi P Myocardial bridging: Contemporary understanding of pathophysiology with implications for diagnostic and therapeutic strategies J Am Coll Cardiol 2014 63 2346 55 24583304 \n4. Corrado D Thiene G Cocco P Frescura C Non-atherosclerotic coronary artery disease and sudden death in the young Br Heart J 1992 68 601 7 1467055 \n5. Dwyer J Coronary artery bridging as an etiology for non-atherosclerotic myocardial infarction: A review of literature and case history J Cardio Case Rep 2019 2 1 6 \n6. Mohlenkamp S Hort W Ge J Erbel R Update on myocardial bridging Circulation 2002 106 2616 22 12427660 \n7. Lovell MJ Knight CJ Invasive assessment of myocardial bridges Heart 2003 89 699 700 12807830 \n8. Hazirolan T Canyigit M Karcaaltincaba M Myocardial bridging on MDCT AmJ Roentgenol 2007 188 1074 80 17377050 \n9. Cerit L Assessment of indirect inflammatory markers in patients with myocardial bridging Cardiovasc J Afr 2017 28 182 85 27805707 \n10. Wan L Wu Q Myocardial bridge, surgery or stenting? Interact Cardiovasc Thorac Surg 2005 4 517 20 17670472 \n11. Ripa C Melatini MC Olivieri F Antonicelli R Myocardial bridging: A ‘forgotten’ cause of acute coronary syndrome – a case report Int J Angiol 2007 16 115 18 22477305 \n12. Tamis-Holland JE Jneid H Reynolds HR Contemporary diagnosis and management of patients with myocardial infarction in the absence of obstructive coronary artery disease Circulation 2019 139 891 908 \n13. Rakowski T De Luca G Sludak Z Characteristics of patients presenting with myocardial infarction with non-obstructive coronary arteries (MINOCA) in Poland: Data from the ORPKI national registry J Thromb Thrombolysis 2019 47 462 66 30565147\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "21()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D002637:Chest Pain; D017023:Coronary Angiography; D005260:Female; D006801:Humans; D008790:Metoprolol; D054084:Myocardial Bridging; D014336:Troponin", "nlm_unique_id": "101489566", "other_id": null, "pages": "e923075", "pmc": null, "pmid": "32683394", "pubdate": "2020-07-19", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "30565147;12807830;29116137;17377050;28007148;30913893;22477305;1467055;27805707;12427660;17670472;24583304", "title": "Myocardial Bridging: A Case Presentation of Atypical Chest Pain Syndrome in a Young Woman.", "title_normalized": "myocardial bridging a case presentation of atypical chest pain syndrome in a young woman" }

[ { "companynumb": "US-APOTEX-2020AP017156", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL BRIDGING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN [ACETYLSALICYLIC ACID]" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074943", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "MYOCARDIAL BRIDGING", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DILTIAZEM." } ], "patientagegroup": null, "patientonsetage": "29", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Restless legs syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dizziness", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DUYMUN S, MISODI E.. MYOCARDIAL BRIDGING: A CASE PRESENTATION OF ATYPICAL CHEST PAIN SYNDROME IN A YOUNG WOMAN.. AMERICAN JOURNAL OF CASE REPORTS. 2020?21: E923075:1?5", "literaturereference_normalized": "myocardial bridging a case presentation of atypical chest pain syndrome in a young woman", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210906", "receivedate": "20210906", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19791088, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "Coronavirus disease 2019 (COVID-19) is a global pandemic, and it is increasingly important that physicians recognize and understand its atypical presentations. Neurological symptoms such as anosmia, altered mental status, headache, and myalgias may arise due to direct injury to the nervous system or by indirectly precipitating coagulopathies. We present the first COVID-19 related cases of carotid artery thrombosis and acute PRES-like leukoencephalopathy with multifocal hemorrhage.", "affiliations": "Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA. Electronic address: [email protected].;Mount Sinai Health System, Internal Medicine, 1000 10th Ave, New York 10019, NY, USA.;Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA.;Mount Sinai Health System, Neurology, 1000 10th Ave, New York 10019, NY, USA.;Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA.;Mount Sinai Health System, Diagnostic, Molecular and Interventional Radiology, 1000 10th Avenue, Radiology, 4B 25, New York 10019, NY, USA.", "authors": "Doo|Florence X|FX|;Kassim|Gassan|G|;Lefton|Daniel R|DR|;Patterson|Shanna|S|;Pham|Hien|H|;Belani|Puneet|P|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clinimag.2020.07.007", "fulltext": null, "fulltext_license": null, "issn_linking": "0899-7071", "issue": "69()", "journal": "Clinical imaging", "keywords": "COVID-19; Carotid thrombosis; Infection; Leukoencephalopathy; Stroke", "medline_ta": "Clin Imaging", "mesh_terms": "D000086382:COVID-19; D002341:Carotid Artery Thrombosis; D018352:Coronavirus Infections; D006801:Humans; D056784:Leukoencephalopathies; D058873:Pandemics; D011024:Pneumonia, Viral; D000086402:SARS-CoV-2", "nlm_unique_id": "8911831", "other_id": null, "pages": "94-101", "pmc": null, "pmid": "32707411", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "32133578;24632711;32469400;32299017;19940660;32167747;17885064;32338827;32305883;31986264;32268022;18356474;32275288;32229625;32299010;32228363;15141377;32240279;18403560;18390877;32385132;32291094;32142651;16252612", "title": "Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.", "title_normalized": "rare presentations of covid 19 pres like leukoencephalopathy and carotid thrombosis" }

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RARE PRESENTATIONS OF COVID?19: PRES?LIKE LEUKOENCEPHALOPATHY AND CAROTID THROMBOSIS. CLINICAL IMAGING. 2021?69:94?101", "literaturereference_normalized": "rare presentations of covid 19 pres like leukoencephalopathy and carotid thrombosis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210531", "receivedate": "20210531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19349929, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "US-009507513-2008USA002228", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPTIFIBATIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "020718", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CAROTID ARTERY THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTEGRILIN" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DOO FX, KASSIM G, LEFTON DR, PATTERSON S, PHAM H, BELANI P.. 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{ "abstract": "This retrospective analysis of data from heroin users screening for clinical research, sought to determine if more naloxone is needed to precipitate opioid withdrawal among those who regularly use heroin with fentanyl, as opposed to those who use heroin without fentanyl.\n\n\n\nOver the course of three to five screening visits, participants completed assessments of drug use, along with urine toxicology tests at each visit. To test for opioid dependence, 29 participants completed a modified Wang test (score: 0-150) during which an intramuscular dose of naloxone (0.2-0.4 mg) was administered and the severity of withdrawal was quantified.\n\n\n\nThe severity of opioid withdrawal was compared between individuals whose urine toxicology regularly tested positive for fentanyl (N = 15), and those only positive for other opioids (N = 14). No significant differences were found in demographic or drug use between the fentanyl-positive (mean: age 41.1 years, 9.1 bags heroin/d) and fentanyl-negative (42.0 years, 10.0 bags heroin/d) groups. Intramuscular naloxone-precipitated robust withdrawal in both samples (P < .01) with no significant difference (P = .8) in the severity (fentanyl positive [100.6 ± 13.4]; fentanyl negative [82.7 ± 9.6]).\n\n\n\nThese data suggest that a standard naloxone dose can be equally effective at precipitating withdrawal in individuals using heroin with fentanyl compared to heroin without fentanyl. These data contribute to our understanding of how naloxone antagonizes the effects of fentanyl and may have significant implications for the clinical laboratory and opioid overdose. A prospective clinical laboratory study with the proper opioid maintenance controls is needed to provide a more definitive finding. (Am J Addict 2019;00:00-00).", "affiliations": "Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.;Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Vagelos College of Physicians and Surgeons, New York, New York.", "authors": "Jones|Jermaine D|JD|0000-0003-4476-2800;Sherwin|Elliana|E|;Martinez|Suky|S|;Comer|Sandra D|SD|", "chemical_list": "D009292:Narcotic Antagonists; D009270:Naloxone; D005283:Fentanyl", "country": "England", "delete": false, "doi": "10.1111/ajad.12979", "fulltext": null, "fulltext_license": null, "issn_linking": "1055-0496", "issue": "29(1)", "journal": "The American journal on addictions", "keywords": null, "medline_ta": "Am J Addict", "mesh_terms": "D000328:Adult; D005260:Female; D005283:Fentanyl; D006556:Heroin Dependence; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D010865:Pilot Projects; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome; D055815:Young Adult", "nlm_unique_id": "9208821", "other_id": null, "pages": "51-56", "pmc": null, "pmid": "31782591", "pubdate": "2020-01", "publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.", "references": "26095483;29042317;18397839;28859052;28687187;30861160;30204554;28068563;27560775;2763981;4422361;720211", "title": "Naloxone-Induced Withdrawal in Individuals With and Without Fentanyl-Positive Urine Samples.", "title_normalized": "naloxone induced withdrawal in individuals with and without fentanyl positive urine samples" }

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NALOXONE-INDUCED WITHDRAWAL IN INDIVIDUALS WITH AND WITHOUT FENTANYL-POSITIVE URINE SAMPLES.. 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NALOXONE-INDUCED WITHDRAWAL IN INDIVIDUALS WITH AND WITHOUT FENTANYL-POSITIVE URINE SAMPLES.. 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NALOXONE-INDUCED WITHDRAWAL IN INDIVIDUALS WITH AND WITHOUT FENTANYL-POSITIVE URINE SAMPLES.. THE AMERICAN JOURNAL ON ADDICTIONS. 2020?29(1):51-6", "literaturereference_normalized": "naloxone induced withdrawal in individuals with and without fentanyl positive urine samples", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200224", "receivedate": "20200224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17452473, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "Introduction Fetal exposition to valproate can lead to a cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. Case Report In this report we describe 2 cases of fetal valproate syndrome. In the first case, the gravida had a valproate medication before and during pregnancy with additional folic acid. She delivered a male premature infant at 25+2 weeks of gestation due to preterm labor and rupture of the membranes. Physical examination showed even in the premature infant typical signs of fetal valproate syndrome with trigonocephaly, epicanthal folds, broad root of the nose, low-set ears, thin upper lip and anteverted nares. In the second case, the gravida was under antiepileptic therapy with valproate and lamotrigine before and during pregnancy without any prophylaxis with folic acid. Sonographic examination during pregnancy diagnosed a spina bifida, Chiari II malformation and clubfeet. A female newborn was delivered at 39+4 weeks of gestation. Besides the prenatally detected anomalies, facial dysmorphism including microcephaly, low-set ears, thin upper lip and shallow philtrum were seen after birth. Conclusion Valproate, a widely used anticonvulsant medication, is known for its teratogenic effects. The risk of congenital anomalies is even higher in combination with other antiepileptic drugs. Therefore, the avoidance of valproate or at least supplementation with a high dose prophylactic folic acid before and during pregnancy is highly recommended for women with epilepsy.", "affiliations": "Neonatology, University Children's Hospital, Würzburg, Germany.;Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.;Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.;Neonatology, University Children's Hospital, Würzburg, Germany.", "authors": "Wiedemann|Katharina|K|;Stüber|Tanja|T|;Rehn|Monika|M|;Frieauff|Eric|E|", "chemical_list": "D000927:Anticonvulsants; D014635:Valproic Acid; D005492:Folic Acid; D000077213:Lamotrigine", "country": "Germany", "delete": false, "doi": "10.1055/s-0043-107619", "fulltext": null, "fulltext_license": null, "issn_linking": "0948-2393", "issue": "221(5)", "journal": "Zeitschrift fur Geburtshilfe und Neonatologie", "keywords": null, "medline_ta": "Z Geburtshilfe Neonatol", "mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000927:Anticonvulsants; D002585:Cesarean Section; D004359:Drug Therapy, Combination; D004827:Epilepsy; D005260:Female; D005492:Folic Acid; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D000077213:Lamotrigine; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications; D011262:Pregnancy Trimester, Second; D012307:Risk Factors; D013577:Syndrome; D014635:Valproic Acid", "nlm_unique_id": "9508901", "other_id": null, "pages": "243-246", "pmc": null, "pmid": "29073690", "pubdate": "2017-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Fetal Valproate Syndrome - Still a Problem Today!", "title_normalized": "fetal valproate syndrome still a problem today" }

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Z-GEBURTSHILFE-NEONATOL 2017?221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190131", "receivedate": "20190131", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15897484, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "DE-BION-006744", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "073484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "3", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": ".9", "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY. Z GEBURTSHILFE NEONATOL. 2017 OCT;221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20171113", "receivedate": "20171113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14182364, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" }, { "companynumb": "DE-TEVA-2019-DE-1007462", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "76941", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MILLIGRAM DAILY; 1/2-0-1 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "76420", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200 MILLIGRAM DAILY; 1-0-1 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z-GEBURTSHILFE-NEONATOL 2017?221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190206", "receivedate": "20190206", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15925777, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "DE-CIPLA LTD.-2017DE20075", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "090035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemangioma of bone", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z GEBURTSHILFE NEONATOL. 2017?221(5):243 TO 246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180220", "receivedate": "20171115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14189447, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" }, { "companynumb": "DE-GLAXOSMITHKLINE-DE2019GSK014579", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "020241", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Spina bifida", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low set ears", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arnold-Chiari malformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital oral malformation", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Microcephaly", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Talipes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysmorphism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ill-defined disorder", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE. 2017?221 (5):243-246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190128", "receivedate": "20190128", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15880557, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "DE-CIPLA LTD.-2017DE20073", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2X0.4 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3X600 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature rupture of membranes", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature labour", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z GEBURTSHILFE NEONATOL. 2017?221(5):243 TO 246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180220", "receivedate": "20171115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14189448, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180508" }, { "companynumb": "DE-ABBVIE-18P-062-2270871-00", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "018081", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL EXPOSURE TIMING UNSPECIFIED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningomyelocele", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital anomaly", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Talipes", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dysmorphism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Spina bifida", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Microcephaly", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Paralysis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrial septal defect", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac aneurysm", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low set ears", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Congenital flaccid paralysis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cerebral ventricle dilatation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arnold-Chiari malformation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Head circumference abnormal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, ET AL. FETAL VALPROATE SYNDROME STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE. 2017 OCT?221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20180409", "receivedate": "20180307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14610306, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180711" }, { "companynumb": "DE-NUVO PHARMACEUTICALS INC-2085930", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "204418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOETAL EXPOSURE DURING PREGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE SODIUM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": ".9", "reaction": [ { "reactionmeddrapt": "Haemangioma", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypospadias", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Prominent epicanthal folds", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Low set ears", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hypermobility syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Dysmorphism", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pericardial cyst", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "23.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Inguinal hernia", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. 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FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. 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FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY. Z GEBURTSH NEONATOL. 2017;221:243-246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20171114", "receivedate": "20171114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14186132, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "DE-CIPLA LTD.-2017DE20078", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SODIUM VALPROATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "077783", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arnold-Chiari malformation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. Z GEBURTSHILFE NEONATOL. 2017?221 (5):243 TO 246", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180220", "receivedate": "20171228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14331535, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "DE-BION-006745", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1-0-1 DOSAGE", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "073484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5-0-1 DOSAGE", "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROIC ACID." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": "2.5", "reaction": [ { "reactionmeddrapt": "Foetal anticonvulsant syndrome", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUFF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY. Z GEBURTSHILFE NEONATOL. 2017 OCT;221(5):243-246.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20171113", "receivedate": "20171113", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14182051, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" }, { "companynumb": "DE-SUNRISE PHARMACEUTICAL, INC.-2079045", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204418", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EPILEPSY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROATE SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALPROATE SODIUM." } ], "patientagegroup": null, "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature labour", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature rupture of membranes", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WIEDEMANN K, STUBER T, REHN M, FRIEAUF E. FETAL VALPROATE SYNDROME - STILL A PROBLEM TODAY!. ZEITSCHRIFT FUR GEBURTSHILFE UND NEONATOLOGIE 221: 243-246, NO. 5, 2017. URL: HTTP://DOI.ORG/10.1055/S-0043-107619.", "literaturereference_normalized": "fetal valproate syndrome still a problem today", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 17272251, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "The aim of this study was to evaluate the incidence of a variety of infectious complications in patients with CLL regarding the duration of CLL and the type of treatment. We present the retrospective analysis of patients with CLL treated at our institution in years 2004-2016. We collected data about the type of infection, pathogenes, treatment and severity of infections surpassed in connection with administration treatment. In the study one hundred and ten patients were evaluated. The average age of patients was 61.7 years (range 34.5-91.9 years). Fludarabine was the most widely used regimen, followed by bendamustine and alemtuzumab. We recorded 393 episodes of infections, of which 114 (29%) were severe and life threatening of degree 3-5, and 279 (71%) of degree 2. The most common infections were the upper respiratory tract infections together with sinusitis (45.03%), pneumonia (26.20%), CMV reactivation occured in 8.14%, infections of the skin was in 7.6 %. Most infections have occurred with the administration of monoclonal antibody alemtuzumab, these patients were at significantly higher risk of infection [RR 2.59 (1.30 to 5.17)] than patients receiving obinutuzumab [RR 0.63 (0.48 to 0.82)] (p = 0.0001). On the contrary, the safety profile of BCR signaling pathway inhibitors was very acceptable [RR 1.17 (0.70 - 1.96)]. The number of infections have decreased during the first 12 months of treatment with ibrutinib. In the study group we recorded 19 deaths, 8 (7.27%) of them were of infectious etiology. The risk of infectious complications is lifelong in patients with CLL, it can be minimized by early detection and aggressive management. Novel targeted agents used in therapy of CLL have a good safety profile, even the risk of infection is decreased during administration.", "affiliations": null, "authors": "Demitrovicova|L|L|;Mikuskova|E|E|;Oravcova|I|I|;Cingelova|S|S|;Drgona|L|L|;Mladosievicova|B|B|", "chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074323:Alemtuzumab; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine", "country": "Slovakia", "delete": false, "doi": "10.4149/neo_2017_320", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-2685", "issue": "64(3)", "journal": "Neoplasma", "keywords": "chronic lymphocytic leukemia; infectious complications; inhibitors of BCR signaling monoclonal antibodies.", "medline_ta": "Neoplasma", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000069461:Bendamustine Hydrochloride; D006801:Humans; D007239:Infections; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008875:Middle Aged; D011014:Pneumonia; D012141:Respiratory Tract Infections; D012189:Retrospective Studies; D012852:Sinusitis; D014740:Vidarabine", "nlm_unique_id": "0377266", "other_id": null, "pages": "474-481", "pmc": null, "pmid": "28503927", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": null, "title": "Infectious complications in chronic lymphocytic leukemia- a retrospective analysis: single institution experience.", "title_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience" }

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"OFATUMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IDELALISIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDELALISIB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cholecystitis infective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterocolitis infectious", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ear infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeria sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L, MIKUSKOVA E, ORAVCOVA I, CINGELOVA S, DRGONA I, MLADOSIEVIGOVA B.. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA.. 2017?64(3):474-81", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20190214", "receivedate": "20190214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15963778, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "SK-FRESENIUS KABI-FK201706792", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L,MIKUSKOVA E,ORAVCOVA I,CINGELOVA S,DRGONA L,MLADOSIEVICOVA B. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA 2017;64(3):474-481.", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20170809", "receivedate": "20170809", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13851148, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20171127" }, { "companynumb": "SK-ACCORD-105870", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CHLORAMBUCIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE/CYCLOPHOSPHAMIDE MONOHYDRATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IDELALISIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDELALISIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OBINUTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OBINUTUZUMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BENDAMUSTINE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "205574", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE/BENDAMUSTINE HYDROCHLORIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OFATUMUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFATUMUMAB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IBRUTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBRUTINIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALEMTUZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia fungal", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Enterocolitis infectious", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary mycosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cholecystitis infective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Viral infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeria sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ear infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Meningitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEMITROVICOVA L,MIKUSKOVA E,ORAVCOVA I,CINGELOVA S,DRGONA L,MLADOSIEVICOVA B. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA 2017?64(3):474-481.", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20190208", "receivedate": "20190208", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15937086, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "SK-ASPEN-GLO2018SK005736", "fulfillexpeditecriteria": "1", "occurcountry": "SK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OBINUTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OBINUTUZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENDAMUSTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BENDAMUSTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBRUTINIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBRUTINIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IDELALISIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IDELALISIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CHLORAMBUCIL" }, "drugadditional": "3", "drugadministrationroute": 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null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OFATUMUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALEMTUZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALEMTUZUMAB" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Fungal infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Upper respiratory tract infection bacterial", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia fungal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Herpes zoster", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cholecystitis infective", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sinusitis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumocystis jirovecii infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Listeria sepsis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary tuberculosis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "21.0", "reactionoutcome": 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INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA - A RETROSPECTIVE ANALYSIS: SINGLE INSTITUTION EXPERIENCE.. NEOPLASMA. 2017?64(3):474-481", "literaturereference_normalized": "infectious complications in chronic lymphocytic leukemia a retrospective analysis single institution experience", "qualification": "3", "reportercountry": "SK" }, "primarysourcecountry": "SK", "receiptdate": "20180615", "receivedate": "20180615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15016180, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20180711" } ]

{ "abstract": "In December 2019, the World Health Organization (WHO) announced a series of pneumonia cases caused by an unknown origin, discovered in Wuhan, China. A dangerous virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a disease named acute respiratory syndrome, which was later popularly called coronavirus infection (COVID-19). Patients with acute COVID-19 are at high risk of thrombosis in various blood vessels due to hypercoagulability, blood stasis, and endothelial damage. In this study, we present a case report of a patient with COVID-19, who was hospitalized in one of the hospitals in Sanandaj, Iran. There were symptoms of fever, chills, muscle aches, cough, and tachycardia. Laboratory tests showed high levels of CRP, ESR, Ferritin CLIA, LDH and D-Dimer in this patient. Doppler ultrasound of the patient also revealed an abnormal finding, thrombosis in the right greater saphenous vein. This suggests that COVID-19 may lead to other negative effects through damage to blood vessels.", "affiliations": "School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia.;Department of Radiology, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.;Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. [email protected].", "authors": "Hesam-Shariati|Negin|N|;Fatehi|Poya|P|;Fathi|Fardin|F|;Abouzaripour|Morteza|M|;Hesam Shariati|Mohammad Bakhtiar|MB|http://orcid.org/0000-0002-2000-5197", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s40794-021-00131-9", "fulltext": "\n==== Front\nTrop Dis Travel Med Vaccines\nTrop Dis Travel Med Vaccines\nTropical Diseases, Travel Medicine and Vaccines\n2055-0936\nBioMed Central London\n\n131\n10.1186/s40794-021-00131-9\nCase Report\nA case report of greater saphenous vein thrombosis in a patient with coronavirus (COVID-19) infection\nHesam-Shariati Negin 1\nFatehi Poya 2\nFathi Fardin 3\nAbouzaripour Morteza 4\nhttp://orcid.org/0000-0002-2000-5197\nHesam Shariati Mohammad Bakhtiar [email protected]\[email protected]\n\n4\n1 grid.1005.4 0000 0004 4902 0432 School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia\n2 grid.484406.a 0000 0004 0417 6812 Department of Radiology, Tohid Hospital, Kurdistan University of Medical Sciences, Sanandaj, Iran\n3 grid.484406.a 0000 0004 0417 6812 Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran\n4 grid.484406.a 0000 0004 0417 6812 Department of Anatomical Sciences, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran\n3 3 2021\n3 3 2021\n2021\n7 630 9 2020\n21 2 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nIn December 2019, the World Health Organization (WHO) announced a series of pneumonia cases caused by an unknown origin, discovered in Wuhan, China. A dangerous virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a disease named acute respiratory syndrome, which was later popularly called coronavirus infection (COVID-19). Patients with acute COVID-19 are at high risk of thrombosis in various blood vessels due to hypercoagulability, blood stasis, and endothelial damage. In this study, we present a case report of a patient with COVID-19, who was hospitalized in one of the hospitals in Sanandaj, Iran. There were symptoms of fever, chills, muscle aches, cough, and tachycardia. Laboratory tests showed high levels of CRP, ESR, Ferritin CLIA, LDH and D-Dimer in this patient. Doppler ultrasound of the patient also revealed an abnormal finding, thrombosis in the right greater saphenous vein. This suggests that COVID-19 may lead to other negative effects through damage to blood vessels.\n\nKeywords\n\nSuperficial vein thrombosis\nCoronavirus\nCOVID-19\nUltrasonography\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nCoronavirus has been widespread around the world since early 2020. The disease is highly contagious and, in severe cases, can lead to acute respiratory syndrome or organ failure [1, 2]. In January 2020, the World Health Organization (WHO) announced the outbreak of the disease as a “public health emergency of international concern” [3]. To date, the virus has led to an unprecedented global health crisis that has resulted in over 2 million death worldwide [4].\n\nSeveral studies have shown that superficial vein thrombosis (SVT) is a common venous disease that appears to be medically benign but can cause serious complications and may be associated with complications such as deep vein thrombosis (DVT) and pulmonary embolism (PE) [5, 6]. The prevalence of SVT is estimated to be about 3 to 11%, while the incidence of thrombosis in the greater saphenous vein (GSV) is about 60 to 80% of the time [7, 8]. The proximity of the greater saphenous vein to the saphenofemoral junction (SFJ) increases the possibility of displacement of blood clots and their entry into the deep venous system and as a result makes SVT a serious concern [9].\n\nThere is a risk for venous and arterial thrombosis in patients with SARS-Cov2 due to excessive coagulation status, blood stasis, and damage to vascular endothelial cells in this condition [10]. As the clinical signs of venous and arterial thrombosis are ambiguous, it is very important to use imaging techniques such as Doppler ultrasound and computed tomography (CT) angiography to prevent catastrophic complications such as pulmonary embolism and mortality [11]. In this case report, the course of a patient with coronavirus is described.\n\nCase presentation\n\nA 40-year-old man with one-week symptoms of cough, fever, fatigue, muscle aches, diarrhea, palpitations, and shortness of breath but no chest pain was admitted to Tohid Hospital, Sanandaj, Iran. Before admission, the patient was diagnosed with COVID-19 by an infectious disease specialist based on the initial symptoms. Both CT scans (Fig. 1) and the real-time reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed the infection. The patient had no history of underlying diseases such as diabetes, heart disease, hypertension, or cancer. At the hospital’s emergency department, the physical examinations showed that the patient had an irregular heart rate of 145 beats/min, blood pressure of 82/75 mmHg, temperature of 38.4 °C, respiratory rate of 26 breaths/min, and oxygen saturation of 89%. Paraclinical and laboratory results showed that routine blood tests, renal function, and electrolytes were completely normal. The influenza A and B antigen tests were also negative. However, the other laboratory findings were all abnormal, which are briefly listed in Table 1. In CT scans of the lungs (Fig. 1), bronchovascular marking is evident. Additionally, multiple foci of parenchymal turbidity and ground-glass opacity were observed with greater density at the margins and at the base of the lungs. Therefore, the patient was started on medical treatment with Naproxen, Hydroxychloroquine, Famotidine, Zinc, Neurobion, and anticoagulants by injecting heparin and taking acetylsalicylic acid tablets. Fig. 1 Axial without contrast-enhanced chest computed tomography (CT) image showing a coronavirus disease (COVID-19) infection\n\nTable 1 The results of laboratory findings\n\n\tTest Name\tUnit\tReference range\tResults\tFlag\t\n1\tBUN\tmg/dl\t6–20\t32\tHi\t\n2\tCPK\tIU/L\tmale: 0–171\t55\t\t\n3\tLDH\tU/L\t235–470\t510\tHi\t\n4\tNa(ser)\tmEq/L\t138–145\t134\tLOW\t\n5\tK(ser)\tmEq/L\t3.6–5.9\t3.8\t\t\n6\tCr\tmg/dl\tmale:0.8–1.3 mg/dl\t0.7\tLOW\t\n7\tCRP\tmg/l\t0–6\t30\tHi\t\n8\tESR\tmm\t5–12\t18\tHi\t\n9\tFerritin CLIA\tng/mL\t50–434\t511\tHi\t\n10\tD-Dimer(CLIA-Siemens)\tng/mL\t< 885\t> 7500\tHi\t\n\nThree days after hospitalization, Doppler ultrasound was performed on the lower limb due to numbness and tingling (paresthesia) in the right leg, in addition to swelling, redness, pain, and sensitivity to touch. Examination of the main veins of both lower limbs showed no evidence of occlusion in the external iliac, common femoral, popliteal, anterior and posterior tibialis, and peroneal. However, more detailed examination revealed that thrombosis was evident at the beginning of the greater saphenous vein of the right leg from distal to proximal (Fig. 2). The patient was discharged after 12 days of hospitalization with complete recovery from COVID-19. The anticoagulation treatment for the GSV thrombosis was continued for the patient, and no negative side effect caused by SVT was reported after the treatment. Fig. 2 Doppler ultrasound images of the lower right limb showing a superficial vein thrombosis (SVT). Anterior accessory saphenous vein (AASV), great saphenous vein (GSV), common femoral vein (CFV), and common femoral artery (CFA) in the Doppler ultrasound images of the lower right limb\n\nDiscussion\n\nIn this case report, we presented a patient with COVID-19 who was hospitalized in Tohid Hospital, Sanandaj, Iran and later was diagnosed with a thrombosis in his right GSV. This patient had common COVID-19 symptoms such as fever, dry cough, shortness of breath, and muscle pain [12] but no risk factor for SVT. Paraclinical tests and CT scans of the chest confirmed the COVID-19 diagnosis, and although there was no obvious evidence of SVT, detailed examination by Doppler ultrasound revealed a thrombosis in the patient’s GSV.\n\nStudies have shown that the most important and stable hemostatic disorders associated with COVID-19 include mild thrombocytopenia [13] and an increase in D-dimer amount [14]. There is evidence showing thrombotic abnormalities, in addition to abnormalities in the function of various organs in patients with COVID-19 [15], which lead to higher mortality. However, as far as we can ascertain there are few reports of SVT and its side effects in patients with COVID-19.\n\nPathophysiologically, patients with COVID-19 may have a higher risk for developing venous thrombosis, usually due to diarrhea, hypotension, recurrent long-term infections, and dehydration [16]. Therefore, in patients with coronavirus, assessing the risk of DVT and SVT are essential to reduce complications and mortality risk. Studies have shown that patients prone to DVT usually have one of the following criteria: age over 75, respiratory and heart failure, history of previous thrombosis, acute onset of chronic pulmonary obstruction, acute cerebral infarction, malignant tumor, limb varicose veins, obesity, chronic kidney disease, inflammatory bowel disease, and more than 3 days of bed rest [17].\n\nIn one study on a patient with COVID-19, CT images of angiography showed signs of acute cerebral infarction and DVT in both lower limbs [18]. In our case report, the patient was suspected of having thromboembolism due to having similar lesions on his leg, however after a CT scan of his chest, his diagnosis with COVID-19 was confirmed, while there was no evidence of pulmonary thromboembolism. The physicians at the hospital also suspected SVT and DVT due to numbness, swelling, and pain in the right leg, which were examined by Doppler ultrasound of all blood vessels, including the common iliac, small saphenous, and greater saphenous. Since many studies have reported respiratory distress along with other clinical evidence of venous thrombosis, pulmonary embolism should be suspected [19, 20].\n\nA recent study on the intensive care unit (ICU) patients with COVID-19 found that the rate of thrombotic disorders in these patients is 31% [21]. Further, medical images have shown that 27% of such thrombotic disorders are due to venous thromboembolism, 3.7% to arterial thrombosis, and 81% to pulmonary embolism, which is the most common complication of thrombosis in ICU patients [21]. The possible reasons for venous thrombosis may include the fact that COVID-19 attacks the human body via the 2-angiotensin converting enzyme, which is found in various blood vessels and organs of the body [22]. Ultimately, coronaviruses cause cytokine waterfalls, including IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα in the body, which can increase the risk of complications such as blood clots. This cytokine storm can be associated with the severity of the disease and its negative consequences [23, 24]. Blood clots formed in DVT may also have a variety of causes, including vascular damage, surgery, special medications, and limited mobility [25], but the exact cause of COVID-19-induced DVT is still unknown [26].\n\nConclusion\n\nCOVID-19 is an emerging source of venous thrombosis due to factors such as excessive coagulation, blood stasis, and endothelial damage. The main mechanism of SVT and DVT formation due to COVID-19 is unknown and has not yet been examined. Although COVID-19 cases presented with SVT and DVT are rare, recognizing SVT and DVT as potential complications of COVID 19 infection will be of great value. Imaging techniques such as CT, MRI, and ultrasound can confirm the diagnosis of SVT and DVT. Due to the possibility of COVID-19 infection in patients presenting with venous thrombosis or other thromboembolic diseases, it seems important to consider the presence of COVID-19 in their diagnosis.\n\nAcknowledgements\n\nThe authors thank all the teaching and medical staff of Kurdistan University of Medical Sciences for their effort in eradicating the virus around the clock.\n\nAuthors’ contributions\n\nMBHS supervised the study and wrote the manuscript; PF collected the clinical data; MA and FF analyzed the data and images; and NHS reviewed the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\n\nNo source of funding.\n\nAvailability of data and materials\n\nI have presented the data of the patient in the manuscript as a Table. I have submitted the figures separately as figures.\n\nDeclarations\n\nEthical approval and consent to participate\n\nThis research has been confirmed by the Research Center of Kurdistan University of Medical Sciences and Ethics Committee with the file number IR.MUK.REC.1399.087.\n\nConsent for publication\n\nWritten informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article which was approved by the Research Center of Kurdistan University of Medical Sciences.\n\nCompeting interests\n\nAll authors declare that there is no conflict of interest that prejudices the impartiality of this scientific work.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Holshue ML, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929–36.\n2. Wang D Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China JAMA 2020 323 11 1061 1069 10.1001/jama.2020.1585 32031570\n3. Li L, et al. Using Artificial Intelligence to Detect COVID-19 and Community-acquired Pneumonia Based on Pulmonary CT: Evaluation of the Diagnostic Accuracy. Radiology. 2020;296(2):E65–71.\n4. Lodigiani C, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9–14.\n5. Sobreira ML Prevalence of deep vein thrombosis and pulmonary embolism in superficial thrombophlebitis of the lower limbs: prospective study of 60 cases Int Angiol 2009 28 5 400 19935595\n6. Subramaniam P Van Doornum S Superficial thrombophlebitis: underlying hypercoagulable states Aust N Z J Surg 1999 69 6 461 463 10.1046/j.1440-1622.1999.01599.x 10392894\n7. Decousus H Leizorovicz A Superficial thrombophlebitis of the legs: still a lot to learn J Thromb Haemost 2005 3 6 1149 1151 10.1111/j.1538-7836.2005.01445.x 15946201\n8. Leon L Clinical significance of superficial vein thrombosis Eur J Vasc Endovasc Surg 2005 29 1 10 17 10.1016/j.ejvs.2004.09.021 15570265\n9. Sover ER Brammer HM Rowedder AM Thrombosis of the proximal greater saphenous vein: ultrasonographic diagnosis and clinical significance J Ultrasound Med 1997 16 2 113 116 10.7863/jum.1997.16.2.113 9166803\n10. NHCotPsRo, C New coronavirus pneumonia prevention and control program (seventh trial edition) 2020\n11. Dunnihoo DR Postpartum ovarian vein thrombophlebitis: a review Obstet Gynecol Surv 1991 46 7 415 427 10.1097/00006254-199107000-00002 1876354\n12. Li Y Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China 2020\n13. Lippi G, et al. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta. 2020;506:145–8.\n14. Terpos E, et al. Hematological findings and complications of COVID-19. Am J Hematol. 2020;95(7):834–47.\n15. Vickers NJ Animal communication: when i’m calling you, will you answer too? Curr Biol 2017 27 14 R713 R715 10.1016/j.cub.2017.05.064 28743020\n16. Zhou B, et al. Venous thrombosis and arteriosclerosis obliterans of lower extremities in a very severe patient with 2019 novel coronavirus disease: a case report. J Thromb Thrombolysis. 2020;50(1):229–32.\n17. Wells PS Forgie MA Rodger MA Treatment of venous thromboembolism JAMA 2014 311 7 717 728 10.1001/jama.2014.65 24549552\n18. Zhou B, et al. A case of coronavirus disease 2019 with concomitant acute cerebral infarction and deep vein thrombosis. Front Neurol. 2020;11:296.\n19. Xie Y COVID-19 complicated by acute pulmonary embolism Radiol Cardiothorac Imaging 2020 2 2 e200067 10.1148/ryct.2020200067\n20. Danzi GB Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J 2020 41 19 1858 10.1093/eurheartj/ehaa254 32227120\n21. Klok FA, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145–7.\n22. Zhang H Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target Intensive Care Med 2020 46 4 586 590 10.1007/s00134-020-05985-9 32125455\n23. Zheng Y-Y COVID-19 and the cardiovascular system Nat Rev Cardiol 2020 17 5 259 260 10.1038/s41569-020-0360-5 32139904\n24. Huang C Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Lancet 2020 395 10223 497 506 10.1016/S0140-6736(20)30183-5 31986264\n25. Tarannum N Azam MS Premchand RK May-Thurner syndrome and recurrent DVT: a case report Indian J Clin Cardiol 2020 1 1 13 16 10.1177/2632463619898010\n26. Davoodi L COVID-19 presented with deep vein thrombosis: an unusual presenting J Investig Med High Impact Case Rep 2020 8 2324709620931239 32493073\n\n", "fulltext_license": "CC BY", "issn_linking": "2055-0936", "issue": "7(1)", "journal": "Tropical diseases, travel medicine and vaccines", "keywords": "COVID-19; Case report; Coronavirus; Superficial vein thrombosis; Ultrasonography", "medline_ta": "Trop Dis Travel Med Vaccines", "mesh_terms": null, "nlm_unique_id": "101674442", "other_id": null, "pages": "6", "pmc": null, "pmid": "33658082", "pubdate": "2021-03-03", "publication_types": "D016428:Journal Article", "references": "24549552;10392894;19935595;32178975;32031570;32282949;32125455;32004427;32353746;32291094;28743020;15570265;1876354;32139904;32306290;32390931;32227120;9166803;32191588;15946201;31986264;32134381;32493073", "title": "A case report of greater saphenous vein thrombosis in a patient with coronavirus (COVID-19) infection.", "title_normalized": "a case report of greater saphenous vein thrombosis in a patient with coronavirus covid 19 infection" }

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{ "abstract": "Solitary cysticercus localized to the head and neck musculature is an unusual form of presentation of cysticercosis. Since it is rare and has non-specific manifestations, it can present a diagnostic challenge to the clinician. Our patient was a 16-year-old female who presented with a gradually increasing, painful swelling over right temple region of 6-month duration. Ultrasound and computed tomography scan revealed the presence of a solitary cysticercus in the right temporalis muscle. Surgical excision of the lesion was combined with a 4-week course of the anti-helminthic drug, Albendazole. Patient had a satisfactory resolution of symptoms and there was no recurrence in a follow-up period of 3 years. We suggest that cysticercosis should be considered as one of the possibilities in the differential diagnosis of swellings in the maxillofacial region, especially in the endemic areas. Imaging studies play an important role in confirmation of the diagnosis.", "affiliations": "Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India.;Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India.", "authors": "Cheruvu|Ved Prakash R|VPR|;Khan|Manal M|MM|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/jscr/rjab223", "fulltext": "\n==== Front\nJ Surg Case Rep\nJ Surg Case Rep\njscr\nJournal of Surgical Case Reports\n2042-8812\nOxford University Press\n\n10.1093/jscr/rjab223\nrjab223\nCase Report\nAcademicSubjects/MED00910\njscrep/090\nSolitary cysticercus in the right temporalis muscle: case report of a rare form of presentation of cysticercosis\nCheruvu Ved Prakash R Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India\n\nKhan Manal M Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Bhopal, Madhya Pradesh, India\n\nCorrespondence address. R. No. 1017, 1st Floor, Academic Block, Department of Burns and Plastic Surgery, All India Institute of Medical Sciences Bhopal, Saketnagar, Bhopal, Madhya Pradesh 462020, India. Tel: +91-8872209777; E-mail: [email protected]\n6 2021\n04 6 2021\n04 6 2021\n2021 6 rjab22322 4 2021\n11 5 2021\nPublished by Oxford University Press and JSCR Publishing Ltd. All rights reserved. © The Author(s) 2021.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]\n\nAbstract\n\nSolitary cysticercus localized to the head and neck musculature is an unusual form of presentation of cysticercosis. Since it is rare and has non-specific manifestations, it can present a diagnostic challenge to the clinician. Our patient was a 16-year-old female who presented with a gradually increasing, painful swelling over right temple region of 6-month duration. Ultrasound and computed tomography scan revealed the presence of a solitary cysticercus in the right temporalis muscle. Surgical excision of the lesion was combined with a 4-week course of the anti-helminthic drug, Albendazole. Patient had a satisfactory resolution of symptoms and there was no recurrence in a follow-up period of 3 years. We suggest that cysticercosis should be considered as one of the possibilities in the differential diagnosis of swellings in the maxillofacial region, especially in the endemic areas. Imaging studies play an important role in confirmation of the diagnosis.\n==== Body\nINTRODUCTION\n\nCysticercosis is a parasitic affliction of the tissues caused by Cysticercus cellulosae, which is the larval stage of pork tape worm Taenia solium. It was described for the first time by Johannes Udalric Rumler in 1555 [1]. It commonly occurs in the areas where there is a combination of uncontrolled pig breeding, poor sanitation and close interaction between humans and animals. This condition is endemic in the developing countries of Asia, Africa and Latin America. In 2010, cysticercosis was designated as one of the 17 ‘neglected tropical diseases (NTDs)’ of worldwide public health importance by the World Health Organization (WHO). In the year 2015, the WHO’s Foodborne Disease Burden Epidemiology Reference Group established that T. solium was a leading cause of mortality from food-borne illnesses, resulting in 2.8 million disability-adjusted life-years [2].\n\nCysticercus cellulosae is found in muscles and other tissues of pigs that usually serve as intermediate hosts, whereas humans are the definitive hosts and harbor the adult worm. Pigs acquire the infection when they ingest contaminated food or water that contains proglottids or eggs from human feces. The eggs develop into cysticerci in pig muscles.\n\nFigure 1 Picture at initial presentation, frontal view, arrow indicates the swelling.\n\nFigure 2 Picture at initial presentation, oblique view.\n\nFigure 3 No restriction of mouth opening at initial presentation.\n\nFigure 4 Intraoperative picture, arrow indicates the cysticercus cyst.\n\nHuman infection occurs when these are ingested through the consumption of raw or undercooked pork. Humans can also acquire infection through T. solium eggs due to poor hygiene (via fecal–oral route) or ingestion of contaminated water or food [2]. In this case, humans become the accidental intermediate hosts. These ova are digested in the stomach and oncospheres are released, which penetrate the intestinal wall and reach the circulation [3]. This may lead to cysticercosis that commonly involves the brain, meninges and eyes, which together constitute 86% of the cases. Less commonly they are located in the muscles, subcutaneous tissues, liver, heart, lungs and peritoneum [4]. Rarely, they are localized to the oral and perioral tissues like the muscles of mastication, muscles of facial expression, suprahyoid muscles, post-cervical musculature, tongue, buccal mucosa and lips [5–7]. Isolated head and neck muscular cysticercosis without the involvement of central nervous system is rare and only few cases are reported in the literature [8]. These cases have non-specific clinical manifestations and present a diagnostic challenge to the clinician [9].\n\nFigure 5 Three months post-surgery, frontal view.\n\nFigure 6 Three months post-surgery, oblique view.\n\nFigure 7 Three months post-surgery, lateral view.\n\nFigure 8 Three-year follow-up, frontal view.\n\nCASE REPORT\n\nA 16-year-old female patient had presented to us with the complaint of a gradually increasing painful swelling over the right temple region of 6 months duration. She had a history of minor trauma to the site due to a fall 6 months back. There was no restriction in mouth opening or difficulty in chewing. There were no symptoms suggestive of neurological involvement.\n\nOn examination, there was a solitary swelling in the right temporal region with ill-defined margins. It had a soft to firm consistency and was mildly tender on palpation. Mouth opening was adequate (Figs 1–3). There were no other significant findings on examination.\n\nUltrasound revealed a hypoechoic cystic lesion in the right temporalis muscle with an eccentric hyperechoic nodule. Computed tomography (CT) scan confirmed the presence of a well-defined cystic lesion with an eccentric hypointense nidus in the right temporalis muscle. There were no other similar lesions in the head and neck region. These features suggested a diagnosis of a solitary cysticercosis involving the right temporalis muscle.\n\nPatient was initially kept on conservative treatment with Albendazole 15 mg/kg body weight/day in two divided doses for 2 weeks. As there was no relief in the pain or swelling, we decided to go for surgical exploration. The lesion was approached through a vertical incision in the right temporal region. Intraoperatively, ~5 ml of pus and a white opalescent cystic lesion, within a cavity were found (Fig. 4). The cavity and surgical field were thoroughly irrigated with Povidone-Iodine before closing the incision over a suction drain. Culture of the pus did not yield growth of any microbes. The suture line healed well and the swelling resolved (Figs 5–7). Histopathological examination confirmed the lesion to be a cysticercus cyst.\n\nAlbendazole was continued for 2 more weeks. Patient was followed-up regularly and there was no recurrence during a 3-year follow-up period (Figs 8–10).\n\nFigure 9 Three-year follow-up, oblique view.\n\nFigure 10 Three-year follow-up, lateral view.\n\nDISCUSSION\n\nThe clinical course of cysticercosis depends on the number of lesions, the tissues affected and the reaction of the tissues to these organisms [6]. Commonly, patients present with multiple lesions such as cysts of different sizes or multiple nodular calcifications and these may be associated with varying degrees of host response [10]. Cysticercosis may remain asymptomatic for a variable period or present with severe local symptoms. Various types of clinical presentations such as myalgic, myopathic, nodular or mass like and the rare pseudohypertrophy have been reported [9]. The cysts are of ovoid or round shape, white or opalescent color, up to 1.5-cm size and contain an invaginated scolex with hooklets [9].\n\nIsolated head and neck muscle cysticercosis is unusual and solitary cysticercosis localized to temporalis muscle is rarer [11]. Since it is rare and has non-specific manifestations, it can present a diagnostic challenge to the clinician [9].\n\nImaging studies (ultrasonography, CT or magnetic resonance imaging) play an important role in the diagnosis of cysticercosis. Vijayaraghavan described four kinds of sonographic appearances of muscular cysticercosis [12].\n\nTreatment of cysticercosis should be based on the clinical manifestations and the tissues affected. Praziquantel and Albendazole are the recommended anti-helminthic medications [13]. Surgical excision is the treatment of choice for ventricular, ocular, spinal and symptomatic subcutaneous cysticerci [14].\n\nIn the maxillofacial region, prognosis is favorable in contrast to the seriousness of the disease in the cerebral, ocular and cardiac sites [15]. There are no reported recurrences after treatment.\n\nWe suggest that cysticercosis should be considered as one of the possibilities in the differential diagnosis of swellings in the maxillofacial region, especially in the endemic areas. Imaging studies play an important role in confirming the diagnosis and should be sought out in cases with non-specific clinical manifestations.\n\nACKNOWLEDGMENTS\n\nWe acknowledge the contributions of our residents and staff in helping with the patient care and follow-up.\n==== Refs\nReferences\n\n1. Chand S, Mishra M, Singh G, Singh A, Tandon S. Orofacial cysticercosis: report of a rare case with review of literature. Natl J Maxillofac Surg 2016;7 :209–12.28356697\n2. World Health Organisation. Taeniasis/Cysticercosis [Internet]. [12 April 2021, date last accessed]. Available from: https://www.who.int/news-room/fact-sheets/detail/taeniasis-cysticercosis.\n3. Singh S, Sreenivasan V, Garg K, Wazir ND, Rajput JS, Sandhu Virk P. Cysticercosis involving muscle of mastication: a review and report of two cases. Case Rep Dent 2013; 2013 :814126.\n4. Rao SC, Sharma H, Vinay KN, Vidya KC. Oral Cysticercosis - A Case Report. Int. Journal of Clinical Dental Science 2011;2 :36–9.\n5. Timoşca G, Gavriliţă L. Cysticercosis of the maxillofacial region. A clinicopathologic study of five cases. Oral Surg Oral Med Oral Pathol 1974;37 :390–400.4521458\n6. Kinnman J, Chi CH, Park JH. Cysticercosis in otolaryngology. Arch Otolaryngol 1976;102 :144–7.1267689\n7. Tschen EH, Tschen EA, Smith EB. Cutaneous cysticercosis treated with metrifonate. Arch Dermatol 1981;117 :507–9.7259247\n8. Abdelwahab IF, Klein MJ, Hermann G, Abdul-Quader M. Solitary cysticercosis of the biceps brachii in a vegetarian: a rare and unusual pseudotumor. Skeletal Radiol 2003;32 :424–8.12730733\n9. Sharma P, Neupane S, Shrestha M, Dwivedi R, Paudel K. An ultrasonographic evaluation of solitary muscular and soft tissue cysticercosis. Kathmandu Univ Med J 2010;8 :257–60.\n10. Nash TE. Human case management and treatment of cysticercosis. Acta Trop 2003;87 :61–9.12781379\n11. Rastogi S, Arora P, Devi P, Wazir SS, Kapoor S. Importance of ultrasonography and magnetic resonance imaging in diagnosis of cysticercosis of temporalis muscle mimicking temporal space infection. Contemp Clin Dent 2013;4 :504.24403797\n12. Vijayaraghavan SB. Sonographic appearances in cysticercosis. Ultrasound Med 2004;23 :423–7.\n13. Kumar V, Abbas A, Faustro N. Pathological Basis of Diseases, 7th edn. New York: W B Saunders, 2004, 406–7.\n14. Kumar BD, Dave B, Meghana SM. Cysticercosis of masseter. Indian J Dent Res 2011;22 :617.22124076\n15. Deshmukh A, Avadhani A, Tupkari JV, Sardar M. Cysticercosis of the upper lip. J Oral Maxillofac Pathol 2011;15 :219.22529585\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2042-8812", "issue": "2021(6)", "journal": "Journal of surgical case reports", "keywords": null, "medline_ta": "J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101560169", "other_id": null, "pages": "rjab223", "pmc": null, "pmid": "34104406", "pubdate": "2021-06", "publication_types": "D002363:Case Reports", "references": "24396612;12781379;22124076;12730733;15055791;4521458;22529585;1267689;24403797;28356697;7259247;21209548", "title": "Solitary cysticercus in the right temporalis muscle: case report of a rare form of presentation of cysticercosis.", "title_normalized": "solitary cysticercus in the right temporalis muscle case report of a rare form of presentation of cysticercosis" }

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{ "abstract": "Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently demonstrated cardiovascular (CV) safety versus placebo in Asians with advanced type 2 diabetes mellitus (T2DM) in the CARMELINA® trial. We assessed its CV safety compared with the sulfonylurea glimepiride in Asians with relatively early T2DM in the CAROLINA® trial.\nBased on prespecified and post hoc subgroup analyses of the multinational CAROLINA® trial in which adults with relatively early T2DM and elevated CV risk were randomized to linagliptin or glimepiride added to usual care, we analyzed data for participants from Asian countries. This included the primary outcome defined as time to first CV death, non-fatal myocardial infarction, or non-fatal stroke [three-point major adverse cardiovascular events (3P-MACE)].\nOf the 6033 participants, 933 (15.5%) were from Asia. During a median follow-up of 6.2 years, 3P-MACE occurred in 9.5% and 11.1% of the linagliptin and glimepiride groups, respectively (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.57-1.26]), consistent with the overall population (HR 0.98; 95% CI 0.84-1.13; P = 0.17 for treatment by region interaction). Similarly, there were no significant differences between groups for other outcomes, including CV death (HR 0.73; 95% CI 0.38-1.38), non-CV mortality (HR 0.76; 95% CI 0.37-1.57) and hospitalization for heart failure (HR 0.89; 95% CI 0.36-2.19). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; 95% CI 0.19-0.33; P < 0.0001) despite similar glycemic control. Body weight was slightly lower with linagliptin relative to glimepiride: weighted average mean difference over 256 weeks of - 1.82 kg (95% CI - 2.28 to - 1.35).\nIn Asian patients, linagliptin demonstrated similar CV safety to glimepiride with a markedly lower rate of hypoglycemia and modestly lower weight.", "affiliations": "Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470 Japan.;Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.;Dallas Diabetes Research Center at Medical City and University of Texas Southwestern Medical Center, Dallas, TX USA.;Department of Diabetes and Endocrinology, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Internal Medicine 1, Faculty of Medicine, Shimane University, Shimane, Japan.;Department of Endocrinology, Chinese People's Liberation Army General Hospital, Beijing, China.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.;Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.;Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.;Boehringer Ingelheim Norway KS, Asker, Norway.;Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.", "authors": "Kadowaki|Takashi|T|;Wang|Guang|G|;Rosenstock|Julio|J|;Yabe|Daisuke|D|;Peng|Yongde|Y|;Kanasaki|Keizo|K|;Mu|Yiming|Y|;Mattheus|Michaela|M|;Keller|Annett|A|;Okamura|Tomoo|T|;Johansen|Odd Erik|OE|;Marx|Nikolaus|N|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1007/s13340-020-00447-5", "fulltext": null, "fulltext_license": null, "issn_linking": "2190-1678", "issue": "12(1)", "journal": "Diabetology international", "keywords": "Cardiovascular; Diabetes mellitus, type 2", "medline_ta": "Diabetol Int", "mesh_terms": null, "nlm_unique_id": "101553224", "other_id": null, "pages": "87-100", "pmc": null, "pmid": "33479584", "pubdate": "2021-01", "publication_types": "D016428:Journal Article", "references": "30291106;28025462;30690856;4926376;30418475;31271669;19470990;1091761;24300015;17070446;32444457;8842603;31497854;23842096;29974673;29582574;6985989;30983138;27464265;32206483;30926258;23803294;16239637;17517853;23589542;26908931;30497881;29527102;23449634;31748210;27133171;31857443;25287289;31536101;31002328;25780262;28428321;23637538;23551121;18539916;31504427;31239281", "title": "Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial.", "title_normalized": "effect of linagliptin a dipeptidyl peptidase 4 inhibitor compared with the sulfonylurea glimepiride on cardiovascular outcomes in asians with type 2 diabetes subgroup analysis of the randomized carolina trial" }

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{ "abstract": "The avoidance of any form of anticoagulation is advised in cases of cholesterol embolization syndrome (CES). We herein describe a case of CES in a man with a history of unprovoked pulmonary embolism for which warfarinization was performed. Despite anecdotal reports of successful anticoagulation in CES patients with certain indications, irreversible renal failure, which was sufficiently severe to require chronic hemodialysis, eventually developed in our patient. Our results emphasize the pitfalls of this procedure, which imply its limited feasibility and safety. Several therapeutic concerns associated with this case are also discussed.", "affiliations": "Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.;Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, Japan.", "authors": "Igarashi|Yusuke|Y|;Akimoto|Tetsu|T|;Kobayashi|Takahisa|T|;Iwazu|Yoshitaka|Y|;Miki|Takuya|T|;Otani-Takei|Naoko|N|;Imai|Toshimi|T|;Sugase|Taro|T|;Masuda|Takahiro|T|;Takeda|Shin-Ichi|SI|;Muto|Shigeaki|S|;Nagata|Daisuke|D|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/1179547616684649", "fulltext": "\n==== Front\nClin Med Insights Case RepClin Med Insights Case RepICRspicrClinical Medicine Insights. Case Reports1179-5476SAGE Publications Sage UK: London, England 2846949710.1177/117954761668464910.1177_1179547616684649ICR-41061Case ReportPerforming Anticoagulation: A Puzzling Case of Cholesterol Embolization Syndrome Igarashi Yusuke Akimoto Tetsu Kobayashi Takahisa Iwazu Yoshitaka Miki Takuya Otani-Takei Naoko Imai Toshimi Sugase Taro Masuda Takahiro Takeda Shin-ichi Muto Shigeaki Nagata Daisuke Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke-Shi, JapanTetsu Akimoto, Division of Nephrology, Department of Internal Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Japan. Email: [email protected] 2 2017 2017 10 11795476166846495 10 2016 21 11 2016 © The Author(s) 20172017SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).The avoidance of any form of anticoagulation is advised in cases of cholesterol embolization syndrome (CES). We herein describe a case of CES in a man with a history of unprovoked pulmonary embolism for which warfarinization was performed. Despite anecdotal reports of successful anticoagulation in CES patients with certain indications, irreversible renal failure, which was sufficiently severe to require chronic hemodialysis, eventually developed in our patient. Our results emphasize the pitfalls of this procedure, which imply its limited feasibility and safety. Several therapeutic concerns associated with this case are also discussed.\n\nCholesterol crystal embolizationpulmonary embolismwarfarinend-stage kidney diseasehemodialysiscover-dateJanuary-December 2017\n==== Body\nIntroduction\nCholesterol embolization syndrome (CES) is a multisystem ischemic damage characterized by the occlusion of small vessels with cholesterol crystals that originate from ruptured atherosclerotic plaques lining the walls of major arteries.1 Plaque rupture may be spontaneous, iatrogenic after arterial manipulations, and/or related to thrombolytic therapy and anticoagulation.1,2 Although any organ may be affected, the brain, kidneys, gastrointestinal tract, skin, and skeletal muscles of the lower extremities are the most frequently involved.2 No specific treatment has been established for CES, and therapeutic modalities for this disease are still symptomatic and preventive.1–3 The avoidance of any form of anticoagulation is an alternative therapeutic option1–3; however, this strategy may not necessarily be appropriate for some subsets of CES patients with separate indications, such as mechanical prosthetic valves, atrial fibrillation, and deep vein thrombosis.1,2,4 In the current report, we describe our experience with one such case of CES in a man who had a history of unprovoked pulmonary embolism (PE), which obliged us to pursue anticoagulation with warfarin during the observation period. Several therapeutic concerns that emerged in this case are also discussed.\n\nCase Report\nA 76-year-old man was admitted in June 2014 due to progressive deterioration of renal function, loss of appetite, and asthenia. Nine months prior to his admission (September 2013), he was diagnosed with effort angina and infrarenal abdominal aortic aneurysm. At the beginning of October 2013, he was found to have unprovoked PE for which he had received oral warfarin, delivering a prothrombin time-international normalized ratio (PT-INR) of 1.7 to 2.1 (reference range: 0.9-1.2) with a favorable clinical course. He had no history of renal disease, and steady serum creatinine (sCr) levels ranging between 0.96 and 1.12 mg/dL (reference range: 0.63-1.03 mg/dL) were noted until mid-December 2013. His sCr level was 1.89 mg/dL in mid-March 2014 and increased to 7.33 mg/dL in early June 2014. Therefore, he was referred and admitted to our hospital for further examination. His medical history included a diagnosis of acute myocardial infarction at 58 years of age. He had been a smoker for more than 40 years but denied the use of any drugs.\n\nAt the time of admission, the patient was alert and had a temperature of 36.4°C, a heart rate of 89 beats/min, and a blood pressure of 176/94 mm Hg. His physical examination revealed livedo reticularis on the soles of his toes and a blue-purple discoloration of all toes bilaterally (Figure 1A), whereas his feet were warm to the touch and the peripheral pulse remained intact. Laboratory examinations revealed the following: blood urea nitrogen (BUN), 64 mg/dL (reference range: 8-20 mg/dL); sCr, 7.23 mg/dL; white blood cell count, 9800/µL (reference range: 3900-9800/µL); eosinophils, 1092/µL (reference range: 0-400/µL); platelet count, 166 × 103/µL (reference range: 130-369 × 103/µL); erythrocyte sedimentation rate (ESR), 59 mm/h (reference range: 0-10 mm/h); serum albumin, 3.5 g/dL (reference range: 6.9-8.4 g/dL); triglycerides, 203 mg/dL (reference range: 40-185 mg/dL); low-density lipoprotein (LDL) cholesterol, 129 mg/dL (reference range: <139 mg/dL), fibrinogen, 410 mg/dL (reference range: 129-271 mg/dL); fibrin/fibrinogen degradation products, 13.5 µg/mL (reference range: 0-5 µg/mL); D-dimer, 5900 µg/L (reference range: 0-1500 µg/L); PT-INR, 1.76; C3, 104 mg/dL (reference range: 86-160 mg/dL); C4, 45 mg/dL (reference range: 17-45 mg/dL); and C-reactive protein, 0.49 mg/dL (reference range: 0-0.14 mg/dL). Tests for anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane antibodies, hepatitis B virus surface antigen (HBsAg), anti-HBsAg antibodies, and antibodies to the hepatitis C virus were all negative. His urine was trace positive for protein, 2+ for occult blood, and contained 0.09 g of protein in a 24-hour specimen, whereas his creatinine clearance was 3.9 mL/min. The urinary excretion of β2-microglobulin and N-acetyl-beta-d-glucosaminidase was 22 856 µg/L (reference range: <200 µg/L) and 5.4 U/g·Cr (reference range: 0.9-2.4 U/g·Cr), respectively. A computed tomographic scan revealed a calcified thoracic aorta without a dimensional disorder and an infrarenal aortic aneurysm with a maximum diameter of approximately 4.4 cm. Diagnostic noncontrast-enhanced T2-weighted half-fourier-acquired single-shot turbo spin ecocho (HASTE) magnetic resonance imaging subsequently revealed hypointense areas and bright signals, which were suggestive of an atheromatous plaque consisting of lipids and fibrous tissues, respectively,5 in the abdominal aorta (Figure 1B). Oral warfarin was discontinued on admission, and the patient was subjected to empirical treatment with pravastatin at a dose of 10 mg/day combined with limaprost alfadex at a dose of 30 µg/day. A 5-mm-deep punch biopsy was performed on clinical day 7 within the territory of livedo reticularis on the lateral aspect of the left first toe. Typical biconvex needle-shaped empty spaces, suggestive of cholesterol clefts,1,3 were observed within the lumen of the arteriole in the subcutis (Figure 1C). A diagnosis of CES was made based on pathological and imaging findings as well as clinical manifestations.\n\nFigure 1. Physical, magnetic resonance imaging (MRI), and pathological findings. Bluish reticulated patches were noted on the soles and tips of the toes (A), whereas T2-weighted HASTE diagnostic MRI (B) at a slightly more cephalic position from the renal arteries revealed an atherosclerotic plaque consisting of lipids (arrow) and fibrous (arrowhead) tissues in the abdominal aorta. Abnormal fluid-filled lesions (*), which may be ascribed to bilateral simple renal cysts, were also noted. Light microscopy of cutaneous biopsy sections revealed characteristic cholesterol clefts occluding the lumen of the arteriole (C, hematoxylin-eosin stain; the scale bar is indicated).\n\nDue to the elevated D-dimer level of 10 600 µg/L confirmed on clinical day 8, the decision was made to resume anticoagulation therapy despite our failure to detect deep venous thrombotic lesions using ultrasonography. The patient was treated with intravenous heparin and then switched to warfarin 2.5 mg/day on clinical day 30. Oral prednisolone (PSL) at a dose of 20 mg/day was also initiated on clinical day 22, resulting in the amelioration of eosinophilia and cutaneous manifestations within a few days and the subsequent stabilization of sCr levels at approximately 4.3 mg/dL. His elevated blood pressure was also controlled at approximately 120-130/70-80 mm Hg with irbesartan (100 mg/day) and amlodipine besilate (5 mg/day). However, sCr levels started to increase when PSL was tapered to 5 mg/day. The patient developed general fatigue, appetite loss, decline in urine output, and progressive swelling in both legs without any calf pain at the end of September 2014, with an elevated sCr level of 8.07 mg/dL, and was readmitted for further examinations. Similar to his initial admission, a laboratory analysis at this point revealed mild hypoalbuminemia (3.6 g/dL), whereas echocardiography and chest radiograph findings did not support the concurrent presence of heart failure. The relationship between deteriorated cutaneous manifestations and recurrent eosinophilia of 1365/µL resulted in the diagnosis of relapsed CES. The patient received hemodialysis (HD). After the resumption of an increased dose of PSL (15 mg/day) and the addition of a transient session of LDL apheresis (LDL-A) to the therapeutic regimen, his cutaneous manifestations improved and eosinophilia disappeared; however, severely deteriorated renal function did not recover, and he was finally started on a periodic HD program with favorable volume control (Figure 2).\n\nFigure 2. Changes in renal parameter values, PT-INR, and percentage of eosinophils. The number “0” was designated as the point of the initial admission, and the patient was discharged on clinical day 51. There was a transient improvement in sCr levels, whereas the irreversible nature of severe renal failure eventually resulted in the initiation of chronic HD despite an increase in the dose of PSL (15 mg/day) combined with 9 sessions of LDL-A. Note that the amounts of urinary excreted proteins, β2MG, and NAG were almost completely constant during the observation period. The conversion of BUN (mg/dL) to urea (mmol/L) is accomplished by multiplying BUN by 0.357. To convert milligram per deciliter to micromole per liter for sCr, multiply by 88.4.\n\nDiscussion\nThe clinical presentation of CES often consists of various signs specific to end-organ damage and systemic inflammatory responses.1 Patients with CES are more likely to be older men with a high prevalence of traditional cardiovascular risk factors and cardiovascular diseases6 and may present with a wide spectrum of clinical symptoms, including fever, weight loss, fatigue, anorexia, and myalgia with an elevated leukocyte count, rapid ESR, elevated C-reactive protein levels, high eosinophil blood counts, and, much more rarely, hypocomplementemia.1–3 The diagnostic hallmark of this disease is the histological confirmation of intravascular cholesterol crystals in biopsy specimens, whereas any organ system may be regarded as a candidate target for the procedure in theory.1,2 Although skin and muscle biopsies have a high diagnostic yield because of their favorable accessibility, it is important to note that tissues affected by CES are at risk of poor wound healing.1,2 Consequently, the clinical features of our patient are not surprising; however, the significance of our results needs to be evaluated carefully in terms of renal outcome after the resumption of anticoagulation.\n\nAlthough a causal link between anticoagulation and CES has yet to be proven or denied,1–3 anticoagulation may lead to plaque hemorrhaging, plaque rupture, and subsequent cholesterol crystal embolization.1,7–10 Thus, therapeutic options for CES ordinarily include a withdrawal from or the avoidance of any form of anticoagulation unless there is a separate indication, such as mechanical prosthetic valves, atrial fibrillation, and deep vein thrombosis.1,2 In the present case, we did not identify any associated triggers nor did we identify risk factors for PE, including recent major surgery, prolonged immobilization, and obesity.11–13 Previous anecdotal case reports demonstrating the successful use of warfarin and/or heparin for specific indications in patients with CES4,14–16 as well as the unprovoked nature of the disease, which may require indefinite long-term anticoagulation,11,17-19 and elevations in D-dimer levels after the suspension of anticoagulation prompted us to resume warfarinization to prevent the recurrence of PE in the present case. The dose of warfarin was controlled according to the recommended target PT-INR for venous thromboembolism based on the Japanese therapeutic guidance.11\n\nOur failure to perform a renal histological analysis may preclude us from precisely evaluating the impact of CES on renal pathology in the present patient. A number of conditions including small-vessel vasculitis and acute interstitial nephritis may simulate renal CES.20,21 However, the results of serological tests, as well as longitudinal data regarding urinary parameters, were unremarkable for these specific types of renal damage. The presence of a triad characterized by precipitating events such as anticoagulation, subacute renal failure, and pathologically confirmed peripheral cholesterol embolization prompted us to diagnose our patient with atheroembolic renal disease, as practiced in ordinary clinical settings.3,6 Fluctuations in estimated glomerular filtration rates may occasionally be observed during the given period of time before the commencement of renal replacement therapy, particularly in patients with cardiovascular disease22; thus, the transient improvement in renal function in our patient may mirror, at least in part, the natural course of end-stage kidney disease. Nevertheless, the tapering of PSL may be expected to attenuate corticosteroid-dependent lipid scavenging,23 thereby precipitating irreversible end-stage kidney disease through the exacerbation of latent inflammatory tissue injury due to warfarinization-mediated cholesterol embolism. We consider our results to emphasize the pitfalls of continuing or resuming anticoagulation even in CES patients who have separate indications, implying the limited feasibility and safety of this procedure.\n\nThe clinical course of the present patient did not allow us to precisely evaluate the therapeutic significance of statins and LDL-A, which have been attempted anecdotally as a therapeutic option for CES with limited success.1,2,24 Otherwise, our case may have emphasized the necessity of an extensive evaluation of the potential benefits of corticosteroids among patients with CES. Although the maintenance dose, duration, and tapering schedule of oral PSL in the present patient may not necessarily be adequate in terms of the overall renal outcome, the immediate decrease observed in sCr levels after the commencement of the treatment implies the therapeutic benefit of immunomodulation with steroids. The discrepancy between the results obtained for sCr and BUN levels after the resumption of the increased dose, as well as the initial dosing of oral PSL, was not unexpected because BUN levels are often elevated by excessive tissue catabolism resulting from the administration of corticosteroids.25,26\n\nRapid improvements in deteriorated renal function caused by CES have been demonstrated in patients treated with various therapeutic regimens using corticosteroids,3,27–29 implying that a number of these decisions are potentially empirical. We need to focus on previous findings showing that the tapering of corticosteroids coincides with the recurrence of CES, as in the present patient. In some subsets of CES patients, it may be necessary to either increase the dose or resume agents with careful monitoring for signs of exacerbation.28,30–33 There are currently no clear recommendations regarding how to administer corticosteroids to CES patients. No reliable indicators that may allow us to assess the optimal timing for the tapering of such agents have been reported. It also remains unclear which CES patients will benefit the most from corticosteroid treatments. Further encounters with similar cases to our patient will contribute to elucidating the therapeutic significance, as well as optimal duration and dosing of corticosteroids for this disease, thereby leading to the development of appropriate strategies for the treatment of CES patients.\n\nPeer Review:Seven peer reviewers contributed to the peer review report. Reviewers’ reports totaled 790 words, excluding any confidential comments to the academic editor.\n\nAuthor Contributions: YIgarashi and TA drafted the manuscript. TK, YIwazu, TMiki, NOT, TI, TS, and TMasuda helped with the acquisition of clinical data. ST, SM, and DN provided a detailed review of the contents and structure of the manuscript, resulting in significant changes to the original document. All the authors have read and approved the final manuscript.\n\nDisclosures and Ethics: As a requirement for publication, the authors have provided the publisher with signed confirmation of compliance with legal and ethical obligations, including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality, and (where applicable) the protection of human and animal research subjects. The authors have read and confirmed their agreement with the International Committee of Medical Journal Editors (ICMJE) authorship and conflict of interest criteria. The authors have also confirmed that this manuscript is unique and not under consideration for publication or published in any other publications and that they have permission from the rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported in part by a Grant-in-Aid for Research on Advanced Chronic Kidney Disease, Practical Research Project for Renal Diseases, from the Japan Agency for Medical Research and Development, AMED.\n==== Refs\nReferences\n1 \nKronzon I Saric M. \nCholesterol embolization syndrome . Circulation . 2010 ;122 :631 –641 .20697039 \n2 \nQuinones A Saric M. \nThe cholesterol emboli syndrome in atherosclerosis . Curr Atheroscler Rep . 2013 ;15 :315 .23423524 \n3 \nMeyrier A. \nCholesterol crystal embolism: diagnosis and treatment . Kidney Int . 2006 ;69 :1308 –1312 .16614719 \n4 \nKim H Zhen DB Lieske JC \nTreatment of cholesterol embolization syndrome in the setting of an acute indication for anticoagulation therapy . J Med Cases . 2014 ;5 :376 –379 .25197328 \n5 \nFrank H. \nCharacterization of atherosclerotic plaques by magnetic resonance imaging . Am Heart J . 2001 ;141 :S45 –S48 .11174358 \n6 \nScolari F Ravani P Gaggi R \nThe challenge of diagnosing atheroembolic renal disease: clinical features and prognostic factors . Circulation . 2007 ;116 :298 –304 .17606842 \n7 \nBruns FJ Segel DP Adler S. \nControl of cholesterol embolization by discontinuation of anticoagulant therapy . Am J Med Sci . 1978 ;275 :105 –108 .665707 \n8 \nHyman BT Landas SK Ashman RF Schelper RL Robinson RA. \nWarfarin-related purple toes syndrome and cholesterol microembolization . Am J Med . 1987 ;82 :1233 –1237 .3605140 \n9 \nTalmadge DB Spyropoulos AC. \nPurple toes syndrome associated with warfarin therapy in a patient with antiphospholipid syndrome . Pharmacotherapy . 2003 ;23 :674 –677 .12741443 \n10 \nCortez AF Sakuma TH Lima RB \nCholesterol crystal embolization caused by anticoagulant therapy . Int J Dermatol . 2009 ;48 :989 –990 .19702986 \n11 \nNakamura M Yamada N Ito M. \nCurrent management of venous thromboembolism in Japan: current epidemiology and advances in anticoagulant therapy . J Cardiol . 2015 ;66 :451 –\n459 .25896176 \n12 \nNakamura M Fujioka H Yamada N \nClinical characteristics of acute pulmonary thromboembolism in Japan: results of a multicenter registry in the Japanese Society of Pulmonary Embolism Research . Clin Cardiol . 2001 ;24 :132 –138 .11214743 \n13 \nGoldhaber SZ. \nPulmonary embolism . N Engl J Med . 1998 ;339 :93 –104 .9654541 \n14 \nWakabayashi T Yoshizawa Y Kawana S. \nSuccessful use of heparin and warfarin in the treatment of cholesterol crystal embolization . J Dermatol . 2008 ;35 :111 –114 .18271808 \n15 \nAcker CG. \nCholesterol microembolization and stable renal function with continued anticoagulation . South Med J . 1992 ;85 :210 –212 .1738893 \n16 \nMoll S Huffman J. \nCholesterol emboli associated with warfarin treatment . Am J Hematol . 2004 ;77 :194 –195 .15389900 \n17 \nKearon C Gent M Hirsh J \nA comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism . N Engl J Med . 1999 ;340 :901 –907 .10089183 \n18 \nGoldhaber SZ Elliott CG. \nAcute pulmonary embolism: part II: risk stratification, treatment, and prevention . Circulation . 2003 ;108 :2834 –2838 .14662690 \n19 \nJaff MR McMurtry MS Archer SL ; and American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology . Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association . Circulation . 2011 ;123 :1788 –1830 .21422387 \n20 \nVidt DG. \nCholesterol emboli: a common cause of renal failure . Annu Rev Med . 1997 ;48 :375 –385 .9046969 \n21 \nScolari F Tardanico R Zani R \nCholesterol crystal embolism: a recognizable cause of renal disease . Am J Kidney Dis . 2000 ;36 :1089 –1109 .11096032 \n22 \nAmbrogi V Thilly N Boini S \nPatterns and predictors of kidney function decline in the last year prior to dialysis . Nephron Clin Pract . 2009 ;111 :c95 –\nc101 .19142021 \n23 \nCheng C Tsuneyama K Zheng H \nEnhanced scavenging of lipid substances is a possible effect of corticosteroids in the treatment of cholesterol crystal embolism . Pathol Res Pract . 2006 ;202 :591 –598 .16814943 \n24 \nHasegawa M Sugiyama S. \nApheresis in the treatment of cholesterol embolic disease . Ther Apher Dial . 2003 ;7 :435 –438 .12887728 \n25 \nDossetor JB. \nCreatininemia versus uremia: the relative significance of blood urea nitrogen and serum creatinine concentrations in azotemia . Ann Intern Med . 1966 ;65 :1287 –1299 .5928490 \n26 \nCauthen CA Lipinski MJ Abbate A \nRelation of blood urea nitrogen to long-term mortality in patients with heart failure . Am J Cardiol . 2008 ;101 :1643 –1647 .18489944 \n27 \nMann SJ Sos TA. \nTreatment of atheroembolization with corticosteroids . Am J Hypertens . 2001 ;14 :831 –834 .11497203 \n28 \nKoga J Ohno M Okamoto K \nCholesterol embolization treated with corticosteroids: two case reports . Angiology . 2005 ;56 :497 –501 .16079936 \n29 \nNakayama M Izumaru K Nagata M \nThe effect of low-dose corticosteroids on short- and long-term renal outcome in patients with cholesterol crystal embolism . Ren Fail . 2011 ;33 :298 –306 .21401354 \n30 \nFabbian F Catalano C Lambertini D Bordin V Di Landro D. \nA possible role of corticosteroids in cholesterol crystal embolization . Nephron . 1999 ;83 :189 –190 .10516511 \n31 \nHasegawa M Kawashima S Shikano M \nThe evaluation of corticosteroid therapy in conjunction with plasma exchange in the treatment of renal cholesterol embolic disease. A report of 5 cases . Am J Nephrol . 2000 ;20 :263 –267 .10970977 \n32 \nStabellini N Rizzioli E Trapassi MR Fabbian F Catalano C Gilli P. \nRenal cholesterol microembolism: is steroid therapy effective? \nNephron . 2000 ;86 :239 –\n240 .11015020 \n33 \nGraziani G Santostasi S Angelini C Badalamenti S. \nCorticosteroids in cholesterol emboli syndrome . Nephron . 2001 ;87 :371 –373 .11287784\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1179-5476", "issue": "10()", "journal": "Clinical medicine insights. Case reports", "keywords": "Cholesterol crystal embolization; end-stage kidney disease; hemodialysis; pulmonary embolism; warfarin", "medline_ta": "Clin Med Insights Case Rep", "mesh_terms": null, "nlm_unique_id": "101531893", "other_id": null, "pages": "1179547616684649", "pmc": null, "pmid": "28469497", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "16614719;11214743;12887728;17606842;18489944;5928490;3605140;19142021;9046969;11174358;10970977;16814943;665707;11497203;20697039;1738893;19702986;16079936;21401354;12741443;11096032;18271808;21422387;15389900;11287784;25197328;14662690;10516511;23423524;25896176;11015020;10089183;9654541", "title": "Performing Anticoagulation: A Puzzling Case of Cholesterol Embolization Syndrome.", "title_normalized": "performing anticoagulation a puzzling case of cholesterol embolization syndrome" }

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CLIN-MED-INSIGHTS-CASE-REP 2017?10:1-5.", "literaturereference_normalized": "performing anticoagulation a puzzling case of cholesterol embolization syndrome", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180109", "receivedate": "20171227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14329449, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180509" }, { "companynumb": "JP-MYLANLABS-2017M1076720", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "WARFARIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "040415", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY EMBOLISM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Chronic kidney disease" }, { "drugrecuraction": "Livedo reticularis" }, { "drugrecuraction": "Atheroembolism" } ], "drugseparatedosagenumb": null, "drugstartdate": "201310", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "WARFARIN" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Livedo reticularis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Atheroembolism", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chronic kidney disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201312" } }, "primarysource": { "literaturereference": "IGARASHI Y, AKIMOTO T, KOBAYASHI T, IWAZU Y, MIKI T, OTANI-TAKEI N, ET AL. PERFORMING ANTICOAGULATION: A PUZZLING CASE OF CHOLESTEROL EMBOLIZATION SYNDROME. CLIN-MED-INSIGHTS-CASE-REP 2017;10:1-5.", "literaturereference_normalized": "performing anticoagulation a puzzling case of cholesterol embolization syndrome", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20171211", "receivedate": "20171211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14271531, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180321" } ]

{ "abstract": "A 49-year-old woman who had previously received treatment with cytotoxic drugs for metastatic gestational trophoblastic disease (GTD) presented with a witnessed tonic-clonic seizure, headache, confusion and blindness, 6 days after the uneventful administration of a general anaesthetic and 2 months after cessation of chemotherapy. Magnetic resonance imaging showed relatively symmetrical, subcortical, white matter abnormalities, predominantly affecting the occipital, posterior temporal and parietal lobes and the cerebellum. T2-dependent abnormalities and elevated regional apparent diffusion coefficient were present in a pattern typical for posterior reversible encephalopathy syndrome (PRES). The clinical and radiological manifestations were resolved completely with supportive therapy. This case of PRES may be a late complication of gemcitabine or cisplatin therapy precipitated by a general anaesthetic, or associated electrolyte or blood pressure disturbance.", "affiliations": "Department of Imaging, Charing Cross Hospital, Fulham Palace Road, London, UK.", "authors": "Rangi|P S|PS|;Partridge|W J|WJ|;Newlands|E S|ES|;Waldman|A D|AD|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine", "country": "Germany", "delete": false, "doi": "10.1007/s00234-005-1376-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-3940", "issue": "47(8)", "journal": "Neuroradiology", "keywords": null, "medline_ta": "Neuroradiology", "mesh_terms": "D000768:Anesthesia, General; D000964:Antimetabolites, Antineoplastic; D001794:Blood Pressure; D001921:Brain; D001927:Brain Diseases; D003841:Deoxycytidine; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D031901:Gestational Trophoblastic Disease; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D013577:Syndrome; D014882:Water-Electrolyte Balance", "nlm_unique_id": "1302751", "other_id": null, "pages": "586-90", "pmc": null, "pmid": "15997391", "pubdate": "2005-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10954269;6150182;9158653;8587375;12063238;7856903;7581123;3178528;184880;1632361;8884627;9541291;7595753;1569451;9536483;9818862;11295355;8559202;9613500;9010526;3531716;11559490;12888158;7282395", "title": "Posterior reversible encephalopathy syndrome: a possible late interaction between cytotoxic agents and general anaesthesia.", "title_normalized": "posterior reversible encephalopathy syndrome a possible late interaction between cytotoxic agents and general anaesthesia" }

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POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME: A POSSIBLE LATE INTERACTION BETWEEN CYTOTOXIC AGENTS AND GENERAL ANAESTHESIA.. 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "NOT REPORTED", "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "NOT REPORTED, FREQ: NOT REPORTED", "drugenddate": null, "drugenddateformat": null, "drugindication": "GESTATIONAL TROPHOBLASTIC TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "49", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Posterior reversible encephalopathy syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "21.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "WALDMAN A, NEWLANDS E, RANGI P, PARTRIDGE W. POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME: A POSSIBLE LATE INTERACTION BETWEEN CYTOTOXIC AGENTS AND GENERAL ANAESTHESIA. NEURORADIOLOGY. 2005?47(8):586-90.", "literaturereference_normalized": "posterior reversible encephalopathy syndrome a possible late interaction between cytotoxic agents and general anaesthesia", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20180216", "receivedate": "20171219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14303107, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "The risk of de novo hepatitis B virus infection is lower after liver transplant using hepatitis B core antibody-negative donors into negative recipients versus hepatitis B core antibody-positive donors but can occur. Here, we present a 34-year-old male patient with acute de novo hepatitis B virus that developed 7 months after successful liver transplant. The case we report here is the first in the literature with regard to both switch from tenofovir to entecavir treatment and the presentation of de novo acute hepatitis B virus after liver transplant. The switch in treatment protocol resulted in significant improvements in serologic and biochemical levels, and the patient was discharged from the hospital on day 35 after admittance.", "affiliations": "From the Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey.", "authors": "Akbulut|Sami|S|;Harputluoglu|Murat|M|;Yilmaz|Sezai|S|", "chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir", "country": "Turkey", "delete": false, "doi": "10.6002/ect.2018.0072", "fulltext": null, "fulltext_license": null, "issn_linking": "1304-0855", "issue": "16(5)", "journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation", "keywords": null, "medline_ta": "Exp Clin Transplant", "mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D057915:Drug Substitution; D006147:Guanine; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D000068698:Tenofovir; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "101207333", "other_id": null, "pages": "635-637", "pmc": null, "pmid": "29790455", "pubdate": "2018-10", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Successful Management of De Novo Acute Hepatitis B Virus Infection With Entecavir in a Living-Donor Liver Transplant Patient.", "title_normalized": "successful management of de novo acute hepatitis b virus infection with entecavir in a living donor liver transplant patient" }

[ { "companynumb": "PHHY2018TR116135", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LIVER TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis B", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AKBULUT S, HARPUTLUOGLU M, YILMAZ S. SUCCESSFUL MANAGEMENT OF DE NOVO ACUTE HEPATITIS B VIRUS INFECTION WITH ENTECAVIR IN A LIVING-DONOR LIVER TRANSPLANT PATIENT. EXPERIMENTAL AND CLINICAL TRANSPLANTATION. 2018?5:635-7", "literaturereference_normalized": "successful management of de novo acute hepatitis b virus infection with entecavir in a living donor liver transplant patient", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20181010", "receivedate": "20181010", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15485498, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "OBJECTIVE\nThis observational study was based on a series of clinical cases in which failure of sinus augmentations occurred in patients who received prophylactic clindamycin therapy.\n\n\nMETHODS\nBetween the years 2006 and 2010, a retrospective observational study was performed. The study consisted of 1,874 patients (723 males and 1,151 females) in whom sinus augmentations were performed prior to placement of dental implants.\n\n\nRESULTS\nIn nine (0.48%) patients (four males and five females), infection of the graft material inside the sinus floor occurred, and six patients developed an abscess in the site of surgery, 4 to 6 weeks postoperatively. In three patients, a buccal fistula with pus draining was observed 5 to 8 weeks postoperatively. In all patients, the source of infection was from the grafted material within the sinus. A common manifestation in all nine patients was that they had self-reported penicillin allergy and had been prescribed clindamycin (300 mg every 6 hours for 10 days).\n\n\nCONCLUSIONS\nProphylactic clindamycin therapy following sinus augmentation procedures seems to be a risk factor for infections and loss of grafting material following these surgical techniques.", "affiliations": null, "authors": "Khoury|Fouad|F|;Javed|Fawad|F|;Romanos|Georgios E|GE|", "chemical_list": "D000900:Anti-Bacterial Agents; D015921:Dental Implants; D002981:Clindamycin", "country": "United States", "delete": false, "doi": "10.11607/jomi.6517", "fulltext": null, "fulltext_license": null, "issn_linking": "0882-2786", "issue": "33(5)", "journal": "The International journal of oral & maxillofacial implants", "keywords": null, "medline_ta": "Int J Oral Maxillofac Implants", "mesh_terms": "D000038:Abscess; D000900:Anti-Bacterial Agents; D016866:Bacteroidaceae Infections; D002981:Clindamycin; D003758:Dental Implantation, Endosseous; D015921:Dental Implants; D005260:Female; D006801:Humans; D008297:Male; D008443:Maxillary Sinus; D015523:Maxillary Sinusitis; D008875:Middle Aged; D011183:Postoperative Complications; D018720:Prevotella; D012189:Retrospective Studies; D012307:Risk Factors; D059546:Sinus Floor Augmentation", "nlm_unique_id": "8611905", "other_id": null, "pages": "1136-1139", "pmc": null, "pmid": "30231102", "pubdate": "2018", "publication_types": "D016428:Journal Article", "references": null, "title": "Sinus Augmentation Failure and Postoperative Infections Associated with Prophylactic Clindamycin Therapy: An Observational Case Series.", "title_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series" }

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SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719957, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089513", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706208, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988160", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20191203", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719958, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-TEVA-2018-US-987954", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719948, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089510", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706986, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089522", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705426, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988163", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15720019, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988162", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719989, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089511", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705889, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055935", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H,DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-9", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055909", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES.. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445629, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055872", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H (DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445442, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055933", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. SEP/OCT. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445762, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-TEVA-2018-US-988166", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719992, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055923", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fistula", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. SEP/OCT?. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445680, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "US-TEVA-2018-US-988158", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719950, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988164", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719990, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089515", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706185, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055924", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fistula", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. SEP/OCT?. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445685, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2019M1055873", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H (DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445441, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2018M1089529", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "47", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705421, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2018M1089517", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Purulent discharge", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Post procedural fistula", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "US-TEVA-2018-US-988165", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "063083", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.2 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20181231", "receivedate": "20181213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15719991, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055875", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, Q6H 9DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT J ORAL MAXILLOFAC IMPLANTS.. 2018?33(5):1136-1139", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445443, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2018M1089528", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15705423, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" }, { "companynumb": "DE-MYLANLABS-2019M1055905", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "050801", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY ORAL DOSE OF 1.2 G PER DAY FOR 10 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "6", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE.. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES.. INT J ORAL MAXILLOFAC IMPLANTS. 2018?33(5):1136-9", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190618", "receivedate": "20190618", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16445633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-MYLANLABS-2018M1089519", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLINDAMYCIN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "203063", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "ORAL SOLUTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLINDAMYCIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Graft infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Postoperative wound infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Surgical failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KHOURY F, JAVED F, ROMANOS GE. SINUS AUGMENTATION FAILURE AND POSTOPERATIVE INFECTIONS ASSOCIATED WITH PROPHYLACTIC CLINDAMYCIN THERAPY: AN OBSERVATIONAL CASE SERIES. INT-J-ORAL-MAXILLOFAC-IMPLANTS 2018?33(5):1136-1139.", "literaturereference_normalized": "sinus augmentation failure and postoperative infections associated with prophylactic clindamycin therapy an observational case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "DE", "receiptdate": "20181210", "receivedate": "20181210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15706583, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "Absolute immature platelet counts (A-IPC) aid in diagnosis and treatment follow-up in thrombotic thrombocytopenic purpura (TTP). A-IPC was used to follow a patient on mycophenolate mofetil (MMF) maintenance therapy treated with a prolonged therapeutic plasma exchange (TPE) regimen for relapsing TTP. On admission, the platelet (PLT) count was 95 × 109/L declining to 14 × 109/L in 5 days. Daily TPE was initiated for suspected TTP, and MMF was discontinued. A-IPC and PLT count were 1 × 109/L and 14 × 109/L, respectively, prior to first TPE. A-IPC improved to 3.2 × 109/L with 1 TPE, and on day 5, A-IPC and PLT count were 7.5 × 109/L and 218 × 109/L, respectively. On day 6, A-IPC and PLT count decreased to 4.8 × 109/L and 132 × 109/L further worsening to 0.4 × 109/L and 13 × 109/L, respectively. ADAMTS13 activity remained <5% with an inhibitor; counts did not recover. Initial improvement followed by rapidly declining A-IPC despite therapy suggested production suppression. In TTP, A-IPC may aid in establishing early therapy effects over PLT production.", "affiliations": "Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.;Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.;Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA, [email protected].", "authors": "Kundrapu|Sirisha|S|;Reeves|Hollie M|HM|;Maitta|Robert W|RW|", "chemical_list": "D000903:Antibiotics, Antineoplastic; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D009173:Mycophenolic Acid", "country": "Switzerland", "delete": false, "doi": "10.1159/000510913", "fulltext": null, "fulltext_license": null, "issn_linking": "0001-5792", "issue": "144(4)", "journal": "Acta haematologica", "keywords": "Absolute immature platelet count; Immature platelets; Thrombotic thrombocytopenic purpura", "medline_ta": "Acta Haematol", "mesh_terms": "D000071120:ADAMTS13 Protein; D000903:Antibiotics, Antineoplastic; D001792:Blood Platelets; D006801:Humans; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D010951:Plasma Exchange; D010976:Platelet Count; D011697:Purpura, Thrombotic Thrombocytopenic; D012008:Recurrence", "nlm_unique_id": "0141053", "other_id": null, "pages": "465-469", "pmc": null, "pmid": "33238282", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": null, "title": "Absolute Immature Platelet Counts Suggest Platelet Production Suppression during Complicated Relapsing Thrombotic Thrombocytopenic Purpura.", "title_normalized": "absolute immature platelet counts suggest platelet production suppression during complicated relapsing thrombotic thrombocytopenic purpura" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NOREPINEPHRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NOREPINEPHRINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombotic thrombocytopenic purpura", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Urinary tract infection pseudomonal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "KUNDRAPU S, REEVES H, MAITTA R.. ABSOLUTE IMMATURE PLATELET COUNTS SUGGEST PLATELET PRODUCTION SUPPRESSION DURING COMPLICATED RELAPSING THROMBOTIC THROMBOCYTOPENIC PURPURA. ACTA HAEMATOL. 2020?25:1?5", "literaturereference_normalized": "absolute immature platelet counts suggest platelet production suppression during complicated relapsing thrombotic thrombocytopenic purpura", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210129", "receivedate": "20201215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18615340, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "OBJECTIVE\nPulmonary thromboembolism (PTE) may be one of the causes of sudden death in hospitalized psychiatric patients. The aim of our study was to investigate whether fatal PTE in these patients may be the result of their prolonged physical immobilization, particularly when there were associated risk factors, and to emphasize the importance of this problem.\n\n\nMETHODS\nA retrospective analysis of medical records of psychiatric patients died suddenly at the Department of Intensive Care of the Clinic of Psychiatry \"Dr Laza Lazarevic\", Belgrade, in the period January 1, 2010 - December 31, 2011, was performed. Data of those for which the autopsy showed PTE as the immediate cause of death were extracted, and the presence of risk factors for the development of deep vein thrombosis analyzed.\n\n\nRESULTS\nIn the observed period, out of 4,001 hospitalized psychiatric patients 53 died, and for 18 of them autopsy was required due to sudden death. In five patients, autopsy revealed PTE as a direct and sole cause of death. All the five patients were males, mean age 45.2 years, and during hospitalization all received strong antipsychotics and diazepam. Of the total duration of their hospital stay (mean 8.2 days), they were temporarily immobilized during an average 4.2 days. Four of them had acute infection, three were active smokers, and the two had a body mass index > 30 kg/m2.\n\n\nCONCLUSIONS\nOur results suggest a possible link between prolonged physical immobilization of psychiatric patients who also receive antipsychotic therapy, and total PTE.", "affiliations": "Clinic for Psychiatric Disorders \"Dr Laza Lazarević\", Belgrade, Serbia. [email protected]", "authors": "Stefanović|Vesna|V|;Kuzmanović|Ana|A|;Stefanović|Slavisa|S|", "chemical_list": "D014150:Antipsychotic Agents", "country": "Serbia", "delete": false, "doi": "10.2298/vsp1310903s", "fulltext": null, "fulltext_license": null, "issn_linking": "0042-8450", "issue": "70(10)", "journal": "Vojnosanitetski pregled", "keywords": null, "medline_ta": "Vojnosanit Pregl", "mesh_terms": "D014150:Antipsychotic Agents; D002423:Cause of Death; D003645:Death, Sudden; D006760:Hospitalization; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D011655:Pulmonary Embolism; D012149:Restraint, Physical; D012189:Retrospective Studies; D012307:Risk Factors; D055771:Serbia; D013997:Time Factors; D020246:Venous Thrombosis", "nlm_unique_id": "21530700R", "other_id": null, "pages": "903-7", "pmc": null, "pmid": "24313170", "pubdate": "2013-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients.", "title_normalized": "fatal pulmonary thromboembolism after prolonged physical immobilization in hospitalized psychiatric patients" }

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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. 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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. 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FATAL PULMONARY THROMBOEMBOLISM AFTER PROLONGED PHYSICAL IMMOBILIZATION IN HOSPITALIZED PSYCHIATRIC PATIENTS. 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{ "abstract": "BACKGROUND\nThis study aimed to determine the efficacy and complications of intravitreal chemotherapy-assisted endoresection for refractory International Classification of Retinoblastoma (ICRB) group D retinoblastoma in monocular patients.\n\n\nMETHODS\nIn this retrospective case series, intravitreal chemotherapy-assisted endoresection by pars plana vitrectomy was performed in 11 eyes with refractory ICRB group D retinoblastoma unresponsive to standard therapies in monocular patients.\n\n\nRESULTS\nAcross a mean follow-up period of 42.7 months, globe salvage was attained in all 11 eyes (100%). There were no cases of extra-ocular tumour seeding or remote metastasis. In 9 eyes (81.8%), tumour control was achieved with one pars plana vitrectomy; in 2 cases (18.2%), repeated treatment, such as laser therapy, intravitreal chemotherapy or a second pars plana vitrectomy, was needed. Retinal reattachment was achieved in all 4 eyes (100%) with previous retinal detachment. Four eyes (36.4%) required subsequent cataract surgery due to secondary cataract. Ten eyes (90.9%) had improvement in best-corrected visual acuity at the last follow-up.\n\n\nCONCLUSIONS\nIntravitreal chemotherapy-assisted endoresection appears to be a safe and effective globe-salvaging method for refractory group D retinoblastoma. It is a promising alternative to enucleation and a supplementary therapeutic strategy for those unresponsive to standard therapies, especially for the monocular retinoblastoma patients.", "affiliations": "Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.;Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China. [email protected].", "authors": "Yu|Xiling|X|;Li|Xueke|X|;Xing|Yue|Y|;Lu|Siduo|S|;Tanumiharjo|Silvia|S|;Ma|Jin|J|http://orcid.org/0000-0003-3072-9065", "chemical_list": "D019772:Topotecan", "country": "England", "delete": false, "doi": "10.1186/s12885-020-07314-1", "fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407 BioMed Central London \n\n7314\n10.1186/s12885-020-07314-1\nResearch Article\nEffectiveness of intravitreal chemotherapy-assisted endoresection in monocular patients with group D retinoblastoma\nYu Xiling Li Xueke Xing Yue Lu Siduo Tanumiharjo Silvia http://orcid.org/0000-0003-3072-9065Ma Jin [email protected] grid.12981.330000 0001 2360 039XZhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China \n26 8 2020 \n26 8 2020 \n2020 \n20 80814 6 2020 18 8 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThis study aimed to determine the efficacy and complications of intravitreal chemotherapy-assisted endoresection for refractory International Classification of Retinoblastoma (ICRB) group D retinoblastoma in monocular patients.\n\nMethods\nIn this retrospective case series, intravitreal chemotherapy-assisted endoresection by pars plana vitrectomy was performed in 11 eyes with refractory ICRB group D retinoblastoma unresponsive to standard therapies in monocular patients.\n\nResults\nAcross a mean follow-up period of 42.7 months, globe salvage was attained in all 11 eyes (100%). There were no cases of extra-ocular tumour seeding or remote metastasis. In 9 eyes (81.8%), tumour control was achieved with one pars plana vitrectomy; in 2 cases (18.2%), repeated treatment, such as laser therapy, intravitreal chemotherapy or a second pars plana vitrectomy, was needed. Retinal reattachment was achieved in all 4 eyes (100%) with previous retinal detachment. Four eyes (36.4%) required subsequent cataract surgery due to secondary cataract. Ten eyes (90.9%) had improvement in best-corrected visual acuity at the last follow-up.\n\nConclusion\nIntravitreal chemotherapy-assisted endoresection appears to be a safe and effective globe-salvaging method for refractory group D retinoblastoma. It is a promising alternative to enucleation and a supplementary therapeutic strategy for those unresponsive to standard therapies, especially for the monocular retinoblastoma patients.\n\nKeywords\nRefractory retinoblastomaIntravitreal chemotherapyEndoresectionPars plana vitrectomy Science and Technology Program of Guangzhou201607010070Ma Jin National Natural Science Foundation of Guangdong2016A0303133642018A0303130293Yu Xiling Ma Jin issue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nOver the past two decades, the management of retinoblastoma has dramatically changed from eye-sacrificing methods to eye-preserving alternatives [1]. Eye preservation can be achieved in as much as 90–100% of eyes classified as group A, B or C retinoblastoma, but it is still challenging in group D and E retinoblastoma classified according to the International Classification of Retinoblastoma (ICRB) criteria [2]. Recent research has suggested that it is safe to attempt eye-preserving methods for group D cases, while enucleation is still recommended for group E cases [3]. Recent studies have shown some progress in the globe salvage of group D retinoblastoma with the single or combined use of intravenous chemotherapy (IVC), intra-arterial chemotherapy (IAC) and intravitreal chemotherapy (IViC), but persistent or recurrent vitreous and subretinal seeding can still occur in some refractory cases [4]. Eye preservation is especially important for monocular patients for whom the other affected eye has been previously enucleated for unmanageable progressive retinoblastoma and who require the remaining eye to retain visual function.\n\nIViC was first introduced in 2003 [5], and it has become one of the most effective treatments against the vitreous seeding of retinoblastoma [6]. Several studies have proven that IViC has increased the eye-preserving rate in group D retinoblastoma [3, 4, 7]. However, the recurrent refractory vitreous and subretinal seeding of the tumour remains a major challenge of this method [6]. The efficiency of IViC is reduced when there is a high burden of vitreous seeding, as tumour growth cannot be controlled even with repeated IViC. Furthermore, sight-threatening tumour-related complications, such as persistent retinal detachment or vitreous haemorrhage, cannot be solved through IViC.\n\nTheoretically, endoresection by pars plana vitrectomy (PPV) is the ideal way to eradicate a tumour and solve vitreoretinal complications, but its use in the treatment of retinoblastoma has been controversial due to the high risk of metastasis, orbital seeding and extraocular extension [8]. However, the recent success of IViC has raised the possibility of surgical intervention again [9, 10]. In this study, we attempted IViC-assisted endoresection in refractory monocular ICRB group D retinoblastoma patients. Intraocular surgery was carefully executed and combined with effective local chemotherapy and a series of safety measures. We evaluated the therapeutic effect and complications with a mean follow-up of 42.7 months.\n\nMethods\nStudy subjects\nThis retrospective cohort study was conducted between May 2013 and March 2019. The children were referred for this study when refractory retinoblastoma was unresponsive with uncontrolled intravitreal seeding or tumour recurrence after receiving six cycles of systemic chemotherapy with a standard vincristine/etoposide/carboplatin (VEC) regimen in all cases and different strategies of local chemotherapy (IAC and/or IViC, Table 1). The children consecutively included were diagnosed with group D retinoblastoma, classified according to International Classification of Retinoblastoma (ICRB) criteria, with the other affected eye previously enucleated due to progressive retinoblastoma. All the included patients had no tumour involvement of the anterior segment or a suggestion of extraocular metastasis on neuroimaging. All of the cases are classified as cT2bN0M0H1 according to the 8th edition American Joint Committee on Cancer/Union for International Cancer Control Clinical Staging System (8th ed. cTNMH).\nTable 1 Characteristics of patients with ICRB group D retinoblastoma underwent intravitreal chemotherapy-assisted endoresection\n\nNo.\tAge (months)\tVitreous seeds Classificationa\tSubretinal seeds\tRetinal detachment\tTMN Classificationb\tTreatment history\t\n01\t36\tDust\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\n02\t48\tDust\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\n03\t8\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n04\t30\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n05\t24\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n06\t78\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n07\t71\tDust\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n08\t65\tCloud\tY\tN\tcT2bN0M0H1\tIVC + IViC\t\n09\t88\tCloud\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\n10\t31\tSpheres\tY\tN\tcT2bN0M0H1\tIVC + IAC + IViC\t\n11\t29\tSpheres\tY\tY\tcT2bN0M0H1\tIVC + IViC\t\nIVC Intravenous chemotherapy, IViC Intravitreal chemotherapy, IAC Intra-arterial chemotherapy\n\naVitreous seeding was classified by the criteria of Francis, J. H. et al. [11]\n\nbAccording to the 8th edition American Joint Committee on Cancer/Union for International Cancer Control Clinical Staging System (8th ed. cTNMH)\n\n\n\nTreatment protocol\nIViC using topotecan (20μg/0.1 ml) was performed once, 1 week before surgery. While performing 25-gauge PPV, intraoperative IViC of 5 μg/ml topotecan in irrigation fluid (balanced salt solution) was applied. The visible intravitreal tumour cells were removed through vitrectomy; the subretinal tumour lesions were removed with extended resection accompanied by electrocoagulation at least 3 mm from the margin of the mass. To avoid retinal detachment, laser coagulation was applied to the boundaries after resection (Fig. 1). Cryotherapy was used when required. Calcified lesions were only removed if they were directly involved with the active tumour, or were located subretinally (Fig. 2). Silicone oil tamponade was applied in all cases. Intravitreal injection of topotecan (20 μg/0.1 ml) was applied at the end of the PPV. In all the cases, the lens was preserved during PPV.\nFig. 1 Chemotherapy-assisted endoresection of subretinal tumour in group D retinoblastoma in case 7. a and b The subretinal tumour was removed with extended resection by electrocoagulation (white arrows show the edge of electrocoagulation, black triangle shows the removed tumour and white asterisks show the scar of the regressed tumour after previous IViC). c One day after the endoresection, white arrows show the laser scarring around the resected lesion. d Sixteen months after endoresection and 1 month after silicone oil removal, no tumour recurrence was found (white asterisks show the scar of the regressed tumour)\n\nFig. 2 Reservation of calcified lesions during chemotherapy-assisted endoresection in group D retinoblastoma in case 11. a Refractory vitreous and subretinal seeds with massive calcification lesion in the only eye of a patient with bilateral retinoblastoma after IVC and IViC. b The resection of the tumour and the reservation of some calcified lesions, 1 month after surgery\n\n\n\nSafety measures were undertaken to prevent orbital/extraocular extension of the tumour from the surgical incisions. All three incisions were sutured with absorbable 8–0 sutures to remain strictly watertight. Cryotherapy and sub-conjunctival injections of topotecan (20 μg/0.1 ml) were applied to all three of the sutured incision sites.\n\nAfter surgery, all patients underwent routine eye examinations as well as neuroimaging (CT and MRI) to evaluate if there was any tumour recurrence, metastasis or orbital/extraocular extension. IViC and laser treatment were applied when there was any sign of recurrence. Additional PPV was performed when recurrence could not be controlled by IViC and/or laser treatment. Cataract surgery was performed for secondary cataract at least 6 months after the first PPV if there was no sign of recurrence or involvement of the anterior segment. Silicon oil removal was considered when any oil-related complications occurred in the eye, such as oil emulsification, oil migration, secondary glaucoma, etc.\n\nThis study was performed after obtaining informed consent from the patients and their family, and it was approved by the Board of Ethics at Sun Yat-Sen University Zhongshan Ophthalmological Center.\n\nResults\nA total of 11 eyes were included in this retrospective cohort study conducted between May 2013 and February 2019. The basic information, ocular features and treatment history of the patients are presented in Table 1. The age of the patients ranged from 8 to 88 months, with an average age of 3.9 years. All of the patients were monocular, in which the other affected eye had been previously enucleated due to progressive retinoblastoma; the eyes included for combined therapy were classified as group D according to ICRB criteria. Subretinal seeding and vitreous seeding were observed in all the included cases. Vitreous seeding was classified according to the criteria by Francis et al [11]. No anterior segment or extraocular metastasis was found in any of the patients. Retinal detachment was observed in 4 patients (cases 1, 2, 9 and 11). Before referral to our hospital, all of the patients had previously received IVC and IViC; 1 patient (case 10) had also received IAC.\n\nThe follow-up time, tumour recurrence and metastasis, post-operative complications and subsequent treatments are presented in Table 2. Until March 2020, the follow-up time from PPV ranged from 12 months to 83 months, with a mean of 42.7 months. There was no case of anterior segment or extraocular tumour extension during follow-up period. Eye preservation was achieved in all 11 cases (100%). Vitreous and subretinal seeding control required PPV, once, in 9 cases (9/11, 81.8%), and no tumour recurrence was observed during follow-up.\nTable 2 Treatment outcomes of patients who underwent chemotherapy-assisted endoresection\n\nNo.\tFollow-up\n(months)\tRecurrence\tMetastasis\tComplicated\ncataract\tRetreatment\tPre-op\nBCVA\tLast BCVA\t\n01\t83\tNo\tNo\tNo\tNo\tHM\tFC\t\n02\t81\tNo\tNo\tNo\tNo\tHM\t20/400\t\n03\t79\tNo\tNo\tNo\tNo\tLP\t20/200\t\n04\t65\tNo\tNo\tNo\tNo\tLP\t20/800\t\n05\t33\tNo\tNo\tNo\tNo\tLP\t20/100\t\n06\t30\tNo\tNo\tNo\tCataract surgery\tLP\t20/125\t\n07\t23\tNo\tNo\tYes\tNo\tHM\t20/400\t\n08\t23\tYes\tNo\tYes\tPPV, IViC, cataract surgery\tLP\t20/200\t\n09\t23\tYes\tNo\tYes\tLaser, IViC, PPV, Cataract surgery\tHM\tFC\t\n10\t18\tNo\tNo\tYes\tCataract surgery\tLP\tHM\t\n11\t12\tNo\tNo\tNo\tNo\tLP\tLP\t\nPPV Pars plana vitrectomy, IViC Intravitreal chemotherapy\n\n\n\nTwo cases (8 and 9) showed tumour recurrence after primary PPV without intravitreal seeding or anterior chamber involvement. In case 9, tumour recurrence was found 2 months after PPV, and it was observed as a focal solid tumour at the edge of previous endoresection. After repeated IViC (topotecan 20 μg/0.1 ml, every 2 weeks for 5 times) and retinal laser photocoagulation, the tumour regressed and no recurrence was observed during the follow-up period (Fig. 3). In case 8, tumour recurrence happened 12 months after PPV; it presented as multi-focal subretinal seeding with pre-retinal haemorrhage, without any vitreous seeding. After repeated IViC (topotecan 20 μg/0.1 ml, every 2 weeks for 3 times) and retinal laser photocoagulation, tumour growth could not be effectively controlled, so PPV with endoresection was performed again and no recurrence was observed by the end of the last follow-up.\nFig. 3 The management and result of focal tumour recurrence and retinal redetachment after chemotherapy-assisted endoresection in case 9. a Refractory vitreous and subretinal seeds with retinal detachment before chemotherapy-assisted endoresection. b White arrows show the edge of the resection of the tumour, 1 week after endoresection. c and d Focal tumour recurrence (white asterisk) with silicon oil tamponade. e and f Regression of the tumour (white asterisk) after 5 sessions of IViC and laser coagulation\n\n\n\nThree of the 4 cases with pre-surgical retinal detachment achieved anatomical restoration of the retina after undergoing PPV once. One case (case 9) had recurrent retinal detachment 12 months after the first surgery, and retinal reattachment was achieved after a second PPV with no recurrent retinal detachment during subsequent follow-up. Secondary cataract was observed in 4 cases (cases 6, 8, 9 and 10) and cataract surgery (phacoemulsification and intraocular lens implantation) was performed. Silicone oil removal was performed in 2 cases (cases 6, 7) when silicone oil emulsification was seen. Silicon oil was not removed when focal recurrence was found (case 9); in this situation, further IViC and laser treatment were done in the silicon oil-filled eye.\n\nThe changes in best corrected visual acuity (BCVA) are shown in Table 2. Up to the last follow-up examination, 10 of the11 patients showed improvement in BCVA; in 4 cases the patient’s vision improved to ≥20/200. One patient (case 11) had no change in BCVA after PPV.\n\nDiscussion\nFor many years, the risk of dissemination, seeding and extraocular spread has been the biggest obstacle for surgical intervention in patients with retinoblastoma. Honavar et al. reported an unfavourable outcome in 75% of patients with retinoblastoma who underwent PPV in 2001 [12]. With the rapid development of local chemotherapy treatments in recent years, this situation may come to an end. Several studies have reported on the combined use of IViC and PPV for advanced retinoblastoma in small sample cases [9, 10, 13]. Recently, Zhao et al. reported on planned PPV with IViC in 21 cases of refractory retinoblastoma, with eye preservation achieved in 85.7% (18/21) of the cases with a median of 5.1 years of follow-up [9]. In our study, eye preservation was achieved in 100% of the cases during an average follow-up of 42.7 months, without any seeding through the surgical tracts or metastasis. These encouraging results revealed that the combined use of IViC (both preoperatively and intraoperatively) significantly improved the safety of a surgical intervention for retinoblastoma. Moreover, to reduce the risk of surgical incision seeding, some safety measures should be taken, such as using a minimally invasive incision and applying strictly water-tight sutures, cryotherapy and subconjunctival injections of anti-tumour drugs at the incision sites. In general, we believe that IViC-assisted endoresection by PPV can be carefully considered as a supplementary therapy in the refractory cases when standard therapies have failed prior to second eye enucleation.\n\nIViC-assisted endoresection should be performed with strict control of the indications and contraindications. We suggest that only previously treated (IVC/IAC/IViC) refractory ICRB group D cases with obvious vitreous and/or subretinal seeding should be considered for this form of treatment. The direct and definite removal of tumour is the significant advantage of endoresection, so it is especially helpful for cases with a high burden of vitreous and/or subretinal seeding. The IViC-assisted endoresection by PPV can reduce the tumour size and its resulting burden while facilitating extensive and uniformed distribution of the chemotherapeutic drug in the vitreous cavity, which further enhances the efficiency of the drug and reduces the amount of treatment required and the retinal toxicity of repeated IViC [6].\n\nThe contraindication of endoresection for retinoblastoma is any sign of tumour metastasis in the anterior segment or extraocular metastasis, which suggests that ICRB group E cases should be excluded. In the study by Zhao et al., the retinoblastoma was not controlled by one-time use of PPV in 4 patients, all of whom demonstrated tumour metastases in the anterior chamber of the eyes, and only one eye was preserved [9]. This result is consistent with the findings reported in many previous studies that anterior chamber tumour metastasis is a danger sign that implies poor prognosis and a high risk of recurrence and extraocular metastasis [14, 15]. Moreover, in these eyes, PPV may greatly increase the risk of iatrogenic seeding because the incision is very close to the anterior segment of the eye. Consequently, we also suggest lens-preserving PPV even when there is partial opacity of the lens, in order to minimise disturbance to the anterior segment during surgery and lower the risk of iatrogenic seeding to the anterior segment. It should be noted that secondary cataract might develop due to silicone tamponade or chemotherapeutic drug toxicity after PPV. In our opinion, cataract surgery should be cautiously considered at least 6 months after PPV when there is no sign of tumour recurrence or metastasis.\n\nAlthough many preventive measures have been used, the tumour can still recur. In our study, two cases had single or multiple focal subretinal tumour recurrence. Fortunately, the recurrent tumours could be eradicated by repeated IViC, laser coagulation or a second PPV. The relatively good prognosis was mostly attributed to the absence of recurrent vitreous seeding. We assumed the silicone oil tamponade helped confine the tumour as a focal lesion of the retina, thus limiting intravitreal tumour seeding. Therefore, intravitreal silicone oil tamponade is recommended during PPV to prevent tumour dissemination, especially vitreous seeding. Since the tumour may recur a long time after surgery (e.g. in case 8, tumour recurrence was observed 12 months after PPV), we suggest that the silicone oil tamponade time should be prolonged appropriately, unless any oil-related complications occur.\n\nIn addition to eradicating intraocular tumours, IViC-assisted PPV can also help address the sight-threatening vitreoretinal complications of retinoblastoma, such as vitreous haemorrhage and persistent retinal detachment. In our study, 4 of the11 eyes had pre-surgical retinal detachment, and all of them achieved successful anatomical retinal reattachment after PPV. This is especially crucial for monocular patients who have no other alternative for retaining visual function and who require eye preservation. In our study,10 of the 11 monocular patient had improved vision after PPV; in 4 cases, the patient’s vision had improved to ≥20/200. The favourable visual function outcomes also proved the value and good prospect of this treatment strategy.\n\nHowever, this study has some limitations. Like any new technique, it is difficult to conduct a randomised controlled trial for treating retinoblastoma, as it is a relatively rare disease. The follow-up period in this study was also relatively short, with a mean of 42.7 months (ranging from 12 months to 83 months). Since retinoblastoma could recur years later, further follow-up is required to evaluate the long-term effects of this treatment method. We also used topotecan instead of melphalan because topotecan was the only chemotherapy drug currently approved in mainland China for the treatment of retinoblastoma.\n\nConclusions\nThis study showed encouraging results for using IViC-assisted endoresection to control ICRB group D retinoblastoma. This suggests that it might be considered to be a supplementary therapeutic strategy for some refractory cases that are unresponsive to standard therapies, especially for monocular patients for whom the other affected eye has been previously enucleated.\n\nAbbreviations\nICRBInternational Classification of Retinoblastoma\n\nIVCIntravenous chemotherapy\n\nIACIntra-arterial chemotherapy\n\nIViCIntravitreal chemotherapy\n\nPPVPars plana vitrectomy\n\nVECVincristine/etoposide/carboplatin.\n\nBCVABest corrected visual acuity\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nXY and JM contributed to the conception and design of the study; XL, YX and SL organised the database; XY performed the statistical analysis; XY wrote the first draft of the manuscript; ST and JM wrote sections of the manuscript. All the authors contributed to the manuscript revision, and to reading and approving the submitted version.\n\nFunding\nThis study was supported by the Science and Technology Program of Guangzhou (201607010070) and the National Natural Science Foundation of Guangdong (2016A030313364, 2020A1515010190 and 2018A0303130293). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nAvailability of data and materials\nThe datasets used during and/or analysed in this study are available from the corresponding author upon request.\n\nEthics approval and consent to participate\nThis study was performed after obtaining written informed consent from the parents/guardians of the minors included in this study (minors are considered anyone under the age of 16). It was approved by the Board of Ethics at Sun Yat-Sen University Zhongshan Ophthalmological Center.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Al-Nawaiseh I Jammal HM Khader YS Jaradat I Barham R Retinoblastoma in Jordan, 2003–2013: ocular survival and associated factors Ophthal Epidemiol 2014 21 6 406 411 10.3109/09286586.2014.967781 \n2. Shields CL Mashayekhi A Au AK Czyz C Leahey A Meadows AT The international classification of retinoblastoma predicts chemoreduction success Ophthalmology 2006 13 12 2276 2280 10.1016/j.ophtha.2006.06.018 \n3. Shields CL Manjandavida FP Arepalli S Kaliki S Lally SE Shields JA Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results JAMA Ophthalmol 2014 132 3 319 325 10.1001/jamaophthalmol.2013.7666 24407202 \n4. Ghassemi F Shields CL Ghadimi H Khodabandeh A Roohipoor R Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma JAMA Ophthalmol. 2014 132 8 936 941 10.1001/jamaophthalmol.2014.414 24789622 \n5. Kaneko A Suzuki S Eye-preservation treatment of retinoblastoma with vitreous seeding Jpn J Clin Oncol 2003 33 12 601 607 10.1093/jjco/hyg113 14769836 \n6. Francis JH Brodie SE Marr B Zabor EC Mondesire-Crump I Abramson DH Efficacy and toxicity of intravitreous chemotherapy for retinoblastoma: four-year experience Ophthalmology 2017 124 4 488 495 10.1016/j.ophtha.2016.12.015 28089679 \n7. Munier FL Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013 Ophthalmic Genet 2014 35 4 193207 10.3109/13816810.2014.973045 \n8. Warden SM Mukai S Pars plana vitrectomy in eyes treated for retinoblastoma Retina (Philadelphia, PA) 2006 26 Suppl 7 S53 S56 10.1097/01.iae.0000244289.01875.78 \n9. Zhao J Li Q Wu S Jin L Ma X Jin M Pars plana vitrectomy and endoresection of refractory intraocular retinoblastoma Ophthalmology 2018 125 2 320 322 10.1016/j.ophtha.2017.10.015 29153457 \n10. Yarovoy AA Ushakova TL Gorshkov IM Polyakov VG Golubeva OV Gorovtsova OV Intraocular surgery with melphalan irrigation for vitreous hemorrhage in an only eye with retinoblastoma Eur J Ophtalmol 2015 26 1 e17 e19 10.5301/ejo.5000683 \n11. Francis JH Abramson DH Gaillard MC Marr BP Beck-Popovic M Munier FL The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan Ophthalmology 2015 122 6 1173 1179 10.1016/j.ophtha.2015.01.017 25795478 \n12. Honavar SG Shields CL Shields JA Demirci H Naduvilath TJ Intraocular surgery after treatment of retinoblastoma Arch Ophthalmol. (Chicago, IL : 1960) 2001 119 11 1613 1621 10.1001/archopht.119.11.1613 \n13. Lee JH Han JW Hahn SM Lyu CJ Kim DJ Lee SC Combined intravitreal melphalan and intravenous/intra-arterial chemotherapy for retinoblastoma with vitreous seeds Graefes Arch Clin Exp Ophthalmol [Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie] 2016 254 2 391 394 10.1007/s00417-015-3202-0 \n14. Abramson DH Shields CL Munier FL Chantada GL Treatment of retinoblastoma in 2015: agreement and disagreement JAMA Ophthalmol 2015 133 11 1341 1347 10.1001/jamaophthalmol.2015.3108 26378747 \n15. Shields CL Lally SE Leahey AM Jabbour PM Caywood EH Schwendeman R Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy Curr Opin Ophthalmol 2014 25 5 374 385 10.1097/icu.0000000000000091 25014750\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "20(1)", "journal": "BMC cancer", "keywords": "Endoresection; Intravitreal chemotherapy; Pars plana vitrectomy; Refractory retinoblastoma", "medline_ta": "BMC Cancer", "mesh_terms": "D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D009366:Neoplasm Seeding; D019572:Retinal Neoplasms; D012175:Retinoblastoma; D012189:Retrospective Studies; D016879:Salvage Therapy; D019772:Topotecan; D016896:Treatment Outcome; D014792:Visual Acuity; D014821:Vitrectomy; D014822:Vitreous Body", "nlm_unique_id": "100967800", "other_id": null, "pages": "808", "pmc": null, "pmid": "32847550", "pubdate": "2020-08-26", "publication_types": "D016428:Journal Article", "references": "26511530;16996605;28089679;11709011;26428220;16946680;26378747;24407202;29153457;24789622;25795478;25014750;25321846;25317653;14769836", "title": "Effectiveness of intravitreal chemotherapy-assisted endoresection in monocular patients with group D retinoblastoma.", "title_normalized": "effectiveness of intravitreal chemotherapy assisted endoresection in monocular patients with group d retinoblastoma" }

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{ "abstract": "A previously healthy 48-year-old active duty man, who had been treated for an elbow abscess 3 weeks earlier, presented to an emergency department in Bahrain with tachycardia, pericardial friction rub and jugular venous distention. Cardiac tamponade was confirmed on transthoracic echocardiogram and he was taken for emergent pericardiocentesis. Pericardial fluid cultures grew community-acquired methicillin-resistant Staphylococcus aureus Despite ongoing treatment with intravenous vancomycin, he developed a recurrent fibrinous pericardial effusion and constrictive pericarditis requiring pericardiectomy. Though he initially did well postoperatively, he developed drug reaction with eosinophilia and systemic symptoms syndrome in response to vancomycin. He was transitioned to ceftaroline and started on high-dose steroids. He recovered during a week-long admission and was discharged home. Several weeks later at follow-up he was doing well and had resumed moderate intensity exercise.", "affiliations": "Department of Aviation Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.;Department of Emergency Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.;Department of Cardiology, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA.", "authors": "DeYoung|Henry|H|;Bloom|Adam|A|;Tamayo|Sally|S|", "chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D013256:Steroids; C490727:T 91825; D014640:Vancomycin", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-221931", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "cardiovascular system; infections", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D063926:Drug Hypersensitivity Syndrome; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009205:Myocarditis; D010490:Pericardial Effusion; D010492:Pericardiectomy; D010493:Pericarditis; D011183:Postoperative Complications; D013203:Staphylococcal Infections; D013256:Steroids; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "29018016", "pubdate": "2017-10-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16933824;24550331;22627263;25855795;8227835;25635199;26320112;28360036;22311935;21115457;20622739;25282211;12923044;24343828;22797874;21575282;19352300;23903515", "title": "Successful treatment of community-acquired methicillin-resistant Staphylococcus aureus purulent myopericarditis.", "title_normalized": "successful treatment of community acquired methicillin resistant staphylococcus aureus purulent myopericarditis" }

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{ "abstract": "Staphylococcus lugdunensis (S. lugdunensis) is a coagulase negative staphylococcus (CoNS) that can cause destructive infective endocarditis. S. lugdunensis, unlike other CoNS, should be considered to be a pathogen. We report the first case of S. lugdunensis endocarditis causing ventricular septal defect and destruction of the aortic and mitral valves. A 53-year-old male with morbid obesity and COPD presented with intermittent fever and progressive shortness of breath for 2 weeks. Chest examination showed bilateral basal crepitations, and a grade 2 systolic murmur along the right sternal border. The leukocyte count was 26,000 cells/μl with 89% neutrophils. He was treated with intravenous vancomycin and ceftriaxone. Blood cultures grew Staphylococcus lugdunensis. Transthoracic echocardiogram, which was limited by body habitus, showed no definite valvular vegetations. Repeat transthoracic echocardiogram performed one week later revealed a large aortic valve vegetation Vancomycin was switched to daptomycin on day 4 because of difficulty achieving therapeutic levels of vancomycin and the development of renal insufficiency. Open heart surgery on day 10 revealed aortic valve and mitral valve vegetations with destruction, left ventricular outflow tract (LVOT) septal abscess and ventricular septal defect (VSD). Bio-prosthetic aortic and mitral valve replacement, LVOT and VSD repair were done. Intraoperative cultures grew Staphylococcus lugdunensis. The patient was discharged home with daptomycin to complete 6 weeks of treatment. S. lugdunensis can cause rapidly progressive endocarditis with valve and septal destruction. Early diagnosis and therapy are essential, with consideration of valve replacement.", "affiliations": "Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.;Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA.", "authors": "Ishiekwene|Celestine|C|;Ghitan|Monica|M|;Kuhn-Basti|Margaret|M|;Chapnick|Edward|E|;Lin|Yu Shia|YS|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.idcr.2016.10.011", "fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(16)30118-410.1016/j.idcr.2016.10.011Case ReportStaphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves Ishiekwene Celestine [email protected]⁎Ghitan Monica Kuhn-Basti Margaret Chapnick Edward Lin Yu Shia Department of infectious Disease, Maimonides Medical Center, 4802 10th Ave, Brooklyn, NY 11219, USA, USA⁎ Corresponding author at: 2775 Shore Parkway, Apt. 1D, Brooklyn, NY, 11223, USA. [email protected] 11 2016 2017 22 11 2016 7 14 15 17 10 2016 28 10 2016 28 10 2016 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Staphylococcus lugdunensis (S. lugdunensis) is a coagulase negative staphylococcus (CoNS) that can cause destructive infective endocarditis. S. lugdunensis, unlike other CoNS, should be considered to be a pathogen. We report the first case of S. lugdunensis endocarditis causing ventricular septal defect and destruction of the aortic and mitral valves.\n\nA 53-year-old male with morbid obesity and COPD presented with intermittent fever and progressive shortness of breath for 2 weeks.\n\nChest examination showed bilateral basal crepitations, and a grade 2 systolic murmur along the right sternal border. The leukocyte count was 26,000 cells/μl with 89% neutrophils. He was treated with intravenous vancomycin and ceftriaxone. Blood cultures grew Staphylococcus lugdunensis. Transthoracic echocardiogram, which was limited by body habitus, showed no definite valvular vegetations. Repeat transthoracic echocardiogram performed one week later revealed a large aortic valve vegetation Vancomycin was switched to daptomycin on day 4 because of difficulty achieving therapeutic levels of vancomycin and the development of renal insufficiency.\n\nOpen heart surgery on day 10 revealed aortic valve and mitral valve vegetations with destruction, left ventricular outflow tract (LVOT) septal abscess and ventricular septal defect (VSD). Bio-prosthetic aortic and mitral valve replacement, LVOT and VSD repair were done. Intraoperative cultures grew Staphylococcus lugdunensis. The patient was discharged home with daptomycin to complete 6 weeks of treatment.\n\nS. lugdunensis can cause rapidly progressive endocarditis with valve and septal destruction. Early diagnosis and therapy are essential, with consideration of valve replacement.\n\nKeywords\nStaphylococcus aureusS. aureusStaphylococcus lugdunensisS. lugdunensisLugdunensisInfective endocarditis\n==== Body\nIntroduction\nStaphylococcus lugdunensis (S. lugdunensis) is a coagulase negative staphylococcus (CoNS) that can cause destructive infective endocarditis as well as broad range of other clinical manifestations. S. lugdunensis, unlike other CoNS, should be taken as a pathogen when reported by microbiology laboratory. We are reporting a rare case of S. lugdunensis endocarditis causing ventricular septal defect; and aortic and mitral valves destruction.\n\nCase presentation\nA 53-year-old Caucasian male presented with intermittent fever, progressive shortness of breath and recurrent left big toe pain for 2 weeks. He had presented twice to the Emergency Department (ED) in the previous month, 2 weeks apart, with intermittent fever and left great toe pain. The leukocyte count was 16,000/μl with 85% neutrophils and fever of 101°F but the other vital signs were normal. He was discharged on a week’s course of oral antibiotics after both visits (clindamycin and prednisone then cefpodoxime and doxycycline on the 1st and 2nd visits respectively) for presumptive gouty arthritis of the left great toe with cellulitis. Symptoms were somewhat improved while on antibiotics but recurred and progressively got worse with associated shortness of breath.\n\nPast medical history was significant for morbid obesity and COPD, obstructive sleep apnea treated with nighttime CPAP (continuous positive airway pressure), abdominal aortic aneurysm, and pericarditis complicated by pericardial effusion requiring a pericardial window 3 years previously. Previous echocardiography done 3 years previously did not show VSD (ventricular septal defect).\n\nOn examination, the temperature was 99.3°F, heart rate 107/min and regular, respiratory rate 34/minute, blood pressure 86/54 mmHg, oxygen saturation 89% on room air. Chest examination showed bilateral basal crepitations, and cardiovascular examination revealed a grade 2 systolic murmur along the right sternal border. Skin around the left great toe was erythematous and mildly tender.\n\nTwo sets of blood cultures were drawn. The leukocyte count was 26,000 cells/μl (reference range 4.8–10.8) with 89% neutrophils (reference range 37.9–70.5), creatinine2.2 mg/dl (reference range 0.7–1.3), blood urea nitrogen 72 mg/dl (reference range 7–21), AST 890 (reference range 8–26), ALT 1173 IU/L (reference range 6–51), total bilirubin1.4 mg/dl (reference range 0.4–1.1) and alkaline phosphatase 200 IU/L (reference range 37–109).\n\nTransthoracic echocardiogram (TTE) showed an ejection fraction of 50%; thickened aortic valve leaflets, mildly increased LVOT/AV velocities; no definite valvular vegetation, and a moderately dilated aortic root (4.8 cm). The study was limited by body habitus. Chest computerize tomography ruled out pulmonary embolism.\n\nThe patient refused a transesophageal echocardiogram, and a repeat transthoracic echocardiogram performed one week later revealed an aortic valve vegetation of 1.9 × 1.2 cm, with partial destruction of the leaflet and baseline thickening of the valve.\n\nHe was treated with intravenous vancomycin and ceftriaxone. Two sets of blood cultures grew Staphylococcus lugdunensis. Vancomycin was switched to daptomycin on day 4 because of difficulty achieving therapeutic levels of vancomycin and the development of renal insufficiency.\n\nThe patient underwent open heart surgery on day 10. Aortic valve vegetation with destruction, a vegetation on the mitral valve with regurgitation, left ventricular outflow tract (LVOT) septal abscess and ventricular septal defect (VSD) were seen. Bio-prosthetic aortic and mitral valve replacement, LVOT and VSD repair were done. Intraoperative cultures grew Staphylococcus lugdunensis. The post-operative course was complicated by complete heart block requiring permanent pacemaker placement, IV line-related infection and pneumonia with respiratory failure.\n\nThe patient was discharged home on hospital day 39 to complete 6 weeks of treatment with daptomycin.\n\nDiscussion\nWe report the first case of S. lugdunensis endocarditis causing VSD. S. lugdunensis is a CoNS first isolated in France in 1988 [1]. It is a commensal of the human skin, especially below the waist, and can be as virulent as Staphylococcus aureus. S. lugdunensis, like other CoNS, has the ability to adhere and produce biofilm, which enables growth on bioprosthetic materials and native tissues [2]. Adhesion to vessel walls and cardiac valves is facilitated by its binding to von Willibrand factor [3], [4]. Fbl is a fibrinogen-binding protein peculiar to S. lugdunensis. Fbl is similar to clumping factor A, which is a fibrinogen-binding protein of S. aureus that plays an important role in its virulence [5]. Though CoNS can be considered a contaminant, S. lugdunensis should be regarded as a pathogen.\n\nS. lugdunensis causes a spectrum of disease including skin and soft tissue infection, bacteremia, infective endocarditis, osteomyelitis, arthritis and catheter related infection [6], [7], [8], [9]. It has been reported as a cause of destructive infective endocarditis with large vegetations visualized on echocardiography and the destruction of the native valves as can occur with S. aureus\n[10]. It mostly cause left sided infective endocarditis [11], although tricuspid valve involvement has been reported [11], [12].\n\nMost S. lugdunensis isolates are susceptible to oxacillin, and the presence of the mecA gene is rare [13]. Our patient was initially treated with intravenous vancomycin and ceftriaxone subsequently switched to daptomycin. Surgical treatment is needed for most patients with S. lugdunensis infective endocarditis [14], [15].\n\nS. lugdunensis can cause rapidly progressive endocarditis with valve and septal destruction. Early diagnosis and therapy are essential, with consideration of valve replacement.\n\nConflict of interest\nNo conflict of interest.\n==== Refs\nReferences\n1 Etienne J. Brun Y. Fleurette J. Staphylococcus lugdunensis endocarditis J Clin Pathol 42 August (8) 1989 892 893 PMID: 2768531 2768531 \n2 Hussain M. Steinbacher T. Peters G. Heilmann C. Becker K. The adhesive properties of the Staphylococcus lugdunensis multifunctional autolysin AtlL and its role in biofilm formation and internalization Int J Med Microbiol 305 January (1) 2015 129 139 PMID: 25515664 25515664 \n3 Speziale P. Pietrocola G. Foster T.J. Geoghegan J.A. Protein-based biofilm matrices in Staphylococci Front Cell Infect Microbiol 10 December (4) 2014 171 PMID: 25540773 \n4 Liesenborghs L. Peetermans M. Claes J. Veloso T.R. Vandenbriele C. Criel M. Shear-resistant binding to von willebrand factor allows Staphylococcus lugdunensis to adhere to the cardiac valves and initiate endocarditis J Infect Dis January (6) 2016 PMID: 26743845 \n5 Mitchell J. Tristan A. Foster T.J. Characterization of the fibrinogen binding surface protein Fbl of Staphylococcus lugdunensis Microbiology 150 11 2004 3831 3841 PMID: 15528668 15528668 \n6 Lin J.F. Cheng C.W. Kuo A.J. Liu T.P. Yang C.C. Huang C.T. Clinical experience and microbiologic characteristics of invasive Staphylococcus lugdunensis infection in a tertiary center in northern Taiwan J Microbiol Immunol Infect 48 August (4) 2015 406 412 PMID: 24529852 24529852 \n7 Matas A. Veiga A. Gabriel J.P. Brain Abscess due to Staphylococcus lugdunensis in the absence of Endocarditis or Bacteremia Case Rep Neurol 7 January (1) 2015 1 5 PMID: 25759658 25759658 \n8 Kear S. Smith C. Mirmiran R. Hofinger D. Staphylococcus lugdunensis : a rare pathogen for osteomyelitis of the foot J Foot Ankle Surg August (21) 2014 PMID: 25154651 \n9 Patel S. Lloyd J.R. Subungual abscess caused by Staphylococcus lugdunensis Cutis 92 September (3) 2013 125 126 PMID: 24153139. 24153139 \n10 Sabe M.A. Shrestha N.K. Gordon S. Menon V. Staphylococcus lugdunensis : a rare but destructive cause of coagulase-negative Staphylococcus infective endocarditis Eur Heart J Acute Cardiovasc Care 3 September (3) 2014 275 280 PMID: 24523355 24523355 \n11 Patil R. Patil T. Hussain K.M. Staphylococcus lugdunensis native tricuspid valve endocarditis: a case report and review of literature J Gen Intern Med 26 October (10) 2011 1209 1211 PMID: 21538169 21538169 \n12 Chung K.P. Chang H.T. Liao C.H. Chu F.Y. Hsueh P.R. Staphylococcus lugdunensis endocarditis with isolated tricuspid valve involvement J Microbiol Immunol Infect 45 June (3) 2012 248 250 PMID: 22041168 22041168 \n13 Becker K. Pagnier I. Schuhen B. Wenzelburger F. Friedrich A.W. Kipp F. Does nasal colonization by methicillin-resistant coagulase-negative staphylococci and methicillin-susceptible Staphylococcus aureus strains occur frequently enough to represent a risk of false-positive methicillin-resistant S. aureus determinations by molecular methods? J Clin Microbiol 44 1 2006 229 PMID: 16390977 16390977 \n14 Anguera I. Río A. Miró J.M. Matínez-Lacasa X. Marco F. Gumá J.R. Hospital clinic endocarditis study group Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles Heart 91 2 2005 PMID: 15657200 \n15 Naji D.I. Pak A. Lawless J. Main M.L. Rapid progression of Staphylococcus lugdunensis mechanical prosthetic valve endocarditis Echo Res Pract 2 September (3) 2015 I11 I12 PMID: 26693342 26693342\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-2509", "issue": "7()", "journal": "IDCases", "keywords": "Infective endocarditis; Lugdunensis; S. aureus; S. lugdunensis; Staphylococcus aureus; Staphylococcus lugdunensis", "medline_ta": "IDCases", "mesh_terms": null, "nlm_unique_id": "101634540", "other_id": null, "pages": "14-15", "pmc": null, "pmid": "27920984", "pubdate": "2017", "publication_types": "D016428:Journal Article; D002363:Case Reports", "references": "16390977;24523355;15657200;25540773;15528668;26743845;24153139;2768531;25515664;21538169;25154651;24529852;26693342;25759658;22041168", "title": "Staphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves.", "title_normalized": "staphylococcus lugdunensis endocarditis with destruction of the ventricular septum and multiple native valves" }

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{ "abstract": "We report a case of an elderly woman on polypharmacy who developed appetite loss, general fatigue and muscle weakness mainly from secondary adrenal insufficiency caused by quitting one semiregular single-dose medicine. Because the degree of insufficiency was mild, her symptoms were eliminated after some time without additional treatment. The present case includes important lessons related to medication management in elderly patients. Additionally, the present case also warns us to be cautious while diagnosing geriatric syndromes as a part of the physiological aging process or additional disease symptoms. Drug-induced geriatric syndrome from quitting semiregular-use drugs should be investigated in future studies.", "affiliations": "Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.;Division of Community Medicine, School of Medicine, Tohoku Medical and Pharmaceutical University, 1-12-1 Fukumuro, Miyaginoku, Sendai, Japan.;Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.", "authors": "Tomita|Naoki|N|;Ishiki|Aiko|A|;Okinaga|Shoji|S|;Furukawa|Katsutoshi|K|;Arai|Hiroyuki|H|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/omcr/omz047", "fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omz047omz047Case ReportDevelopment of geriatric syndromes after taking countermeasures for polypharmacy: an overlooked issue of quitting semiregular single-dose medicine Tomita Naoki 1Ishiki Aiko 1Okinaga Shoji 1Furukawa Katsutoshi 2Arai Hiroyuki 11 Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan2 Division of Community Medicine, School of Medicine, Tohoku Medical and Pharmaceutical University, 1-12-1 Fukumuro, Miyaginoku, Sendai, JapanCorrespondence address. Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Tel: +81-22-717-7182; Fax: +81-22-717-8498; E-mail: [email protected] 2019 14 6 2019 14 6 2019 2019 6 omz04720 1 2019 29 3 2019 22 4 2019 © The Author(s) 2019. Published by Oxford University Press.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]\nWe report a case of an elderly woman on polypharmacy who developed appetite loss, general fatigue and muscle weakness mainly from secondary adrenal insufficiency caused by quitting one semiregular single-dose medicine. Because the degree of insufficiency was mild, her symptoms were eliminated after some time without additional treatment. The present case includes important lessons related to medication management in elderly patients. Additionally, the present case also warns us to be cautious while diagnosing geriatric syndromes as a part of the physiological aging process or additional disease symptoms. Drug-induced geriatric syndrome from quitting semiregular-use drugs should be investigated in future studies.\n==== Body\nINTRODUCTION\nAdverse drug reactions (ADRs) in elderly patients can be mistaken as part of physiological aging or an additional disease symptom (1). The differentiation of ADRs from physiological aging or disease symptoms requires utmost care, particularly when the ADRs are caused by reducing the number of drugs (2). This becomes difficult if a patient is taking semiregular-use drugs.\n\nCASE REPORT\nAt the end of July 2015, a 78-year-old woman visited a general hospital for appetite loss, general fatigue and muscle weakness. Because she was taking several drugs, her doctor stopped some medications, including antidiabetics (metformin 500 mg/day and vildagliptin 100 mg/day), antihypertensive agents (amlodipine 5 mg/day, candesartan 8 mg/day and doxazocine 1 mg/day) and statins (pitavastatin calcium 1 mg/day), as these could cause ADRs. She was also directed to stop all over-the-counter and semiregular-use drugs. However, her symptoms did not improve. Over 2 months, her weight reduced by ~2.0–50.7 kg (body mass index: 23.2 kg/m2). By the end of September, she developed mild fever and was admitted to our hospital, accompanied by her granddaughter. Her children took turns with her hospital visits, except when she was temporarily admitted to a nearby clinic.\n\nShe had some concomitant disease, including hypertension, type II diabetes mellitus, osteoporosis, osteoarthritis, insomnia, bronchial asthma and skin rash, resulting in regular hospital visits. She regularly took more than 10 oral medications (including diabetic drugs, antihypertensive drugs, benzodiazepine and proton pump inhibitors). Besides hearing difficulties, she was diagnosed with mild cognitive impairment 1 year before admission. Her daughter-in-law helped her manage regular drugs. She had good adherence to regular medicines.\n\nAlthough she had right knee osteoarthritis, she could walk independently. Pretibial and pedal edema was observed in both legs. She had a rash, a mild headache with no neck stiffness and a body temperature of ~ 37.5°C. She had no diarrhea, vomiting or abdominal pain, and she defecated every other day without laxatives. There were no signs of upper respiratory tract infections. Her muscle strength was not sufficient to open a bottle cap. Pyramidal/extra-pyramidal signs and ataxia was not observed. She had no significant family history of disease.\n\nIn blood tests, inflammation was negative (white blood cell count: 6.3 × 103/μL; C-reactive protein: 0.2 mg/dL). Eosinophilia (16.6% [1046/μL]) and hypokalemia (2.8 mmol/L) with normal serum sodium level (144 mmol/L) were observed with indications of malnutrition (albumin: 3.0 g/dL; total cholesterol: 139 mg/dL; total lymphocyte count: 29.0% [1827/μL]). Procalcitonin level was 0.08 ng/mL. Total serum calcium corrected for albumin level was 11.0 mg/dL. Zinc deficiency was not observed. Thyroid hormones were within normal range (FT3: 4.72 pg/mL; FT4: 1.63 ng/dL; human thyroid-stimulating hormone: 0.646 μIU/mL). Hemoglobin A1c, fasting blood glucose, blood urea nitrogen and creatinine levels were 6.4%, 105 mg/dL, 5.0 mg/dL and 0.60 mg/dL, respectively, with normal transaminase and biliary enzyme activity. Autoantibodies were negative, and urine was clear. Occult blood was not detected in her stool.\n\nChest x-ray was normal. Electrocardiogram showed sinus arrhythmia (75 bpm). Abdominal ultrasonography, computed tomography and upper gastrointestinal tract endoscopy showed no significant abnormalities.\n\nHer mini mental state examination score was 24/30, and immediate recall failure was observed. Her geriatric depression scale score was 6/15. Magnetic resonance imaging of brain showed only bilateral hippocampal atrophy.\n\nImmediately after admission, we stopped donepezil 5 mg/day as it was found to be prescribed for 2 months. However, improvement was negligible to alleviate malnutrition. There were no other potentially inappropriate medications (PIMs) or risky combinations in her regular drugs (3–5).\n\nAs fever was sustained at ~ 37.5°C, and we performed lumbar puncture; cerebrospinal fluid and laboratory tests were normal. One month after the patient’s admission, her granddaughter informed that the patient sometime visited a clinic and obtained ointments and medicines to relieve itching, which she managed herself. Based on doctor’s instruction, in July 2015, the family had taken these drugs away. Shortly afterwards, she developed mild fever. We asked the concerned doctor what types of medicines he had prescribed. We found she had been taking an antihistamine (d-crolefeniraminmarein acid) containing a steroid (betametazone 0.25 mg/tablet) almost every other week for 10 years, without anybody’s knowledge. There seemed to be no non-adherence to the drug.\n\nBased on the information provided, we speculated that her symptoms were related to adrenal insufficiency, derived from quitting semiregular use of this steroid-containing agent. One month after admission, we performed the adrenocorticotropic hormone (ACTH) loading test. Peak cortisol level was 16.0 μg/dL after 90 min, which was slightly lower than standard, indicating mild adrenal insufficiency. Fortunately, her appetite and pyrexia began to recover when the test was performed. Two months after admission, fever lysis was achieved without the initiation of steroid medications. Eosinophilia and hypokalemia gradually improved toward the date of discharge. On her visit to our outpatient clinic after discharge, we found that muscle strength and cognition had recovered, even though we did not restart cholinesterase inhibitors. Likewise, it was unnecessary to restart medications for diabetes mellitus and dyslipidemia. We restarted olmesartan 10 mg/day a few days after admission, during the hospital stay and after discharge. No additional anti-hypertensive drugs were required.\n\nBased on her symptoms, clinical course and recovery without additional treatment, infectious, malignant and autoimmune diseases were unlikely. The ACTH test results indicated that secondary adrenal insufficiency occurred from quitting semiregular use of a steroid-containing antihistamine agent. We conclude that appetite loss, which was caused by multiple factors (i.e. hot climate, initiation of cholinesterase inhibitor), and subsequent cessation of steroid-containing agent has triggered mild secondary adrenal insufficiency. We asked her family to fix a person in charge of her health and warned them to consult a specialist when symptomatic treatment is not effective.\n\nDISCUSSION\nWe described an elderly woman on polypharmacy who developed appetite loss, muscle weakness and general fatigue from multiple factors, mainly secondary adrenal insufficiency caused by quitting one semiregular single-dose medicine. Reducing polypharmacy, even semiregular-use drugs, should be performed carefully (6, 7), especially when multiple prescribers are present.\n\nThe detection of ADRs becomes difficult if symptoms are like those of geriatric syndrome (1). Distinction becomes even more difficult if the symptoms are derived from semiregular-use medicines and if stopping the prescription is the cause. Adrenal insufficiency manifests symptoms that can be confused with geriatric syndrome or multimorbidity (8). Several reports of secondary adrenal insufficiency from the steroid-containing antihistamine exist in Japan. The present case report adds an important lesson for the management of PIMs.\n\nConflict of interest statement\nNone declared.\n\nFunding\nThis study did not receive any external funding.\n\nEthical approval\nAs this is a case report, we did not obtain any ethical approval. Written informed consent was obtained.\n\nConsent\nWritten permission was granted by the patient and the primary caregiver of the patient.\n\nGuarantor\nNaoki Tomita.\n\nAuthor contributions\n.T. is responsible for patient diagnosis and care and manuscript preparation; A.I., S.O. and K.F. also helped with patient diagnosis and gave advice on the manuscript; and H.A. contributed with intellectual inputs, patient diagnosis and gave advice on the manuscript. All authors read the final version of the manuscript.\n==== Refs\nReferences\n1. \nShah BM , Hajjar ER \nPolypharmacy, adverse drug reactions, and geriatric syndromes . Clin Geriatr Med 2012 ;28 :173 –86 .22500537 \n2. \nMishima E , Nishimiya K , Fujiwara Y , Nishizawa M , Kiyomoto H , Ito S \nSerious hypocalcemia after withdrawal of vitamin D analog in bedridden nonagenarians with previous thyroidectomy: a report of two cases . J Am Geriatr Soc 2016 ;64 :1374 –6 .27321630 \n3. \nAmerican Geriatric Society 2015 Beers Criteria Update Expert Panel \nAmerican Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults . J Am Geriatr Soc 2015 ;63 :2227 –46 .26446832 \n4. \nO'Mahony D , O'Sullivan D , Byrne S , O'Connor MN , Ryan C , Gallagher P \nSTOPP/START criteria for potentially inappropriate prescribing in older people: version 2 . Age Aging 2015 ;44 :213 –8 .\n5. \nKojima T , Mizukami K , Tomita N , Arai H , Ohrui T , Eto M, et al. \nScreening tool for older persons’ appropriate prescriptions for Japanese: report of the Japan Geriatrics Society Working Group on “guidelines for medical treatment and its safety in the elderly” . Geriatr Gerontol Int 2017 ;17 :363 .28240452 \n6. \nScott IA , Hilmer SN , Reeve E , Potter K , Le Couteur D , Rigby D, et al. \nReducing inappropriate polypharmacy: the process of deprescribing . JAMA Intern Med 2015 ;175 :827 –34 .25798731 \n7. \nSergi G , De Rui M , Sarti S , Manzato E \nPolypharmacy in the elderly: can comprehensive geriatric assessment reduce inappropriate medication use? Drugs Aging 2011 ;28 :509 –18 .21721596 \n8. \nKojima G , Laurel P , Inaba M , Tanabe M \nUnveiling adrenal insufficiency can make a difference in elderly adults . J Am Geriatr Soc 2014 ;62 :2456 –7 .25516051\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2053-8855", "issue": "2019(6)", "journal": "Oxford medical case reports", "keywords": null, "medline_ta": "Oxf Med Case Reports", "mesh_terms": null, "nlm_unique_id": "101642070", "other_id": null, "pages": "omz047", "pmc": null, "pmid": "31214359", "pubdate": "2019-06", "publication_types": "D002363:Case Reports", "references": "21721596;22500537;25324330;25516051;25798731;26446832;27321630;27594406", "title": "Development of geriatric syndromes after taking countermeasures for polypharmacy: an overlooked issue of quitting semiregular single-dose medicine.", "title_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine" }

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"drugtreatmentdurationunit": null, "medicinalproduct": "DOXAZOCINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANDESARTAN" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PITAVASTATIN CALCIUM" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 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"reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Sinus arrhythmia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cognitive disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201507" } }, "primarysource": { "literaturereference": "TOMITA N, ISHIKI A, OKINAGA S, FURUKAWA K, ARAI H. DEVELOPMENT OF GERIATRIC SYNDROMES AFTER TAKING COUNTERMEASURES FOR POLYPHARMACY: AN OVERLOOKED ISSUE OF QUITTING SEMIREGULAR SINGLE-DOSE MEDICINE. OXF-MED-CASE-REPORTS 2019?2019(6):259-261.", "literaturereference_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190802", "receivedate": "20190802", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16660254, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "PHHY2019JP173295", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "91198", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL." } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Decreased appetite", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Muscular weakness", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Weight decreased", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Secondary adrenocortical insufficiency", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "TOMITA N, ISHIKI A, OKINAGA S, FURUKAWA K, ARAI H. DEVELOPMENT OF GERIATRIC SYNDROMES AFTER TAKING COUNTERMEASURES FOR POLYPHARMACY: AN OVERLOOKED ISSUE OF QUITTING SEMIREGULAR SINGLE-DOSE MEDICINE.. OXFORD MEDICAL CASE REPORTS. 2019?1-3", "literaturereference_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190802", "receivedate": "20190802", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16661785, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191004" }, { "companynumb": "JP-ACCORD-150262", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DONEPEZIL HYDROCHLORIDE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201335", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201505", "drugstartdateformat": "610", "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DONEPEZIL/DONEPEZIL HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANDESARTAN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANDESARTAN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VILDAGLIPTIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VILDAGLIPTIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PITAVASTATIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ITAVASTATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXAZOSIN MESYLATE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXAZOSIN" }, { "actiondrug": "1", "activesubstance": null, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OLMESARTAN/OLMESARTAN MEDOXOMIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE\\DEXCHLORPHENIRAMINE MALEATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "EVERY OTHER WEEK, STRENGTH 0.25 MG", "drugenddate": "201507", "drugenddateformat": "610", "drugindication": "PRURITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CELESTAMINE" } ], "patientagegroup": "6", "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Secondary adrenocortical insufficiency", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Eosinophilia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2015" } }, "primarysource": { "literaturereference": "TOMITA N, ISHIKI A, OKINAGA S, FURUKAWA K, ARAI H. DEVELOPMENT OF GERIATRIC SYNDROMES AFTER TAKING COUNTERMEASURES FOR POLYPHARMACY: AN OVERLOOKED ISSUE OF QUITTING SEMIREGULAR SINGLE-DOSE MEDICINE. OXFORD MEDICAL CASE REPORTS. 2019?6:ARTICLE NUMBER OMZ047 (259 - 261).", "literaturereference_normalized": "development of geriatric syndromes after taking countermeasures for polypharmacy an overlooked issue of quitting semiregular single dose medicine", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190805", "receivedate": "20190805", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16667121, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy. Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily. The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.\n\n\n\nThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.\n\n\n\nThis was a phase I study with a 3+3 design in patients with treatment-naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.\n\n\n\nA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose-limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment-related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression-free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated-ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated-ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.\n\n\n\nTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.", "affiliations": "Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Moffitt Cancer Center, Tampa, Florida, USA.;Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.;Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.;Department of Internal Medicine, Advent Health, Orlando, Florida, USA.;Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida, USA.", "authors": "Kim|Richard|R|https://orcid.org/0000-0002-8448-844X;Tan|Elaine|E|;Wang|Emily|E|;Mahipal|Amit|A|;Chen|Dung-Tsa|DT|;Cao|Biwei|B|;Masawi|Fadzai|F|;Machado|Cindy|C|;Yu|James|J|;Kim|Dae Won|DW|", "chemical_list": "D010671:Phenylurea Compounds; D011728:Pyridones; D011744:Pyrimidinones; D009536:Niacinamide; C560077:trametinib; D000077157:Sorafenib", "country": "United States", "delete": false, "doi": "10.1634/theoncologist.2020-0759", "fulltext": null, "fulltext_license": null, "issn_linking": "1083-7159", "issue": "25(12)", "journal": "The oncologist", "keywords": null, "medline_ta": "Oncologist", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D006528:Carcinoma, Hepatocellular; D006801:Humans; D007963:Leukocytes, Mononuclear; D008113:Liver Neoplasms; D009536:Niacinamide; D010671:Phenylurea Compounds; D011728:Pyridones; D011744:Pyrimidinones; D000077157:Sorafenib", "nlm_unique_id": "9607837", "other_id": null, "pages": "e1893-e1899", "pmc": null, "pmid": "32776632", "pubdate": "2020-12", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "18650514;25294897;29030911;29950351;26644411;19910069;19698189;30030148;28276530;9223425;22663011;19095497;22805291;24204195;27681866", "title": "A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer.", "title_normalized": "a phase i trial of trametinib in combination with sorafenib in patients with advanced hepatocellular cancer" }

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{ "abstract": "We report the case of a young patient treated with rituximab-containing chemotherapy who was infected with measles despite previous vaccination. Treatment with vitamin A, ribavirin, and immunoglobulins was started; nevertheless he developed severe pneumonitis and deceased. Broad vaccination coverage is crucial in protecting vulnerable subjects.", "affiliations": "Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Institute of Pathology, University of Bern, Bern, Switzerland.;Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.", "authors": "Jent|Philipp|P|0000-0002-1838-9208;Trippel|Mafalda|M|;Frey|Manuel|M|;Pöllinger|Alexander|A|;Berezowska|Sabina|S|;Langer|Rupert|R|;Furrer|Hansjakob|H|;Béguelin|Charles|C|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1093/ofid/ofy244", "fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidOpen Forum Infectious Diseases2328-8957Oxford University Press US 10.1093/ofid/ofy244ofy244Brief ReportsFatal Measles Virus Infection After Rituximab-Containing Chemotherapy in a Previously Vaccinated Patient http://orcid.org/0000-0002-1838-9208Jent Philipp 1Trippel Mafalda 2Frey Manuel 3Pöllinger Alexander 4Berezowska Sabina 2Langer Rupert 2Furrer Hansjakob 1Béguelin Charles 11 Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland2 Institute of Pathology, University of Bern, Bern, Switzerland3 Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland4 Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, SwitzerlandCorrespondence: P. Jent, MD, Department of Infectious Diseases, Inselspital, Bern University Hospital, Freiburgstrasse 16p, CH-3010 Bern, Switzerland ([email protected]).11 2018 01 11 2018 01 11 2018 5 11 ofy24419 7 2018 20 9 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact [email protected]\nWe report the case of a young patient treated with rituximab-containing chemotherapy who was infected with measles despite previous vaccination. Treatment with vitamin A, ribavirin, and immunoglobulins was started; nevertheless he developed severe pneumonitis and deceased. Broad vaccination coverage is crucial in protecting vulnerable subjects.\n\nimmunocompromisedmeaslesrituximabvaccination\n==== Body\nCASE PRESENTATION\nWe present the case of a 26-year-old man who was hospitalized with fever and neutropenia. He was known to have chronic lymphocytic leukemia (CLL; small lymphocytic lymphoma, low risk, Binet stade B, Rai II; 11q deletion, no TP53 mutation), diagnosed 7 months before admission, and had been treated with 7 cycles of chemotherapy with fludarabine, cyclophosphamide, and rituximab until 1 month before admission. He had been receiving Pneumocystis pneumonia prophylaxis with trimethoprim/sulfamethoxazole and herpes simplex virus prophylaxis with valaciclovir. There was no recent travel history, no known animal contact, no recent sexual risk exposure, and no known infectious disease in close contacts. Vaccinations had been completed according to Swiss national recommendations, including 2 documented measles, mumps, and rubella (MMR) vaccine doses in 1993 and 1999.\n\nAt hospital entry, the patient reported sore throat, unproductive cough, and fever without chills since 1 day before admission. The clinical exam was only remarkable for pharyngitis and the previously known cervical lymphadenopathy. C-reactive protein was moderately elevated (53 mg/L). The patient was thrombocytopenic (73 G/L) and had a leukocytopenia (1.08 G/L; 0.67 G/L neutrophile granulocytes). A chest x-ray showed no infiltrates, and a rapid-antigen detection test for group A streptococci from a throat swab was negative.\n\nEmpirical treatment with cefepime was started. Blood cultures and multiplex polymerase chain reaction (PCR) for respiratory viruses using a nasopharyngeal swab remained negative. Four days after symptom onset, the patient developed a confluent maculopapular rash of the face and upper trunk. Skin biopsy showed a perivascular lymphohistiocytic infiltrate and necrotic keratinocytes—changes compatible with an exanthematous drug eruption. For this reason, trimethoprim/sulfamethoxazole was stopped, and cefepime was switched to meropenem.\n\nBesides a progressive craniocaudal evolution of the maculopapular rash (Figure 1B), the patient developed ulcerative stomatitis compatible with Koplik spots (Figure 1A) and bilateral conjunctivitis on day 7 after symptom onset. These findings raised the suspicion of a measles virus infection, although the patient had been vaccinated as a child, as previously described. Positive measles real-time PCR from a throat swab confirmed the suspected diagnosis. In the month before, there had been no measles outbreaks in the patient’s region of residence, and he was not aware of any contact with a measles-infected individual. Measles IgG and IgM (Serion ELISA classic, Virion/Serion GmbH, Würzburg, Germany) and rubella virus IgG were negative on day 6 after symptom onset, and mumps virus IgG was borderline positive (93 U/mL; cutoff, 70 U/mL), despite documented prior vaccination with 2 doses. Total IgG was in the lower normal range (8.6 G/L; normal range, 7–16 G/L).\n\nFigure 1. A, Enanthema, no scale available. B, Maculopapular rash (back of the patient), no scale available. C, Computed tomography lung scan with nodular peribronchial infiltrates. D, Histology of the lung section (hematoxylin and eosin stain, 80× magnification) of the patient. Giant cell pneumonitis: numerous syncytial multinuclear giant cells with intracytoplasmic and intranuclear inclusions lining the alveolar walls, with a background of diffuse alveolar damage.\n\nTreatment with intravenous ribavirin, intravenous immunoglobulins, and vitamin A was started. On day 8 after symptom onset, the patient developed progressive dyspnea and hypoxia in addition to the unproductive cough, while the fever persisted. A chest computed tomography scan showed bilateral, in part nodular pulmonary consolidations with adjacent ground glass infiltrations, compatible with pneumonitis (Figure 1C). Elevated transaminases up to 2 to 3 times the upper norm were observed as well. On day 15, he fulfilled the definition of acute respiratory distress syndrome (ARDS) and required invasive ventilation, and on the following day veno-venous extracorporeal membrane oxygenation (VV-ECMO). On day 17 after the onset of symptoms, the patient developed venous bleeding at the puncture site of the VV-ECMO and succumbed to mixed shock and severe pneumonitis.\n\nPostmortem examination showed macroscopically severe diffuse micronodular parenchymal consolidations of the lungs. Apart from the aspect of a diffuse alveolar damage, correlating with the clinical picture of ARDS, histology revealed numerous syncytial multinuclear giant cells with intracytoplasmic and intranuclear inclusions lining the alveolar walls, consistent with measles pneumonitis (Figure 1D).\n\nDISCUSSION\nThe presented case demonstrates the severity of measles infections in immunocompromised patients and highlights the importance of herd immunity, as rituximab can compromise previously acquired humoral immunity.\n\nMeasles in immunocompromised patients bears serious complications in about 80% of cases. Pneumonitis is the principal complication, accounting for most measles-associated deaths [1]. Clinical presentation in immunocompromised patients frequently is atypical, with 27%–40% of patients presenting without a rash [1].\n\nHumoral immunity plays the main role in preventing measles virus infection, with neutralizing antibody titers at the time of exposure correlating with protection from disease [2]. In our patient, a serum sample from before the start of rituximab was not available, but he had received 2 documented MMR vaccine doses before his infection, which induces long-lasting protection in 97% of vaccinated subjects [3]. However, at the time of diagnosis, he had no measurable antibodies to measles or rubella, and he had borderline mumps IgG. We assume this is due to his rituximab-containing chemotherapy. Additionally, the patient’s underlying disease may have played a role in his vulnerability, although pretreatment hypogammaglobulinemia in CLL is far less commonly seen than after treatment with rituximab [4]. Rituximab, a monoclonal CD-20 antibody, is known to induce transient hypogammaglobulinemia in 39% of patients [5]. After application of rituximab, the immune response to recall antigens is reduced [6]. Additionally, fludarabine, in addition to its effect on T-lymphocytes, also leads to prominent B-cell depletion [7]; the combination of fludarabine with rituximab has been independently associated with higher infection rates [8]. A primary vaccine failure cannot be ruled out as an explanation for the missing immunity against measles; however, it is a far less probable explanation given the vaccine’s high 2-dose effectiveness and the multiple reasons for humoral immunodeficiency depicted above.\n\nImmune control of measles infection is primarily dependent on T-lymphocyte cytolytic response, whereas humoral immunity seems to play only a minor role in disease control. B-lymphocyte-depleted rhesus monkeys have a clinical and virological course of measles infection that is indistinguishable from that of healthy monkeys [9]. Children with hypogammaglobinemia have a normal disease course, in contrast to children with cellular immune defects [1, 10], in whom measles infection is associated with a high risk of complications. Mainly the T-lymphocyte cytolytic response is associated with clearance of infection [11]. In our patient, the T-lymphocyte cytolytic response was heavily compromised due to chemotherapy with fludarabine and cyclophosphamide.\n\nEvidence on treatment options in severe measles infection is limited. Management consists primarily of supportive therapy and treatment of secondary bacterial infections.\n\nRibavirin, a ribosyl purine analogue, shows in vitro activity against measles virus [12]. One nonblinded randomized trial with ribavirin vs supportive therapy in 100 nonimmunocompromised patients found a reduced time to resolution of fever with ribavirin (mean, 7.3 vs 3.2 days). Furthermore, in the ribavirin group, there were no complications vs 11% with respiratory symptoms, 2% with encephalitis, and 2% with a fatal outcome in the control group [13]. The use of intravenous or aerosolized ribavirin in severe measles infection in immunocompromised patients has also been reported in a few case reports and series, but a significant survival benefit could not be proven in these series [1]. One case series [14] found significantly higher mortality in pediatric oncologic patients with measles infection if ribavirin application was delayed, but the observation was based on only 2 patients with a fatal outcome.\n\nReduced mortality and major complications after oral application of vitamin A in children with measles infection have been demonstrated in several randomized controlled trials in third world or developing countries [15]. It is unclear if this effect is transferable to immunocompromised patients in populations with a lower prevalence of vitamin A deficiency. Nevertheless, in most case series of severe measles infection, the patients have received oral vitamin A.\n\nThe use of intravenous immunoglobulins in severe measles infection in immunocompromised patients is common, but there is no evidence of its ability to improve the disease course. On the other side, its effect as postexposure prophylaxis is well established. Given the limited role of humoral immunity in disease control (see further up), a relevant benefit of intravenous immunoglobulin administration for a therapeutic indication in measles is improbable.\n\nGiven the fact that therapeutic options in severe measles infection are limited, as described above, the role of herd immunity to protect vulnerable (eg, immunocompromised, children younger than age 1 year) subjects is crucial. A recent drop in vaccination coverage in Europe, with 2-vaccine-dose coverage below the World Health Organization (WHO) herd immunity threshold of 95% in 20 of 27 reporting countries, led to an epidemic of more than 14 000 cases, including 30 fatal ones in 2017. MMR 1-dose coverage in the United States is still below the WHO herd immunity threshold, with local variation. In this epidemiologic situation of limited herd immunity, a cocooning vaccination strategy should be envisaged, namely to vaccinate people with close contact to patients whose immunosuppressive therapy is hampering their vaccination protection.\n\nCONCLUSIONS\nMeasles virus infections in immunocompromised patients often have an atypical presentation and can even occur in previously vaccinated individuals (eg, after rituximab), as shown in this case presentation. Given the limited therapeutic options, herd immunity, namely high immunization coverage and a cocooning strategy, is crucial to the protection of vulnerable subjects. Ongoing efforts to raise confidence in vaccines and increase population immunity should be intensified.\n\nAcknowledgments\nWe thank the family of the patient for giving us the opportunity to publish this case.\n\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nKaplan LJ , Daum RS , Smaron M , McCarthy CA \nSevere measles in immunocompromised patients . JAMA 1992 ; 267 :1237 –41 .1538561 \n2. \nChen RT , Markowitz LE , Albrecht P , et al \nMeasles antibody: reevaluation of protective titers . J Infect Dis 1990 ; 162 :1036 –42 .2230231 \n3. \nMarkowitz LE , Preblud SR , Fine PE , Orenstein WA \nDuration of live measles vaccine-induced immunity . Pediatr Infect Dis J 1990 ; 9 :101 –10 .2179836 \n4. \nBaliakas P , Xochelli A , Minga E , et al \nRevisiting hypogammaglobulinemia in chronic lymphocytic leukemia: a combined clinicobiological approach . Blood 2014 ; 124 :5633 .\n5. \nCasulo C , Maragulia J , Zelenetz AD \nIncidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections . Clin Lymphoma Myeloma Leuk 2013 ; 13 :106 –11 .23276889 \n6. \nvan der Kolk LE , Baars JW , Prins MH , van Oers MH \nRituximab treatment results in impaired secondary humoral immune responsiveness . Blood 2002 ; 100 :2257 –9 .12200395 \n7. \nTakada K , Danning CL , Kuroiwa T , et al \nLymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects . Ann Rheum Dis 2003 ; 62 :1112 –5 .14583577 \n8. \nCabanillas F , Liboy I , Pavia O , Rivera E \nHigh incidence of non-neutropenic infections induced by rituximab plus fludarabine and associated with hypogammaglobulinemia: a frequently unrecognized and easily treatable complication . Ann Oncol 2006 ; 17 :1424 –7 .16966368 \n9. \nPermar SR , Klumpp SA , Mansfield KG , et al \nLimited contribution of humoral immunity to the clearance of measles viremia in rhesus monkeys . J Infect Dis 2004 ; 190 :998 –1005 .15295708 \n10. \nPermar SR , Griffin DE , Letvin NL \nImmune containment and consequences of measles virus infection in healthy and immunocompromised individuals . Clin Vaccine Immunol 2006 ; 13 :437 –43 .16603610 \n11. \nPermar SR , Klumpp SA , Mansfield KG , et al \nRole of CD8(+) lymphocytes in control and clearance of measles virus infection of rhesus monkeys . J Virol 2003 ; 77 :4396 –400 .12634396 \n12. \nShigeta S , Mori S , Baba M , et al \nAntiviral activities of ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, and 6’-®-6’-C-methylneplanocin A against several ortho- and paramyxoviruses . Antimicrob Agents Chemother 1992 ; 36 :435 –9 .1605607 \n13. \nPal G \nEffects of ribavirin on measles . J Indian Med Assoc 2011 ; 109 :666 –7 .22480102 \n14. \nRoy Moulik N , Kumar A , Jain A , Jain P \nMeasles outbreak in a pediatric oncology unit and the role of ribavirin in prevention of complications and containment of the outbreak . Pediatr Blood Cancer 2013 ; 60 :E122 –4 .23629813 \n15. \nHussey GD , Klein M \nA randomized, controlled trial of vitamin A in children with severe measles . N Engl J Med 1990 ; 323 :160 –4 .2194128\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2328-8957", "issue": "5(11)", "journal": "Open forum infectious diseases", "keywords": "immunocompromised; measles; rituximab; vaccination", "medline_ta": "Open Forum Infect Dis", "mesh_terms": null, "nlm_unique_id": "101637045", "other_id": null, "pages": "ofy244", "pmc": null, "pmid": "30397623", "pubdate": "2018-11", "publication_types": "D016428:Journal Article", "references": "12200395;16966368;22480102;12634396;14583577;23276889;15295708;2179836;1605607;1538561;2194128;2230231;23629813;16603610", "title": "Fatal Measles Virus Infection After Rituximab-Containing Chemotherapy in a Previously Vaccinated Patient.", "title_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia measles", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Vaccination failure", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "JENT P, TRIPPEL M, FREY M, POLLINGER A, BEREZOWSKA S, LANGER R, ET AL. FATAL MEASLES VIRUS INFECTION AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY IN A PREVIOUSLY VACCINATED PATIENT. OPEN-FORUM-INFECT-DIS 2018?5:NO. 11.", "literaturereference_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20181224", "receivedate": "20181224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15756209, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "CH-MYLANLABS-2018M1091992", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, 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}, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACICLOVIR" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonia measles", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "21.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "JENT P, TRIPPEL M, FREY M, POLLINGER A, BEREZOWSKA S, LANGER R, ET AL. FATAL MEASLES VIRUS INFECTION AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY IN A PREVIOUSLY VACCINATED PATIENT. OPEN-FORUM-INFECT-DIS 2018?5:NO. 11.", "literaturereference_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20181220", "receivedate": "20181220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15746832, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" }, { "companynumb": "CH-ROCHE-2215172", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHRONIC LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALACICLOVIR" } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute respiratory distress syndrome", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Measles", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pneumonitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "JENT P, TRIPPEL M, FREY M, POLLINGER A, BEREZOWSKA S, LANGER R, FURRER H AND BEGUELIN C. FATAL MEASLES VIRUS INFECTION AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY IN A PREVIOUSLY VACCINATED PATIENT. OPEN FORUM INFECTIOUS DISEASES 2018 NOV 01?5(11):1-3.", "literaturereference_normalized": "fatal measles virus infection after rituximab containing chemotherapy in a previously vaccinated patient", "qualification": "1", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20181116", "receivedate": "20181116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15624751, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190205" } ]

{ "abstract": "To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.\n\n\n\nProspective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.\n\n\n\nTwo hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.\n\n\n\nGH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.", "affiliations": "Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain;Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain", "authors": "Martín-Begué|Nieves|N|0000-0003-0365-1266;Mogas|Eduard|E|0000-0001-8501-5364;Wolley Dod|Charlotte|C|0000-0001-9442-3802;Alarcón|Silvia|S|0000-0003-1467-4797;Clemente|María|M|0000-0002-3721-5043;Campos-Martorell|Ariadna|A|0000-0002-8134-4934;Fábregas|Ana|A|0000-0001-8137-6189;Yeste|Diego|D|0000-0002-6620-6525", "chemical_list": null, "country": "Turkey", "delete": false, "doi": "10.4274/jcrpe.galenos.2020.2020.0007", "fulltext": "\n==== Front\nJ Clin Res Pediatr Endocrinol\nJ Clin Res Pediatr Endocrinol\nJCRPE\nJournal of Clinical Research in Pediatric Endocrinology\n1308-5727\n1308-5735\nGalenos Publishing\n\n33006547\n10.4274/jcrpe.galenos.2020.2020.0007\n40516\nOriginal Article\nGrowth Hormone Treatment and Papilledema: A Prospective Pilot Study\nMartín-Begué Nieves 1*https://orcid.org/0000-0003-0365-1266\n\nMogas Eduard 2https://orcid.org/0000-0001-8501-5364\n\nDod Charlotte Wolley 1https://orcid.org/0000-0001-9442-3802\n\nAlarcón Silvia 1https://orcid.org/0000-0003-1467-4797\n\nClemente María 234https://orcid.org/0000-0002-3721-5043\n\nCampos-Martorell Ariadna 23https://orcid.org/0000-0002-8134-4934\n\nFábregas Ana 2https://orcid.org/0000-0001-8137-6189\n\nYeste Diego 234https://orcid.org/0000-0002-6620-6525\n\n1 Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain\n2 Hospital Universitari Vall d’Hebron, Department of Paediatric Endocrinology, Barcelona, Spain\n3 Universitat Autònoma de Barcelona (UAB), Barcelona, Spain\n4 Centro de Investigación Biomédica en Red: Enfermedades Raras (CIBERER), Madrid, Spain\n* Address for Correspondence: Hospital Universitari Vall d’Hebron, Department of Paediatric Ophthalmology, Barcelona, Spain Phone: +034934893166 E-mail:[email protected]\n6 2021\n2 6 2021\n13 2 146151\n16 1 2020\n16 9 2020\n©Copyright 2021 by Turkish Pediatric Endocrinology and Diabetes Society | The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective:\n\nTo investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.\n\nMethods:\n\nProspective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.\n\nResults:\n\nTwo hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.\n\nConclusion:\n\nGH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.\n\nGrowth hormone treatment\npseudotumor cerebri syndrome\nidiopathic intracranial hypertension\npapilledema\nrisk factors\n==== Body\nWhat is already known on this topic?\n\nGrowth hormone (GH) replacement therapy is a risk factor for secondary pseudotumor cerebri. The incidence of this complication can vary depending on different GH indications.\n\nWhat this study adds?\n\nChildren with intracranial hypertension could be asymptomatic, so the diagnosis should be based on fundus examination and not on patient’s symptoms. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. A previous history of pseudotumor cerebri should be investigated.\n\nIntroduction\n\nPseudotumor cerebri syndrome (PTCS) is a condition defined by elevated intracranial pressure (ICP) in the absence of clinical, laboratory or radiologic evidence of infection, vascular abnormality, intracranial space-occupying lesion or hydrocephalus (1,2). It can be primary, or secondary if there are any identifiable risk factors. Primary PTCS most commonly occurs in obese adult women of childbearing age (12-32/100,000). However, it is a rare condition in childhood (0.5-0.9/100,000) with an identifiable risk factor in 53-77% of paediatric cases (3,4,5). Papilledema is a hallmark in PTCS, which is not a benign disorder; there is a risk of severe and permanent visual loss. Even patients with mild visual loss experience reduction in quality of life (6).\n\nGrowth hormone (GH) replacement therapy was first associated with PTCS by The Food and Drug Administration in 1993 (7). Since then, multiple publications have described this association. Reeves and Doyle (8) found that the prevalence in the GH treated population was approximately 100 times greater than in the general paediatric population. This complication usually occurs in the first weeks after initiating treatment (approximately 2-12 weeks) and the papilledema (optic disc swelling from raised ICP) resolves on stopping treatment (8,9).\n\nPseudopapilledema is an elevated optic disc with obscured margins that may occur in hyperopic eyes and in the presence of buried optic disc drusen, rather than from raised ICP. Optic disc drusen are acellular deposits located within the optic disc. Sometimes it can be very difficult to differentiate between pseudopapilledema and papilledema, requiring the opinion of a suitably experienced ophthalmologist and complementary tests (10).\n\nThe aim of this study was to investigate the incidence of PTCS in children treated with GH in a paediatric hospital and to identify risk factors for this complication. A secondary aim was to identify which children really need fundus examination during GH treatment in order to detect this complication.\n\nMethods\n\nA prospective pilot study was conducted in paediatric patients who started GH treatment from February 2013 to September 2017. Inclusion criteria were patients under 16 years of age prescribed GH by the Paediatric Endocrinology Department. Exclusion criteria were: absence of fundus examination prior to or at 3-4 months from starting treatment; severe optic disc atrophy where optic disc swelling would not develop; and cases where GH was prescribed by the Paediatric Nephrology Department. Predisposing pathology for intracranial hypertension was not considered an exclusion criterion, as fundus examinations were conducted before initiating treatment to rule out prior pathology of the optic nerve. The following variables were recorded: previous medical history; anthropometric data; and compliance with treatment.\n\nFundus was explored prior to and after 3-4 months of starting treatment or at any time when severe constant headache, vomiting or other presenting symptoms suggestive of intracranial hypertension arose. Prior fundus examination identified possible cases of pseudopapilledema and avoided possible confusion between this entity and newly developed papilledema in subsequent fundus follow-up examinations.\n\nFundus examination was carried out with indirect ophthalmoscopy and retinography was taken in cases of pseudopapilledema to facilitate follow up. In cases when papilledema was detected, GH was stopped and fundus examination was repeated four weeks later. If papilledema persisted, the patient was referred for neurological assessment, lumbar puncture and possible medical treatment with acetazolamide. Once papilledema resolved, if GH treatment was still considered necessary, treatment was re-initiated at a lower dose and progressively increased until the objective dose was achieved, with monthly ophthalmology visits until four months were completed at the target GH dose.\n\nCerebral magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis was performed in all patients with GH deficiency, prior to treatment. Initial GH doses were as indicated: 0.028-0.035 mg/kg/day for patients with GH deficiency and small for gestational age (SGA), 0.042 mg/kg/day for those with mutations in the SHOX gene and 1 mg/m2/day for patients with Prader-Willi syndrome (PWS).\n\nEthics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383). All subjects (or their parents or guardians) gave their written informed consent.\n\nStatistical Analysis\n\nIn this case series, simple descriptive statistics were sufficient to delineate our populations. Variables are expressed as number, mean and percent (%) or range, as appropriate.\n\nResults\n\nThere were 306 patients to whom GH was prescribed by the Paediatric Endocrinology Department between February 2013 and September 2017. Only 289 patients were enrolled in this study, 17 were excluded because of loss of ophthalmological follow up.\n\nThe mean age was nine years (range 1-16) and 53% of the patients were male. The patients were categorized according to their indication for GH treatment: 244 patients (84.4%) with GH deficiency; 36 patients (12.5%) with short stature associated with SGA; six patients (2%) with a mutation in the SHOX gene; and three (1%) with PWS. Patients diagnosed with chronic kidney disease were not included in the study as their indication for GH treatment and follow up was made by the Paediatric Nephrology Department.\n\nIn the first visit, prior to starting GH treatment, there were 546 eyes with normal optic discs, 16 eyes with pale optic discs, 11 eyes with pseudopapilledema, two eyes with optic disc and chorioretinal coloboma and one eye with dysplastic optic disc. Pale optic discs and optic disc and chorioretinal coloboma were secondary to the patient background pathology, suprasellar cerebral tumours and CHARGE anomaly respectively. In the follow up visit, five patients had optic disc swelling, suggesting papilledema, despite there being no symptoms of intracranial hypertension. None of the patients who presented with headache, who were visited urgently, presented with papilledema on fundus examination.\n\nTable 1 outlines the characteristics of the five patients with papilledema. All these patients had GH deficiency: three had hypothalamic-pituitary axis abnormalities on brain MRI; two were congenital cases; and one was secondary to a suprasellar tumour. The patient with a suprasellar tumour had a ventriculoperitoneal shunt and was treated with external radiotherapy. The only patient with an isolated GH deficiency with normal MRI, had developed primary PTCS five years before and he was obese. The incidence of obesity in children without PTCS in our population is 10.3%.\n\nThe papilledema resolved on discontinuing GH treatment in four patients, whereas in the remaining patient, a lumbar puncture confirmed the diagnosis and was also therapeutic. The opening pressure was 25 cm H2O. The glucose was 61 mg/dL (38-82); protein 20 mg/dL (15-45) and there were neither leukocytes nor red blood cells present in the cerebrospinal fluid (CSF). Medical treatment was not required. In four cases GH treatment was reintroduced at a lower dose with progressive incremental doses, without the reappearance of papilledema.\n\nDiscussion\n\nGH treatment is a risk factor for developing secondary PTCS although the mechanism is little understood. Two hypotheses have been proposed. The first is that GH could have a physiological antidiuretic effect, causing retention of sodium and water and expansion in blood volume, and reducing CSF resorption by the arachnoid villi. The second hypothesis proposes that GH would cross the blood-brain barrier, resulting in raised cerebral levels of GH and its mediator, insulin-like growth factor 1, and finally increasing CSF production (11,12,13,14).\n\nGH was initially obtained from human pituitary gland, and was given at lower doses and frequency, and prescribed in fewer clinical situations. Since 1985, when recombinant human GH became commercially available, more patients were treated with larger doses and more often. Since then, indications for GH treatment have increased, as well as the potential adverse effects (15).\n\nIn our study, there were five patients with papilledema (1.7%), a higher incidence compared with the expected incidence in the general paediatric population (8,9,11,13). All of them had GH deficiency. Other indications for GH treatment did not appear to cause papilledema in this series, although these results may be biased due the small populations with these other indications.\n\nAs all the patients with papilledema were found to have GH deficiency, we analysed this group, classifying patients into three subgroups (Table 2):\n\n1. Isolated GH deficiency (no other associated hormone deficiencies) with normal hypothalamic-pituitary axis anatomy on MRI.\n\n2. Isolated GH deficiency or associated with other hormone deficiencies with altered hypothalamic-pituitary axis anatomy on MRI and/or past history of cerebral radiotherapy.\n\n3. GH deficiency in patients with genetic or chromosomal diseases.\n\nWhen considering patients who presented with papilledema, three completed criteria for subgroup 2, presenting with hypothalamic-pituitary axis abnormalities and external radiotherapy treatment in one case for a suprasellar tumour. These three patients in subgroup 2 had an intracranial hypertension, but not technically a PTCS, because the brain MRI was not normal. One other patient was classified as subgroup 3 for a non-specific genetic disease. Only one patient presented with an isolated GH deficiency with normal cerebral MRI, however this patient had had primary PTCS five years earlier. The patient with a suprasellar tumour also had a ventriculoperitoneal shunt, suggesting that the presence of a shunt is not protective against a rise in ICP induced by GH therapy.\n\nFor each GH indication, the incidence of this adverse effect can vary. Reeves and Doyle (8), reported higher incidences in patients with renal failure and Turner syndrome. Souza and Collet-Solberg (11), also detected a higher incidence in patients with chronic kidney disease. Darendeliler et al (16) proposed that patients with Turner syndrome, organic GH deficiency, PWS and chronic renal insufficiency might be more prone to develop papilledema when receiving GH. In our study, patients with renal disease were excluded, as the GH was not prescribed by the Paediatric Endocrinology Department. However, we have conducted a retrospective study of these patients with renal disease on GH treatment during the same time period and have also detected a higher incidence of papilledema, as described in the literature.\n\nThe association between the dose of GH and the risk of PTCS is not clearly established. Malozowski et al (15) reported that higher doses and increased frequency of administration since the introduction of recombinant human GH in 1985 may be contributing to the development of PTCS in some patients. However, Reeves and Doyle found no relationship between the GH dose and PTCS development (8). One of our patients received GH at the usual dose without complications, later on it was withdrawn due to lack of therapeutic effect. Interestingly, papilledema appeared three months after restarting GH at a higher dose. Patients with PWS and mutations in the SHOX gene, who received higher doses of GH did not present with papilledema, although these subgroups were small in this study. Even though there is no evidence that the GH dose is directly related with this complication, we recommend starting at lower dose and increasing it progressively, in order to minimize this complication.\n\nPatients with a previous history of PTCS may experience recurrence at rates reported to vary between 6-22% (4,17,18,19). There is usually a triggering factor, such as weight gain or the introduction of known medications associated with secondary PTCS (20). In our series, the only patient with a previous history of PTCS, presented with papilledema. This patient was obese, which could have been a further risk factor for primary PTCS recurrence, however his weight had remained stable prior to starting GH treatment, at one month and at two months of treatment, when papilledema was diagnosed. For this reason, we believe it is important to identify patients initiating GH therapy with a previous history of PTCS because of the risk of recurrence. Also, consideration should be taken for starting treatment at a lower dose with progressive increases, accompanied by with careful follow-up including fundus examination during the first months of treatment.\n\nHeadache is a common symptom in the general paediatric population, and is also relatively frequent in patients on GH therapy, being the third most prevalent side effect described in KIGS (Pfizer International Growth study database) (16). On the other hand, headache is the main manifestation of intracranial hypertension at any age. However, in the paediatric population, headache is less common and 33% of children with PTCS may be totally asymptomatic (21,22), and diagnosis is only made on the observation of papilledema on fundus examination. It is important to highlight that papilledema is a cause of visual morbidity, including irreversible vision loss, independent of the patient symptoms. In our series, all patients with papilledema were asymptomatic, whereas no patients examined urgently for headache presented with papilledema.\n\nStopping GH is usually enough to treat this complication. Once papilledema has resolved GH can be reintroduced at a lower dose and progressively increased until the required dose is achieved to prevent recurrence and optimum growth. In the four patients where GH was reintroduced there were no recurrences of papilledema.\n\nStudy Limitations\n\nThe strengths of our study are the prospective design and the number of patients included in it. As children may be asymptomatic, prospective studies are the only way to establish the real incidence of this complication. The main limitation of our study is that patients with kidney diseases were not included and this group of patients has been reported to be at greatest risk of this complication in a different series.\n\nConclusion\n\nIn this study, we have shown that GH therapy is a risk factor for intracranial hypertension and the at-risk group were patients with GH deficiency and hypothalamic-pituitary axis abnormalities on MRI or genetic or chromosomal diseases. Patients may be totally asymptomatic, so fundus examination should be systematically implemented in this at-risk group, irrespective of the presence or absence of symptoms.\n\nWe thank Dr. Susana Noval for her valuable contribution in the analysis and interpretation of data and Dr. Silvia Muñoz for critical review of the manuscript.\n\nTable 1 Characteristics of patients treated with growth hormone who developed papilledema\n\nTable 2 Distribution of patients with growth hormone deficiency according to our classification in subgroups\n\nEthics\n\nEthics Committee Approval: Ethics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383, date: 17.05.2019).\n\nInformed Consent: All subjects (or their parents or guardians) gave their written informed consent.\n\nPeer-review: Externally peer-reviewed.\n\nAuthorship Contributions\n\nSurgical and Medical Practices: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Concept/Design: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Data Collection or Processing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Analysis or Interpretation: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Literature Search: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Writing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste.\n\nFinancial Disclosure: The authors declared that this study received no financial support.\n==== Refs\nReferences\n\n1 Friedman DI Liu GT Digre KB Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children Neurology 2013 81 1159 1165 23966248\n2 Rangwala LM Liu GT Pediatric Idiopathic Intracranial Hypertension Surv Ophthalmol 2007 52 597 617 18029269\n3 Matthews YY Dean F Lim MJ Mclachlan K Rigby AS Solanki GA White CP Whitehouse WP Kennedy CR Pseudotumor cerebri syndrome in childhood: incidence, clinical profile and risk factors in a national prospective population-based cohort study Arch Dis Child 2017 102 715 721 28356250\n4 Ko MW Liu GT Pediatric idiopathic intracranial hypertension (Pseudotumor cerebri) Horm Res Paediatr 2010 74 381 389 20962512\n5 Scott IU Siatkowski RM Eneyni M Brodsky MC Lam BL Idiopathic intracranial hypertension in children and adolescents Am J Ophthalmol 1997 124 253 255 9262557\n6 Digre KB Bruce BB McDermott MP Galetta KM Balcer LJ Wall M; NORDIC Idiopathic Intracranial Hypertension Study Group Quality of life in idiopathic intracranial hypertension at diagnosis: IIH treatment trial results Neurology 2015 84 2449 2456 25995055\n7 Malozowski S Tanner A Wysowski D Fleming GA Growth hormone, insulin-like growth factor I, and benign intracranial hypertension N Engl J Med 1993 329 665 666 8341354\n8 Reeves GD Doyle DA Growth hormone treatment and pseudotumor cerebri: coincidence or close relationship? J Pediatr Endocrinol Metab 2002 15(Suppl 2) 723 730 12092686\n9 Rogers AH Rogers GL Bremer DL McGregor ML Pseudotumor cerebri in children receiving recombinant human growth hormone Ophthalmology 1999 106 1186 1189 10366091\n10 Mollan SP Markey KA Benzimra JD Jacks A Matthews TD Burdon MA Sinclair AJ A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension Pract Neurol 2014 14 380 390 24809339\n11 Souza FM Collet-Solberg PF Adverse effects of growth hormone replacement therapy in children Arq Bras Endocrinol Metab 2011 55 559 565\n12 Johansson JO Larson G Andersson M Elmgren A Hynsjö L Lindahl A Lundberg PA Isaksson OG Lindstedt S Bengtsson BA Treatment of growth hormone-deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters Neuroendocrinology 1995 61 57 66 7537355\n13 Darendeliler F Safety of Growth Hormone Treatment J Clin Res Pediatr Endocrinol 2009 1(Suppl 1) 36 43\n14 Saenger P Metabolic consequences of growth hormone treatment in paediatric practice Horm Res 2000 53(Suppl 19) 60 69 10895045\n15 Malozowski S Tanner LA Wysowski DK Fleming GA Stadel BV Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone J Pediatr 1995 126 996 999 7776116\n16 Darendeliler F Karagiannis G Wilton P Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database Horm Res 2007 68(Suppl 5) 41 47 18174706\n17 Soiberman U Stolovitch C Balcer LJ Regenbogen M Constantini S Kesler A Idiopathic intracranial hypertension in children Visual outcome and risk of recurrence Childs Nerv Syst 2011 27 1913 1918 21538129\n18 Tibussek D Schneider DT Vandemeulebroecke N Turowski B Messing- Juenger M Willems PH Mayatepek E Distelmaier F Clinical spectrum of the pseudotumor cerebri complex in children Childs Nerv Syst 2010 26 313 321 19902218\n19 Aylward SC Way AL Pediatric Intracranial hypertension: a current review Curr Pain Headache Rep 2018 22 14 29441432\n20 Ko MW Chang SC Ridha MA Ney JJ Ali TF Friedman DI Mejico LJ Volpe NJ Galetta SL Balcer LJ Liu GT Weight gain and recurrence in idiopathic intracrnial hypertension: a case-control study Neurology 2011 76 1564 1567 21536635\n21 Bassan H Berkner L Stolovitch C Kesler A Asymptomatic idiopathic intracranial hypertension in children Acta Neurol Scand 2008 118 251 255 18341683\n22 Aylward SC Reem RE Pediatric Intracranial Hypertension Pediatr Rev 2018 39 121 129\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": null, "issue": "13(2)", "journal": "Journal of clinical research in pediatric endocrinology", "keywords": "idiopathic intracranial hypertension; pseudotumor cerebri syndrome; Growth hormone treatment; papilledema; risk factors", "medline_ta": "J Clin Res Pediatr Endocrinol", "mesh_terms": null, "nlm_unique_id": "101519456", "other_id": null, "pages": "146-151", "pmc": null, "pmid": "33006547", "pubdate": "2021-06-02", "publication_types": "D016428:Journal Article", "references": "28356250;7776116;9262557;20962512;21538129;18029269;23966248;7537355;18341683;10895045;21536635;12092686;8341354;18174706;22218437;29441432;24809339;19902218;25995055;10366091", "title": "Growth Hormone Treatment and Papilledema: A Prospective Pilot Study", "title_normalized": "growth hormone treatment and papilledema a prospective pilot study" }

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GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. 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GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423707, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9245323", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REINTRODUCED AT A LOW DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".32", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "3", "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "11", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CAMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423396, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9244268", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".21", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "3", "patientonsetage": "11", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "27", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423769, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-EMD SERONO-9245321", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REINTRODUCED AT A LOW DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "SOMATROPIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "19764", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GROWTH HORMONE DEFICIENCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".23", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SOMATROPIN." } ], "patientagegroup": "3", "patientonsetage": "3", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "11", "reaction": [ { "reactionmeddrapt": "Papilloedema", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MARTIN?BEGUE N, MOGAS E, DOD C, ALARCON S, CLEMENTE M, CAMPOS?MARTORELL A, FABREGAS A, YESTE D. GROWTH HORMONE TREATMENT AND PAPILLEDEMA: A PROSPECTIVE PILOT STUDY.. JOURNAL OF CLINICAL RESEARCH IN PEDIATRIC ENDOCRINOLOGY. 2021 JUN 02?13 (2):146?151. DOI:10.4274/JCRPE.GALENOS.2020.2020.0007", "literaturereference_normalized": "growth hormone treatment and papilledema a prospective pilot study", "qualification": "1", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210616", "receivedate": "20210616", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19423725, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "OBJECTIVE\nTo explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH).\n\n\nMETHODS\nClinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed.\n\n\nRESULTS\nThe child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans-retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died.\n\n\nCONCLUSIONS\nThe latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia.", "affiliations": "Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.;Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.;Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.;Hematology-Oncology Center,Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.", "authors": "Su|Yan|Y|;Zhou|Xuan|X|;Zhang|Li|L|;Zhang|Rui|R|", "chemical_list": "D000970:Antineoplastic Agents; D014212:Tretinoin; D005047:Etoposide; D003630:Daunorubicin", "country": "China", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0578-1310", "issue": "51(12)", "journal": "Zhonghua er ke za zhi = Chinese journal of pediatrics", "keywords": null, "medline_ta": "Zhonghua Er Ke Za Zhi", "mesh_terms": "D000208:Acute Disease; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D003630:Daunorubicin; D020031:Epstein-Barr Virus Infections; D005047:Etoposide; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D016609:Neoplasms, Second Primary; D018570:Risk Assessment; D016896:Treatment Outcome; D014212:Tretinoin", "nlm_unique_id": "0417427", "other_id": null, "pages": "938-42", "pmc": null, "pmid": "24495767", "pubdate": "2013-12", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review", "references": null, "title": "Report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature.", "title_normalized": "report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature" }

[ { "companynumb": "CN-WATSON-2014-21043", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074968", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HISTIOCYTOSIS HAEMATOPHAGIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE (UNKNOWN)" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GANCICLOVIR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "074968", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute promyelocytic leukaemia", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SU Y, ZHOU X, ZHANG L, ZHANG R. [REPORT OF A CASE WITH SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA AFTER THERAPY FOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND REVIEW OF LITERATURE]. ZHONGHUA ER KE ZA ZHI. 2013;51(12):938-42. CHINESE", "literaturereference_normalized": "report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20140930", "receivedate": "20140930", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10484859, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "CN-CORDEN PHARMA LATINA S.P.A.-CN-2016COR000220", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "018768", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CUMULATIVE DOSE = 3520 MG/M^2", "drugenddate": null, "drugenddateformat": null, "drugindication": "HISTIOCYTOSIS HAEMATOPHAGIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute promyelocytic leukaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SU Y, ZHOU X, ZHANG L, ZHANG R. REPORT OF A CASE WITH SECONDARY ACUTE PROMYELOCYTIC LEUKEMIA AFTER THERAPY FOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND REVIEW OF LITERATURE. ZHONGHUA ER KE ZA ZHI. 2013;51 (12):938-942", "literaturereference_normalized": "report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20160928", "receivedate": "20160928", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12789239, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "BACKGROUND\nThe compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient.\n\n\nMETHODS\nA 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance.\n\n\nCONCLUSIONS\nIt is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.", "affiliations": "Diakonissenkrankenhaus und Paulinenhilfe gGmbH, Diakonie-Klinikum Stuttgart, Rosenbergstraße 38, 70176, Stuttgart, Germany.;Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.;Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.;Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany. [email protected].", "authors": "Jung|Susanne|S|;Michel|Manuela|M|;Stamminger|Thomas|T|;Michel|Detlef|D|http://orcid.org/0000-0003-2188-1815", "chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C109367:UL54 protein, Human herpesvirus 5; C090238:UL56 protein, cytomegalovirus; D014764:Viral Proteins; D015678:Viral Structural Proteins; C000588473:letermovir; D004259:DNA-Directed DNA Polymerase; D000077562:Valganciclovir", "country": "England", "delete": false, "doi": "10.1186/s12879-019-4016-1", "fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 401610.1186/s12879-019-4016-1Case ReportFast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient Jung Susanne [email protected] 1Michel Manuela [email protected] 2Stamminger Thomas [email protected] 2http://orcid.org/0000-0003-2188-1815Michel Detlef 0049 (0) 731 500 [email protected] 21 0000 0004 0560 4858grid.477279.8Diakonissenkrankenhaus und Paulinenhilfe gGmbH, Diakonie-Klinikum Stuttgart, Rosenbergstraße 38, 70176 Stuttgart, Germany 2 grid.410712.1Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany 8 5 2019 8 5 2019 2019 19 3888 8 2018 24 4 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nThe compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient.\n\nCase presentation\nA 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance.\n\nConclusion\nIt is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.\n\nKeywords\nAntiviral resistanceCytomegalovirusLetermovirGenotypingAllogenic hematopoietic-cell transplantationAcute myeloid leukemiaissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCytomegalovirus (CMV) is still one of the reasons for causing severe complications after allogeneic hematopoietic-cell transplantation [1, 2]. Ganciclovir (GCV) and valganciclovir (valGCV) are routinely used for treating CMV infection in solid-organ transplantation. However, after hematopoietic-cell transplantation, GCV and valGCV are avoided due to the possibility of myelosuppression [3–5]. All traditional anti-CMV agents like GCV, foscarnet, and cidofovir target the viral DNA polymerase [6]. In contrast, the compound letermovir (LMV) inhibits CMV replication by binding to components of the viral terminase complex and therefore offers a different mode of action [7–9]. In a recently published phase III study, CMV-seropositive transplant recipients received LMV at either a dose of 240 mg per day for patients taking cyclosporine A or 480 mg per day for patients without cyclosporine co-medication (https://www.accessdata.fda.gov/drugsatfda_docs/labe/2017/209939orig1s000,209940orig1s000lbl.pdf) [10]. The lack of cross-resistance with other anti-CMV compounds, the absence of myelosuppression as well as the positive results from the phase III study led to the recent approval of letermovir for the prophylaxis of CMV infection in CMV-seropositive adult hematopoietic-cell transplant recipients.\n\nGenotypic resistance testing was performed directly from patient specimens. Therefore, fragments of 2100 bp of the open reading frame (ORF) UL56 and 800 bp of the ORF UL89 were amplified by polymerase chain reaction followed by Sanger sequencing. The sequencing analyses of UL56 and UL89 allow detection of all known mutations conferring LMV resistance. Genotyping of the viral polymerase UL54 and the UL97 kinase were performed as previously described [11].\n\nCase presentation\nThe 44-year-old male acute myeloid leukemia (AML) patient received an unmanipulated graft from an unrelated donor (CMV D−/R+) after conditioning with the FLAMSA protocol. The patient received acyclovir (ACV, 400 mg twice per day) continuously, except between days + 43 to + 70 and day + 110 to + 145 (summarized in Fig. 1). For maintenance of immunosuppression, the patient received cyclosporine A per os (measured blood concentrations 180–220 μg/L), mycophenolate (360 mg twice daily), and prednisolone.Fig. 1 Time course of antiviral treatments and events. The CMV DNA loads (detection limit of 50 international units per ml (IU/ml)) were determined on serum samples. CMV DNA loads below the lower limit of quantization (125 IU/ml) are not to scale. The durations and the daily dosages of anti-CMV treatments with valganciclovir (450 mg or 900 mg twice a day) and letermovir are shown as black and grey boxes, respectively. Acyclovir (400 mg twice a day) was administered, when valGCV was paused. First detection of mutation C325Y (cytosine at amino acid 325 to tyrosine) in the specimens is depicted by a black star. The retrospective analysis revealed that the mutation was already present in earlier specimens shown by white stars. CsA, cyclosporine A; LMV, letermovir; valGCV, valganciclovir. ACV, acyclovir\n\n\n\nIt was planned to start LMV prophylaxis directly after the transplantation. However, due to a delay in delivery, administration of LMV could only be initiated at day + 34, under the assumption that CMV viral load was still below detection limit (50 IU/ml in serum). The compound was given at 240 mg once per day per os, along with cyclosporine. In retrospect, it turned out that the virus DNA load at the last check on day + 28 was 190 IU/ml in serum. Over the next 8 days, increasing CMV loads were measured up to 39.600 IU/ml. Therefore, letermovir treatment was discontinued and the patient was switched to valganciclovir (valGCV, 900 mg twice per day) at day + 42. Treatment was maintained for 4 weeks until CMV DNA was negative. At this time, the patient suffered from an intestinal graft-versus-host disease (GvHD) and a mucositis. Therefore, prednisolone was administered at day + 46 for 7 days with 10 mg and then was reduced to 1 mg until discontinuation at day + 82.\n\nAs neutropenia occurred during valGCV therapy, stimulation with G-CSF was necessary. After discontinuation of valGCV, neutropenia was resolved and LMV secondary prophylaxis was started at day + 70 with 240 mg once per day. At this time point CMV DNA was not detectable. At day + 80, mycophenolate was discontinued. For 4 weeks, CMV DNA remained undetectable or at the limit of quantitation of 125 IU/ml. At day + 97, tapering of cyclosporine A was initiated. However, several days later, the patient failed to maintain virologic suppression. CMV viral loads rapidly increased to 236.400 IU/ml in serum samples, between days + 104 and + 110. In order to avoid neutropenia, valGCV treatment with a reduced dosage of 450 mg twice per day was initiated at day + 110. Concomitantly, LMV dosage was increased to 480 mg per day. During the next 4 weeks, CMV viral loads decreased to 1.200 IU/ml. ValGCV treatment, which meanwhile necessitated daily stimulation with G-CSF, was discontinued.\n\nHowever, CMV DNA levels increased up to 33.000 IU/ml during the following 2 weeks. Therefore, genotyping of the CMV terminase UL56 as well as the other relevant genes (UL97 kinase, viral polymerase UL54, and UL89) was initiated. Thereby, a mutation corresponding to amino acid 325 (C325Y, cytosine at amino acid 325 to tyrosine) of UL56 was detected (see Fig. 1). This mutation is associated with a high resistance to LMV in vitro [12]. Therefore, LMV was discontinued at day + 167.\n\nNo further mutation was detected. Retrospective analysis revealed that the UL56 mutation C325Y was already present at day + 117, within 6 weeks after the start of the second letermovir administration. Unfortunately, no other patient specimens were available in order to further elucidate the time point of emergence of the mutation.\n\nSince then CMV DNA loads remained at a low level of 1300 to 2500 IU/ml. Due to the lack of clinical symptoms and increasing CD4 T-cells since day + 145, no further anti-CMV therapy was carried out.\n\nUntil today, the patient is clinically stable and participates in a professional reintegration.\n\nDiscussion and conclusions\nRecent clinical studies indicated that letermovir might be an important addition to the current strategies for prevention of active CMV infection and disease after allogeneic hematopoietic-cell transplantation and it may be useful for salvage therapies in solid organ recipients [13, 14]. However, since the approval of the compound at the end of 2017, several patients have been reported who developed genotypically confirmed resistance to LMV while on therapy [15–18]. Thereby, LMV resistance emerged both in solid organ transplant and in hematopoietic stem cell transplant recipients. In nearly all cases which have been reported, LMV was used for salvage treatment, with considerable viral loads and for longer exposure times. In one case a breakthrough of CMV disease in a HSCT recipient occurred after more than 4 months of letermovir prophylaxis [18]. Contrary to the later, in the present case, we observed a rapid breakthrough of a resistant CMV upon secondary prophylaxis with LMV. Our patient has been re-challenged with the compound after a first short time exposure of 8 days. Thus, the question arose whether the selection of LMV-resistant viruses has already occurred during the first period of administration, because at that time virus loads were very high. On the other hand, re-administration of the drug resulted in successful suppression of virus replication for at least 30 days. Then, however, the resistant CMV subpopulation apparently prevailed. Unfortunately, due to the lack of appropriate patient specimens the question concerning the exact time point of emergence of LMV resistance cannot be answered unequivocally. Additional studies are needed to decide whether the re-exposure to letermovir during repeated periods of CMV reactivation poses a particular risk for the development of antiviral drug resistance.\n\nAnother question is, whether the dosage of LMV was too low for virus suppression at the time when cyclosporine was tapered. In a phase II prophylaxis trial, a single case of breakthrough CMV viremia on LMV prophylactic treatment had been published. Thereby, the UL56 mutation V236 M emerged on a daily dose of 60 mg suggesting that low-dose prophylaxis may confer letermovir resistance [19]. However, although cyclosporin is known to alter LMV pharmacokinetics, a dosage of 240 mg letermovir even in the absence of CsA has been reported to be sufficient for complete suppression of viremia [19, 20].\n\nWe cannot exclude that individual reasons in this specific patient (e.g. compliance issues, nausea or atypical metabolism) led to low drug levels since no pharmacokinetic monitoring of LMV is available. Nonetheless, it is presently unclear whether higher doses of the drug would be more effective or safe during prolonged use since a recent study reported two patients who developed genotypically confirmed resistance to LMV while on therapy with 720 mg and 960 mg daily, respectively [16].\n\nIn vitro studies with serial viral passage in the presence of the compound have been associated with relatively rapid selection of several different UL56 mutations, particularly within codons 25 and 231 to 369 [21, 22]. Thereby, the different mutations led to diverse levels of resistance, ranging from a 5-fold increase in EC50 for V231L to > 5000-fold for C325Y [21, 22]. Remarkably, in all reports published after the approval of letermovir, the amino acid 325 in UL56 was exclusively affected [15–18]. In our case the mutation is also located at this codon. This suggests that amino acid 325 of UL56 may represent a hot spot for the occurrence of resistance upon clinical treatment. The presently available data suggest the necessity for fast genotyping for early detection of relevant mutations before treatment failure is evident.\n\nAccording to the currently available data, letermovir should, if possible, only be used within the scope of the approval. Administration in patients at high risk with active CMV infections and considerable virus loads requires caution and close clinical and virological monitoring concerning the emergence of drug-resistant virus variants. Furthermore, LMV administration at high virus loads combined with (short time) drug exposures may foster the rapid selection of resistant CMV variants.\n\nAbbreviations\nallo-HCTHematopoietic-cell transplantation\n\nAMLAcute myeloid leukemia\n\nCMVHuman cytomegalovirus\n\nLMVLetermovir\n\nPCRPolymerase chain reaction\n\nUL54Unique long open reading frame 54\n\nUL56Unique long open reading frame 56\n\nUL89Unique long open reading frame 89\n\nUL97Unique long open reading frame 97\n\nAcknowledgements\nThe consent of the patient for publication of this case is highly appreciated. DM thanks Dr. Peter Lischka and the reviewers for their constructive comments.\n\nFunding\nThe authors have received no funding for the preparation of this manuscript. The authors declare that they have no conflicts of interests. The information has not been presented on any meeting.\n\nAvailability of data and materials\nThe datasets used and/or analyzed for the case study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll authors read and approved the final manuscript. SJ and DM have been involved in acquisition and interpretation of data. SJ has been involved in patient clinical care and reviewing medical records. MM and DM carried out the CMV genotyping and contributed to analysis. TS and DM drafted the manuscript. TS reviewed and revised this paper, and gave final approval to submit for publication.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nD.M. was consultant for virological diagnosis for AiCuris GmbHCo.KG. The authors have received no funding for the preparation of this manuscript. The authors declare that they have no conflicts of interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Teira P Battiwalla M Ramanathan M Barrett AJ Ahn KW Chen M Green JS Saad A Antin JH Savani BN Lazarus HM Seftel M Saber W Marks D Aljurf M Norkin M Wingard JR Lindemans CA Boeckh M Riches ML Auletta JJ Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis Blood 2016 127 2427 2438 10.1182/blood-2015-11-679639 26884374 \n2. Ljungman P Hakki M Boeckh M Cytomegalovirus in hematopoietic stem cell transplant recipients Hematol Oncol Clin North Am 2011 25 151 169 10.1016/j.hoc.2010.11.011 21236396 \n3. 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Marty FM Ljungman P Chemaly RF Maertens J Dadwal SS Duarte RF Haider S Ullmann AJ Katayama Y Brown J Mullane KM Boeckh M Blumberg EA Einsele H Snydman DR Kanda Y DiNubile MJ Teal VL Wan H Murata Y Kartsonis NA Leavitt RY Badshah C Letermovir prophylaxis for Cytomegalovirus in hematopoietic-cell transplantation N Engl J Med 2017 377 2433 2444 10.1056/NEJMoa1706640 29211658 \n11. Michel D Höhn S Haller T Jun D Mertens T Aciclovir selects for ganciclovir-cross-resistance of human cytomegalovirus in vitro that is only in part explained by known mutations in the UL97 protein J Med Virol 2001 65 1 70 76 10.1002/jmv.2003 11505446 \n12. Ligat G Czal R Hantz S Alain S The human cytomegalovirus terminase complex as an antiviral target: a close-up view FEMS Microbiol Rev 2018 42 137 145 10.1093/femsre/fuy004 29361041 \n13. Lischka P Zimmermann H Antiviral strategies to combat cytomegalovirus infections in transplant recipients Curr Opin Pharmacol 2008 8 541 548 10.1016/j.coph.2008.07.002 18662804 \n14. Chemaly RF Ullmann AJ Stoelben S Richard MP Bornhäuser M Groth C Einsele H Silverman M Mullane KM Brown J Nowak H Kölling K Stobernack HP Lischka P Zimmermann H Rübsamen-Schaeff H Champlin RE Ehninger G AIC246 Study Team. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation N Engl J Med 2014 370 1781 1789 10.1056/NEJMoa1309533 24806159 \n15. Frietsch JJ Michel D Stamminger T Hunstig F Birndt S Schnetzke U Scholl S Hochhaus A Hilgendorf I In vivo emergence of UL56 C325Y Cytomegalovirus resistance to Letermovir in a patient with acute myeloid leukemia after hematopoietic cell transplantation Mediterr J Hematol Infect Dis 2019 11 1 e2019001 10.4084/MJHID.2019.001 30671207 \n16. Turner N, Strand A, Grewal DS, Cox G, Arif S, Baker AW, Maziarz EK, Saullo JH, Wolfe CR. 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Chou S Approach to drug-resistant cytomegalovirus in transplant recipients Curr Opin Infect Dis 2015 28 293 299 10.1097/QCO.0000000000000170 26098499\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2334", "issue": "19(1)", "journal": "BMC infectious diseases", "keywords": "Acute myeloid leukemia; Allogenic hematopoietic-cell transplantation; Antiviral resistance; Cytomegalovirus; Genotyping; Letermovir", "medline_ta": "BMC Infect Dis", "mesh_terms": "D000085:Acetates; D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004259:DNA-Directed DNA Polymerase; D024882:Drug Resistance, Viral; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009154:Mutation; D011799:Quinazolines; D055502:Secondary Prevention; D000077562:Valganciclovir; D019562:Viral Load; D014764:Viral Proteins; D015678:Viral Structural Proteins", "nlm_unique_id": "100968551", "other_id": null, "pages": "388", "pmc": null, "pmid": "31068147", "pubdate": "2019-05-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11505446;18662804;18771048;19236193;19299333;20047911;20353469;21236396;21752907;24189264;24806159;26098499;26113373;26884374;28967706;29211658;29361041;30286286;30401966;30642941;30671207;8380242", "title": "Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient.", "title_normalized": "fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient" }

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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "240 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "240", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "480 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "480", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "900 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS VIRAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "360", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "205220", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1800 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "65078", "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MEASURED BLOOD CONCENTRATIONS 180-220 MICROGRAM/L", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pathogen resistance", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JUNG S, MICHEL M, STAMMINGER T, MICHEL D. FAST BREAKTHROUGH OF RESISTANT CYTOMEGALOVIRUS DURING SECONDARY LETERMOVIR PROPHYLAXIS IN A HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENT. BMC-INFECT-DIS 2019?19:388.", "literaturereference_normalized": "fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190613", "receivedate": "20190613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16425459, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "DE-ROCHE-2329759", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021304", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LETERMOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LETERMOVIR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "PER OS (MEASURED BLOOD CONCENTRATIONS 180-220 PG/L)", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "021304", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN,UNKNOWN,UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FOR 7 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACYCLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG TWICE PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACYCLOVIR [ACICLOVIR]" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "021304", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AT DAY + 110", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "900", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "360 MG TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "720", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." } ], "patientagegroup": null, "patientonsetage": "44", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JUNG S, MICHEL M, STAMMINGER T, MICHEL D. FAST BREAKTHROUGH OF RESISTANT CYTOMEGALOVIRUS DURING SECONDARY LETERMOVIR PROPHYLAXIS IN A HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENT.. BMC INFECT DIS. DOI: 10.1186/S12879-019-4016-1. 2019 MAY 08?19 (1):388:-.", "literaturereference_normalized": "fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20190909", "receivedate": "20190531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16376545, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "Persistence of various symptoms in patients who have recovered from coronavirus disease 2019 (COVID-19) was recently defined as 'long COVID' or 'post-COVID syndrome' (PCS). This article reports a case of a 58-year-old woman who, although recovering from COVID-19, had novel and persistent symptoms including neurological complications that could not be explained by any cause other than PCS. In addition to a low inflammatory response, persistence of immunoglobulin G anticardiolipin autoantibody positivity and eosinopenia were found 1 year after acute COVID-19 infection, both of which have been defined previously as independent factors associated with the severity of COVID-19. The pathophysiological mechanism of PCS is unknown, but the possibility of persistence of the virus, especially in the nervous system, could be suggested with a post-infectious inflammatory or autoimmune reaction.", "affiliations": "Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France. Electronic address: [email protected].;Service de Neurologie, Pôle de Neurosciences Cliniques, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service de Médecine Interne et d'Immunologie Clinique, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix Marseille Université, C2VN, INSERM UMR_S 1263, Marseille, France.;Service de Médecine Interne, Aix-Marseille Université, AP-HM, Hôpital La Timone, Marseille, France.;Institut Hospitalo-Universitaire Méditerranée Infection, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Aix Marseille Université, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix-Marseille Université, IRD, MEPHI, Institut Hospitalo-Universitaire Méditerranée Infection, Marseille, France.;Service d'Immunologie, Pôle de Biologie, Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; Aix Marseille Université, C2VN, INSERM UMR_S 1263, Marseille, France.", "authors": "Bertin|Daniel|D|;Kaphan|Elsa|E|;Weber|Samuel|S|;Babacci|Benjamin|B|;Arcani|Robin|R|;Faucher|Benoit|B|;Ménard|Amélie|A|;Brodovitch|Alexandre|A|;Mege|Jean Louis|JL|;Bardin|Nathalie|N|", "chemical_list": null, "country": "Canada", "delete": false, "doi": "10.1016/j.ijid.2021.09.079", "fulltext": null, "fulltext_license": null, "issn_linking": "1201-9712", "issue": "113()", "journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases", "keywords": "COVID-19; anticardiolipin antibodies; antiphospholipid antibodies; long COVID syndrome; post-COVID syndrome", "medline_ta": "Int J Infect Dis", "mesh_terms": null, "nlm_unique_id": "9610933", "other_id": null, "pages": "23-25", "pmc": null, "pmid": "34614444", "pubdate": "2021-12", "publication_types": "D002363:Case Reports", "references": null, "title": "Persistent IgG anticardiolipin autoantibodies are associated with post-COVID syndrome.", "title_normalized": "persistent igg anticardiolipin autoantibodies are associated with post covid syndrome" }

[ { "companynumb": "FR-LUPIN PHARMACEUTICALS INC.-2022-01449", "fulfillexpeditecriteria": "2", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "065398", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "1", "drugtreatmentdurationunit": "803", "medicinalproduct": "AZITHROMYCIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "065125", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "1", "drugtreatmentdurationunit": "803", "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "210543", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "1", "drugtreatmentdurationunit": "803", "medicinalproduct": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20200101" } }, "primarysource": { "literaturereference": "Bertin D, Kaphan E, Weber S, Babacci B, Arcani R, Faucher B, et al. Persistent IgG anticardiolipin autoantibodies are associated with post-COVID syndrome. International Journal of Infectious Diseases. 2021;113:23-25", "literaturereference_normalized": "persistent igg anticardiolipin autoantibodies are associated with post covid syndrome", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20220207", "receivedate": "20220207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20435568, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220424" } ]

{ "abstract": "Metamizole was the second most common drug prescribed in Germany in 2018 despite the known risk of agranulocytosis and the strict indication. According to Stammschulte et al. up to 25 % of all prescriptions are off-label use. Although mandatory according to the prescribing information of metamizole, regular blood cell counts are not performed in up to 50 % of the patients with long-term use of this drug.\n\n\n\nRetrospective analysis of eight cases metamizole-induced agranulocytosis over a period of five years (2016-2020) in the university ENT department in Erlangen. Five patients were men and three women. Mean age of diagnosis was 52,4 years (± 25,6).\n\n\n\nAgranulocytosis after use of metamizole is a serious adverse drug reaction that may affect patients of all ages. Frequently, only distinct clinical symptoms such as temperature of unknown origin, dysphagia and tonsillitis in combination with abscesses in the head and neck area result in the detection of a metamizole-induced agranulocytosis. An agranulocytosis provokes partially radical surgery and/ or intensive-care measures and could lead to sepsis with organ failure or even to death.\n\n\n\nThese patient cases show that agranulocytosis is a dangerous or even deadly adverse drug reaction after use of metamizole. Although the risk of agranulocytosis appears to increase with duration of use, we would recommend patient education as well as documentation of even a single administration of metamizole. This may facilitate early diagnosis of metamizole-induced agranulocytosis and thus prevent the onset of severe complications with possible lethal outcome.", "affiliations": "Hals-Nasen-Ohren-Klinik, Kopf- und Halschirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.;Hals-Nasen-Ohren-Klinik, Kopf- und Halschirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.;Radiologisches Institut, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.;Hals-Nasen-Ohren-Klinik, Kopf- und Halschirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.", "authors": "Schinz|Katharina|K|;Waldfahrer|Frank|F|;Wüst|Wolfgang|W|;Iro|Heinrich|H|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004177:Dipyrone", "country": "Germany", "delete": false, "doi": "10.1055/a-1190-4445", "fulltext": null, "fulltext_license": null, "issn_linking": "0935-8943", "issue": "99(10)", "journal": "Laryngo- rhino- otologie", "keywords": null, "medline_ta": "Laryngorhinootologie", "mesh_terms": "D000380:Agranulocytosis; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002675:Child, Preschool; D004177:Dipyrone; D005260:Female; D005858:Germany; D006801:Humans; D008297:Male; D012189:Retrospective Studies", "nlm_unique_id": "8912371", "other_id": null, "pages": "707-712", "pmc": null, "pmid": "32588405", "pubdate": "2020-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Agranulocytosis after use of metamizole - an underestimated risk?", "title_normalized": "agranulocytosis after use of metamizole an underestimated risk" }

[ { "companynumb": "DE-TEVA-2020-DE-1861122", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXEPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "071239", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXEPIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075347", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DIPYRONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIPYRONE" } ], "patientagegroup": "5", "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abscess neck", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Agranulocytosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCHINZ K, WALDFAHRER F, WUST W, IRO H. AGRANULOCYTOSIS AFTER USE OF METAMIZOLE - AN UNDERESTIMATED RISK?. [GERMAN]. LARYNGORHINOOTOLOGIE 2020?99(10):707-712.", "literaturereference_normalized": "agranulocytosis after use of metamizole an underestimated risk", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201223", "receivedate": "20201223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18653488, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271954", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207891", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMEPRAZOLE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METAMIZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METAMIZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXEPIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXEPIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Agranulocytosis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCHINZ K, WALDFAHRER F, WUST W, IRO H. AGRANULOCYTOSIS AFTER USE OF METAMIZOLE - AN UNDERESTIMATED RISK?. LARYNGORHINOOTOLOGIE. 2020?99(10):707-712", "literaturereference_normalized": "agranulocytosis after use of metamizole an underestimated risk", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201222", "receivedate": "20201222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18645813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]

{ "abstract": "Backgroung: This study investigated the efficacy and safety of TNF antagonists in sarcoid uveitis in unselected cases. Design: This is a multicentre study on patients with sarcoidosis who received TNF antagonists in pneumology and internal medicine departments in France. We present here the subgroup of patients with biopsy-proven sarcoid uveitis included in the nationwide registry STAT (Sarcoidosis treated with TNF AnTagonists). Results: Among the 132 patients included in this multicenter study, 18 patients with refractory uveitis were treated as a first-line TNF antagonist with infliximab (n=14), adalimumab (n=3) and certolizumab (n=1). Before anti-TNF initiation, the median duration of sarcoidosis was 42 months and 83% of the patients have been treated with at least one immunosuppressive drug. Six patients switched for a second-line TNF antagonist. After a mean time under treatment of 29 months, the treatment resulted in a significant decrease of the ophthalmic extrapulmonary Physician Organ Severity Tool (ePOST) (mean score: 4.2 vs. 2.6) scores and a steroid sparing effect (29.4±20.7 vs. 6.2±5.2 mg/d). Overall, the ophthalmic response, either complete or partial, was 67%. Nine patients (50%) presented adverse events, including severe infectious complications in 5 patients, which required anti-TNF treatment interruption in 6 cases (33%). Among the 7 responder patients who discontinued anti-TNF therapy, 71% relapsed. Finally, 12 patients (67%) could continue TNF antagonist treatment. Conclusions: TNF antagonists were efficient in 67% of biopsy-proven refractory sarcoid uveitis. Severe adverse events, mainly infectious complications, were frequent. The high frequency of relapses after anti-TNF-α discontinuation requires a close patient follow-up thereafter. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 74-80).", "affiliations": "Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.;Département de Médecine Interne et d'Immunologie Clinique II, Assistance Publique-Hôpitaux de Paris (AP-HP), CHU Pitié Salpêtrière, Université Pierre et Marie Curie (UPMC), F-75006, Paris, France.;Service de Biostatistique, Hospices Civils de Lyon, F-69003, Lyon, France.;Département de Médecine Interne et d'Immunologie Clinique, AP-HP, CHU Pitié Salpêtrière, Institut E3M, Université Pierre et Marie Curie, F-75006, Paris, France.;Université Claude Bernard, Lyon 1, F-69100, Villeurbanne, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-38700, Grenoble, France.;Département de Médecine Interne, Hôpital Avicenne, Université Paris 13, F-93000, Bobigny, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-21000, Dijon, France.;Département de Pneumologie, Hôpital Avicenne, AP-HP, Université Paris 13, F-93000, Bobigny, France.;Département de Médecine Interne, CHU Gabriel Montpied, F-63000, Clermont-Ferrand, France.;Département de Médecine Interne et d'Immunologie Clinique, AP-HP, CHU Bicêtre, Université Paris Sud, UMR 1184, F-94270, Le Kremlin Bicêtre, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-14033, Caen, France.;Département de Médecine Interne de Gériatrie Thérapeutique, Hôpital Saint-Julien, CHU de Rouen, F-76031 Rouen Cedex, France.;Université Claude Bernard, Lyon 1, F-69100, Villeurbanne, France.;Département d'Ophtalmologie, AP-HP, CHU Pitié Salpêtrière, F-75013, Paris, France.;Département de Médecine Interne, Centre Hospitalier Universitaire, F-38700, Grenoble, France.;Service de Biostatistique, Hospices Civils de Lyon, F-69003, Lyon, France.;Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.;Département de Médecine Interne et d'Immunologie Clinique II, Assistance Publique-Hôpitaux de Paris (AP-HP), CHU Pitié Salpêtrière, Université Pierre et Marie Curie (UPMC), F-75006, Paris, France.;Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.;Département de Pneumologie, Hôpital Avicenne, AP-HP, Université Paris 13, F-93000, Bobigny, France.;Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, F-69004, Lyon, France.", "authors": "Marquet|Alicia|A|;Chapelon-Abric|Catherine|C|;Maucort-Boulch|Delphine|D|;Cohen-Aubart|Fleur|F|;Pérard|Laurent|L|;Bouillet|Laurence|L|;Abad|Sébastien|S|;Bielefeld|Philip|P|;Bouvry|Diane|D|;André|Marc|M|;Noël|Nicolas|N|;Bienvenu|Boris|B|;Proux|Alice|A|;Vukusic|Sandra|S|;Bodaghi|Bahram|B|;Sarrot-Reynaud|Françoise|F|;Iwaz|Jean|J|;Broussolle|Christiane|C|;Saadoun|David|D|;Jamilloux|Yvan|Y|;Valeyre|Dominique|D|;Sève|Pascal|P|;|||", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.36141/svdld.v34i1.5368", "fulltext": null, "fulltext_license": null, "issn_linking": "1124-0490", "issue": "34(1)", "journal": "Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG", "keywords": "TNF antagonists; efficacy; safety; sarcoidosis; uveitis", "medline_ta": "Sarcoidosis Vasc Diffuse Lung Dis", "mesh_terms": null, "nlm_unique_id": "9610928", "other_id": null, "pages": "74-80", "pmc": null, "pmid": "32476825", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "26092330;19585358;23276549;24090799;23988768;22885144;16840744;10209662;22119879;23470459;25325834;23311120;24401994;10430755;27015607;21191712;19386069;23392263;23983404;18256069;24704868;22387045;26120779;19382527", "title": "Efficacy and safety of TNF antagonists in ocular sarcoidosis: data from the French registry STAT.", "title_normalized": "efficacy and safety of tnf antagonists in ocular sarcoidosis data from the french registry stat" }

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EFFICACY AND SAFETY OF TNF ANTAGONISTS IN OCULAR SARCOIDOSIS: DATA FROM THE FRENCH REGISTRY STAT. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES 2017;34 (1):74-80.", "literaturereference_normalized": "efficacy and safety of tnf antagonists in ocular sarcoidosis data from the french registry stat", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20171005", "receivedate": "20171005", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14047712, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "Traction alopecia (TA) is a form of hair loss caused by continuous and prolonged tension to the hair, most commonly seen in Black/African American women and children who wear hairstyles that pull excessively at the frontotemporal hairline. Dermatologists have recommended the use of intralesional triamcinolone acetonide injections (ILK) to decrease the inflammatory process, however, evidence-based proof is lacking in the literature. In this case series, we evaluate the effectiveness and safety of ILK in the TA management of 6 African American women. A retrospective chart review was done of patients with a diagnosis of TA, who were treated with ILK at an academic dermatology clinic, yielding 6 patients. Management of TA was assessed by comparing the photographs for changes in hair density along the frontotemporal hairline. ILK with a concentration of 5 mg/mL, was administered in areas of low hair density along the frontotemporal hairline at 6 to 8-week intervals, for 3 successive visits. All subjects demonstrated visible increase in hair density along the frontotemporal hairline following their first or second treatment, and no severe adverse effects were observed or reported. The use of ILK is currently an effective and safe method of treating TA, particularly in the early to mid-stages. Common adverse effects are pain, and subsequent transient atrophy at the injection site. The transient atrophy is not an indication to stop treatment. Avoidance of treating dented areas is sufficient to allow it to revert. Patient education is pivotal in the prevention and management of TA. It is imperative that dermatologists caution against grooming practices that exert tension on the hairline.\n\nJ Drugs Dermatol. 2020;19(2)128-130. doi:10.36849/JDD.2020.4635", "affiliations": null, "authors": "Uwakwe|Laura N.|LN|;De Souza|Brianna|B|;Tovar-Garza|Andrea|A|;McMichael|Amy J.|AJ|", "chemical_list": "D014222:Triamcinolone Acetonide", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1545-9616", "issue": "19(2)", "journal": "Journal of drugs in dermatology : JDD", "keywords": null, "medline_ta": "J Drugs Dermatol", "mesh_terms": "D000328:Adult; D000505:Alopecia; D005260:Female; D006801:Humans; D015552:Injections, Intralesional; D008875:Middle Aged; D012189:Retrospective Studies; D014222:Triamcinolone Acetonide", "nlm_unique_id": "101160020", "other_id": null, "pages": "128-130", "pmc": null, "pmid": "32129955", "pubdate": "2020-02-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Intralesional Triamcinolone Acetonide in the Treatment of Traction Alopecia", "title_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia" }

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INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. JOURNAL OF DRUGS IN DERMATOLOGY. 2020?19(2):128-130.", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201210", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573414, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-JNJFOC-20201144022", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "5MG/ML, 3 INJECTION 6-8 WEEK INTERVAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": "021812", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." } ], "patientagegroup": "5", "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapeutic response unexpected", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "UWAKWE L, DE SOUZA B, TOVAR-GARZA A, MCMICHAEL A. INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. 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INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. JOURNAL OF DRUGS IN DERMATOLOGY. 2020?19 (2):128-130.", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201203", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573426, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" }, { "companynumb": "US-APOTEX-2020AP022466", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "209243", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXYCYCLINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": null, "drugadministrationroute": "026", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIAMCINOLONE ACETONIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MINOXIDIL" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TOPICAL SOLUTION", "drugdosagetext": "5 PERCENT, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ALOPECIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "030", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MINOXIDIL." } ], "patientagegroup": null, "patientonsetage": "32", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "UWAKWE LN, DE SOUZA B, TOVAR-GARZA A, MCMICHAEL AJ. INTRALESIONAL TRIAMCINOLONE ACETONIDE IN THE TREATMENT OF TRACTION ALOPECIA. J-DRUGS-DERMATOL. 2020?19(2):128-130", "literaturereference_normalized": "intralesional triamcinolone acetonide in the treatment of traction alopecia", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201216", "receivedate": "20201216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18623292, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]

{ "abstract": "Epidural steroid injections are widely used for the treatment of lumbago and sciatica although their efficacy has not yet been demonstrated in a convincing way. Moreover, systemic complications, although rare, have been documented. The present case report illustrates that even a single low-dose epidural injection may induce Cushing's syndrome and even steroid myopathy.", "affiliations": "Department of Internal Medicine, University Hospital, Katholieke Universiteit Leuven, Belgium.", "authors": "Boonen|S|S|;Van Distel|G|G|;Westhovens|R|R|;Dequeker|J|J|", "chemical_list": "D014221:Triamcinolone", "country": "England", "delete": false, "doi": "10.1093/rheumatology/34.4.385", "fulltext": null, "fulltext_license": null, "issn_linking": "0263-7103", "issue": "34(4)", "journal": "British journal of rheumatology", "keywords": null, "medline_ta": "Br J Rheumatol", "mesh_terms": "D000368:Aged; D001416:Back Pain; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D007268:Injections, Epidural; D009135:Muscular Diseases; D014221:Triamcinolone", "nlm_unique_id": "8302415", "other_id": null, "pages": "385-6", "pmc": null, "pmid": "7788158", "pubdate": "1995-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Steroid myopathy induced by epidural triamcinolone injection.", "title_normalized": "steroid myopathy induced by epidural triamcinolone injection" }

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{ "abstract": "To investigate the histopathological findings in ketamine-associated uropathy (KU) and their clinical association.\n\n\n\nThirty-eight KU patients had received history investigation and video urodynamic study. Twelve of them were clinically mild KU who were admitted for cystoscopic hydrodistention. The other 26 patients were severe KU who were admitted for enterocystoplasty with or without ureter reimplantation. Bladder and ureter specimens were harvested during operation, and a single pathologist reviewed all specimens under hematoxylin and eosin stain. The severity of histopathological findings was graded with a 4-point scale (0: none, 1: mild, 2: moderate, and 3: severe) RESULTS: Inflammatory cells infiltrations and nerve hyperplasia were found in the mucosa, muscle, and subserosal layers of KU bladders and ureter. In the mild KU bladder mucosa, the predominant component of the infiltrating inflammatory cells was lymphocytes. In contrast, neutrophils, eosinophils, lymphocytes, and plasma cells infiltration were noted in the mucosa of almost all severe KU bladders. Clinical severe KU was significantly correlated with severe to moderate lymphocytes, plasma cells, neutrophils, eosinophils infiltration, and nerve hyperplasia in bladder mucosa. KU patients with moderate or severe neutrophils or lymphocytes infiltration in bladder mucosa had significantly more severe bladder pain and smaller bladder capacity.\n\n\n\nThe histological findings of KU showed whole-layer inflammation and nerve hyperplasia in bladder mucosa. The severity of inflammatory cell infiltration in the bladder mucosa is associated with clinical symptoms. A histopathological examination might be a useful tool to discriminate the KU severity in patients.", "affiliations": "Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.;Department of Urology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien, Taiwan.", "authors": "Jhang|Jia-Fong|JF|;Hsu|Yung-Hsiang|YH|;Jiang|Yuan-Hong|YH|;Lee|Cheng-Ling|CL|;Kuo|Hann-Chorng|HC|0000-0001-7165-4771", "chemical_list": "D007649:Ketamine", "country": "United States", "delete": false, "doi": "10.1002/nau.23514", "fulltext": null, "fulltext_license": null, "issn_linking": "0733-2467", "issue": "37(5)", "journal": "Neurourology and urodynamics", "keywords": "fibrosis; histology; pathogenesis; surgery; upper tract", "medline_ta": "Neurourol Urodyn", "mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007649:Ketamine; D008297:Male; D017699:Pelvic Pain; D014513:Ureter; D014563:Urodynamics; D014570:Urologic Diseases; D013520:Urologic Surgical Procedures; D055815:Young Adult", "nlm_unique_id": "8303326", "other_id": null, "pages": "1764-1772", "pmc": null, "pmid": "29441609", "pubdate": "2018-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Histopathological characteristics of ketamine-associated uropathy and their clinical association.", "title_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association" }

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HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. 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NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321868, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063023", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15312418, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063037", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316198, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063072", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321886, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063024", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15315686, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063091", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321866, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063048", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321876, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063029", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316199, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063082", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321889, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063080", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321869, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063049", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321882, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063042", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316192, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063125", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321872, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063071", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321870, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063047", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316195, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063069", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321881, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063106", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180827", "receivedate": "20180827", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15321871, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063031", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316191, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063032", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316211, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063027", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180824", "receivedate": "20180824", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15316193, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" }, { "companynumb": "TW-MYLANLABS-2018M1063095", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETAMINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076092", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "JHANG J?F, HSU Y?H, JIANG Y?H, LEE C?L, KUO H?C. HISTOPATHOLOGICAL CHARACTERISTICS OF KETAMINE?ASSOCIATED UROPATHY AND THEIR CLINICAL ASSOCIATION. NEUROUROL?URODYN 2018?37(5):1764?1772.", "literaturereference_normalized": "histopathological characteristics of ketamine associated uropathy and their clinical association", "qualification": "3", "reportercountry": "TW" }, "primarysourcecountry": "TW", "receiptdate": "20180823", "receivedate": "20180823", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15312413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20181010" } ]

{ "abstract": "Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study.", "affiliations": "Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, 89-1, Enya, Izumo-City 693-8501, Japan.;Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1, Asahi, Takamatsu-City 760-8557, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Dentistry and Dental Surgery, Tsuyama Chuo Hospital, 1756, Kawasaki, Tsuyama-City 708-0841, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.;Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan.", "authors": "Obata|Kyoichi|K|0000-0002-6569-7406;Okui|Tatsuo|T|0000-0002-7640-3274;Ono|Sawako|S|;Umemori|Koki|K|;Ryumon|Shoji|S|;Ono|Kisho|K|;Yao|Mayumi|M|;Yoshioka|Norie|N|;Ibaragi|Soichiro|S|;Sasaki|Akira|A|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/diagnostics11081375", "fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n10.3390/diagnostics11081375\ndiagnostics-11-01375\nCase Report\nComparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review\nhttps://orcid.org/0000-0002-6569-7406\nObata Kyoichi 1*\nhttps://orcid.org/0000-0002-7640-3274\nOkui Tatsuo 2*\nOno Sawako 3\nUmemori Koki 1\nRyumon Shoji 1\nOno Kisho 1\nYao Mayumi 4\nYoshioka Norie 1\nIbaragi Soichiro 1\nSasaki Akira 1\nGenina Elina A. Academic Editor\n1 Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata, Okayama-City 700-8558, Japan; [email protected] (K.U.); [email protected] (S.R.); [email protected] (K.O.); [email protected] (N.Y.); [email protected] (S.I.); [email protected] (A.S.)\n2 Department of Oral and Maxillofacial Surgery, Shimane University Faculty of Medicine, 89-1, Enya, Izumo-City 693-8501, Japan\n3 Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1, Asahi, Takamatsu-City 760-8557, Japan; [email protected]\n4 Department of Dentistry and Dental Surgery, Tsuyama Chuo Hospital, 1756, Kawasaki, Tsuyama-City 708-0841, Japan; [email protected]\n* Correspondence: [email protected] (K.O.); [email protected] (T.O.); Tel.: +81-86-235-6702 (K.O.); +81-853-20-2301 (T.O.)\n30 7 2021\n8 2021\n11 8 137512 7 2021\n28 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nMethotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study.\n\nmethotrexate\nlymphoproliferative disorders\nEpstein-Barr virus\nmucocutaneous ulcer\nrheumatoid arthritis\n==== Body\n1. Introduction\n\nMethotrexate (MTX) is an immunosuppressive antifolate that was approved as a therapeutic agent for rheumatoid arthritis (RA) by the FDA in 1988. MTX is the anchor drug in RA treatment because of its high efficacy rate, continuation rate, and inhibitory effect on bone destruction and improvement of quality of life [1,2]. However, MTX also has various side effects, such as bone marrow suppression, increased risk of interstitial pneumonia, and gastrointestinal tract disorders [1,3,4,5]. In 1991, Ellman et al. reported MTX-associated lymphoproliferative disorder (MTX-LPD) as a lymphoma that occurred in RA patients using MTX, with more than 100 cases reported at that time [6]. In 2008, MTX-LPD was classified as one of the “other iatrogenic immunodeficiency-associated lymphoproliferative disorders” in the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue [7]. The progression of RA is considered to be a risk factor for the onset of MTX-LPD, however, the pathogenesis of MTX-LPD remains poorly understood [8].\n\nEpstein-Barr virus (EBV) was detected in approximately half of MTX-LPD cases by blood exam, immunohistochemistry, and in situ hybridization. Latently EBV-infected B-cells, which are normally suppressed, are thought to be reactivated by the immunosuppressive action of MTX, allowing MTX-LPD to develop in EBV-infected patients [9]. EBV-infected MTX-LPD patients usually have a good prognosis upon withdrawal of MTX. Dojcinov et al. reported EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease that can be histopathologically diagnosed as a lymphoma with ulcers localized to the skin and mucosa [10]. In 2017, EBV-MCU was newly added to the WHO Classification [11]. The use of immunosuppressive drugs is a major risk factor for the development of EBV-MCU and MTX is the most frequently reported causal agent [12]. Immunosenescence due to ageing and primary immunodeficiency are also known risk factors of EBV-MCU. Currently, reports of EBV-MCU and MTX-LPD with lesions in the oral mucosa are increasing. However, there are few studies that have aggregated and compared MTX-LPD and EBV-MCU in the oral mucosa. In addition, it is not clear how the pathogenesis and pathophysiology of MTX-LPD and EBV-MCU differ in the oral mucosa. Also, MTX-LPD and EBV-MCU does not occur in all patients with risk factors and it is reasonable to assume that there are some additional risk factors that have yet to be discovered.\n\nHere, we report our experience with the treatment of EBV-MCU and MTX-LPD in the oral mucosa and provide a comprehensive review of the clinical features.\n\n2. Materials and Methods\n\nThis case series was composed of 10 patients with MTX-LPD or EBV-MCU occurring in the oral mucosa who visited the Department of Oral and Maxillofacial Surgery, Okayama University Hospital (Okayama, Japan) and the Department of Dentistry and Oral Surgery, Tsuyama Chuo Hospital (Okayama, Japan) during the nine year period from 2012 to 2021. The patients were identified retrospectively and evaluated for age, sex, autoimmune disease and immunosuppressive therapy details, site of onset, EBV infection, histological findings, treatment, and prognosis.\n\n3. Results\n\nTable 1 summarizes the detailed characteristics of 10 patients with MTX-LPD and EBV-MCU in our department and at Tsuyama Chuo Hospital. The average age of patients was 75.1 ± 8.05 years (range 58–87 years) and the male-to-female ratio was 1:4, revealing a predominance of females. Eight patients were referred from general dentists (Case No. 1–6, 9, 10), one was referred from the general hospital dentist (Case No. 8), and one was referred from other departments in our hospital (Case No. 7). All patients were receiving immunosuppressive therapy with MTX for RA; one had an additional autoimmune disease of interstitial pneumonia (Case No. 6). The average period since the diagnosis of RA was 20.0 years (range 5–40 years), and the duration of MTX treatment was 12.7 years (range 5–30 years). Immunosuppressive agents used other than MTX were as follows: prednisolone (PSL) in five patients (Case No. 1, 3, 4, 8, 9), tacrolimus (TAC) in two patients (Case No. 5, 6), and bucillamine in one patient (Case No. 7). The primary site was the gingiva in all cases and the maxillary to mandibular ratio was 1:1 (maxillary: Case No. 2–5, 9; mandibular: Case No. 1, 6–8, 10). One patient had a lesion on the lung as well as the oral mucosa (Case No. 3). All patients were confirmed to be infected with EBV by blood test and histopathological examination. In all cases, partial biopsy under local anesthesia was performed to suspect malignancy. Immunohistochemistry staining showed CD20-positive atypical large lymphocytes in all cases; CD3, CD5, and CD10-positive lymphocytes were not detected in many cases. EBV-encoded small RNA in situ hybridization (EBER-ISH) showed positivity in all cases. Therefore, the histopathological diagnosis was diffuse large B-cell lymphoma with EBV infection in all cases. All patients achieved complete clinical remission with discontinued MTX, without chemotherapy or radiotherapy. Tacrolimus was initiated in two patients after withdrawal of MTX to prevent reactivation of RA (Case No. 1, 4). Below, we present two cases as typical examples.\n\n3.1. Case 1\n\nThe patient was a 75-year-old Japanese man who visited our department complaining of a painful right mandibular gingiva after first molar extraction. He had had RA for 40 years and had been treated with several immunosuppressive drugs, including MTX (8 mg/week for 20 years), PSL (5 mg/day for 10 years), and golimumab (50 mg/month for 3 years). The intraoral examination showed redness and ulceration of the right mandibular gingiva. There was exposure of necrotic bone in the extraction wound (Figure 1A). Head and neck computed tomography (CT) showed bone destruction from perilesional alveolar bone to the mandibular canal (Figure 1B), but no lymph node abnormality was detected. A blood examination revealed EBV infection [EBV viral capsid antigen (EBV-VCA) IgG = 320, IgM < 10, IgA < 10, EBV nuclear antigen (EBNA) = 20] and a high level of soluble interleukin-2 receptor (sIL-2R = 1224). Fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) indicated the presence of increased uptake in the right mandibular (maximum standardized uptake value: SUVmax = 11.9; Figure 1C) and the right superior internal jugular nodes (SUVmax = 3.78). The biopsy material showed diffuse proliferation of atypical lymphocytes in the subepithelium (Figure 1E). Immunohistochemistry staining showed that the atypical large-sized lymphocytes were positive for CD20 (Figure 1F) and negative for CD3, CD5, and CD10; the Ki-67 labeling index was high (Figure 1G). The result of EBER-ISH was positive (Figure 1H) and the histopathological diagnosis was EBV-MCU (Figure 1E–H).\n\nThe patient’s primary physician changed MTX to TAC. The lesion decreased and symptoms disappeared within two weeks. FDG-PET/CT at one year since the withdrawal of MTX showed no increased uptake anywhere. At 20 months after the withdrawal of MTX, the patient was in good condition without recurrence (Figure 1D).\n\n3.2. Case 5\n\nThe patient was a 73-year-old Japanese woman who visited our department desiring an examination for bone exposure of the left maxillary gingiva. She had RA for 11 years and had been treated with immunosuppressive drugs, including MTX (14 mg/week for 6 years) and TAC (1.5 mg/day for 1 year). The intraoral examination showed painless ulceration of the gingiva on the palatal side of the first molar with bone exposure (Figure 2A). CT showed cortical bone destruction around the lesion and exposure of the first molar palatal root (Figure 2B). Blood examination for sIL-2R and EBV infection were not performed. FDG-PET/CT indicated only the presence of increased uptake around the lesion (SUVmax = 11.9; Figure 2C). The biopsy material showed diffuse proliferation of lymphocytes with a background of inflammatory cell infiltration (Figure 2E); the lymphocytes were large and atypical (Figure 2F). Immunohistochemistry staining showed that the atypical large-sized lymphocytes were positive for CD20 (Figure 2G), 30, and negative for CD3. EBER-ISH was positive (Figure 2H). The histopathological diagnosis was MTX-LPD (in the current definition, EBV-MCU).\n\nThe patient’s primary physician discontinued MTX and the lesion gradually became epithelialized. FDG-PET/CT at seven months after the withdrawal of MTX showed no increased uptake anywhere. At six years after the withdrawal of MTX, the patient was in good condition (Figure 2D).\n\n4. Discussion\n\nAlthough EBV-MCU was newly registered as a subtype of mature B-cell neoplasm in the 2017 WHO classification, it was treated as MTX-LPD until then [7,11]. Lymphoproliferative is a descriptive term that sets this disease group apart from physiological lymphadenopathy and lymphocytosis. The WHO classifies lymphoproliferative disorders (LPD) according to etiology, i.e., LPD associated with primary immune disorders, lymphomas associated with HIV infection, post-transplant LP disorders, and other iatrogenic immunodeficiency-associated LP disorders, including MTX-LPD [7]. Previously, the last of the four classes was identified solely with MTX-LPD because MTX was thought to be the only causative drug for this disease. However, the category has been revised to a broader concept because it was found that immunosuppressive drugs other than MTX can also cause LPD [11,13].\n\nA previous study found that 40–50% of MTX-LPDs develop in extranodal sites, with lesion sites throughout the body, such as the gastrointestinal tract, skin, lung, and head and neck region, including the gingiva, tongue, and mouth floor [7]. EBV infection has been detected in about half of MTX-LPDs and many EBV-positive MTX-LPD cases have shown resolution or reduction of lesions with MTX withdrawal. The prognosis of the latter type of case is relatively good, while cases without response to drug withdrawal require chemotherapy and have poor outcomes [7,11,14].\n\nEBV is a virus belonging to the family of Herpesviridae. More than 90% of infections occur via saliva or sexual secretion in adulthood. Initial infection often occurs in infancy, however, these infections usually only cause mild symptoms, if any. In the case of initial infection after adolescence, infectious mononucleosis with fever, pharyngitis, and generalized lymphadenopathy develops. After initial infection, EBV continues to infect B-cells or epithelial cells of the nasopharynx, although the immune mechanism induces a latent infection state in which virus is not produced. However, in an immunosuppressive state caused by an autoimmune disease or the use of an immunosuppressive drug, reactivation of latent EBV-infected B-cells and subsequent proliferation of viral particles induces various diseases. Diseases caused by reactivation of EBV-infected B-cells include chronic active EBV infection and EBV-positive diffuse large B-cell lymphoma; EBV-MCU is also one of these pathological conditions [15,16].\n\nIn terms of research on EBV-MCU, Sinit reported that the most common risk factor for developing EBV-MCU was the use of immunosuppressive drugs, with MTX being the most commonly associated drug (46%), followed by azathioprine, mycophenolate, prednisone, rituximab, and cyclosporine A. The most common reason for immunosuppressive drug use was autoimmune disease (64%), followed by organ or stem-cell transplantation and hematologic malignancies. The most common scenario was an RA patient being treated with MTX (20% of cases). The sites of onset were the oral and oropharyngeal mucosa, gastrointestinal tract, and skin [12]. The high frequency of onset in the oral mucosa was attributed to the mode of EBV infection (lytic vs. latent infection) and the chronic irritation associated with colonization by anaerobic bacteria. During lytic infection, EBV easily colonizes oral mucosa. In this infection mode, the infected B-cells sequestered in the lymphoid tissues of Waldeyer’s ring, etc., are activated due to immunosuppression. After cell death, the lysed B-cells release infectious viral particles, and the mucosal epithelial cells of the oral cavity and ductal epithelial cells of the salivary gland become infected. In addition, the oral mucosa is often chronically irritated by dental caries, periodontal disease, inadequate crown-bridge restorations, dentures, occlusion, etc., leading to the occurrence of cell-level microtrauma. Due to these factors, EBV-MCU is thought to occur frequently in the oral mucosa [12,17,18]. We conjectured that EBV-MCU may be triggered by immunosuppression caused by MTX and that oral peculiarities may be strongly involved in the development of the disease. A disease with a similar pathogenic mechanism is Merkel cell carcinoma. Merkel cell carcinoma has been demonstrated to be triggered by iatrogenic immunosuppression due to the biologics employed in autoimmune diseases therapy, and Merkel cell polyomavirus is reactivated when certain conditions are combined [19]. Therefore, EBV-MCU does not occur in all patients using MTX. We suspect that risk factors such as the degree of infection of the mucosal epithelial cells of the oral cavity and ductal epithelial cells of the salivary gland, and the presence of chronic irritation of the oral mucosa, are strongly involved in the development of EBV-MCU.\n\nWhen MTX-LPD or EBV-MCU develop, treatment for autoimmune disease becomes difficult because immunosuppressive drugs need to be withdrawn or changed. In particular, after the withdrawal of MTX in RA patients, the majority of patients experience a reactivation of RA. The latest guidelines suggest the use of rituximab or tacrolimus for patients with RA reactivation [20]. Satou et al. reported that rituximab may be effective to prevent regrowth of EBV-MCU [21]. MTX was withdrawn in all 10 cases we experienced, and although RA worsened in some patients, it was controlled with rituximab or tacrolimus.\n\nThe 10 cases we experienced had the following characteristics. (1) All patients were being treated for RA with MTX. Immunosuppressive drugs used in combination with MTX included prednisolone. (2) EBV infection was positive in all cases by in situ hybridization and, in some cases, by blood test. (3) In all patients, withdrawal of immunosuppressive drugs without chemotherapy or surgery was selected. (4) Regarding prognosis, a complete or partial response was obtained in all cases without additional treatment. A total of three patients were diagnosed with MTX-LPD before the WHO approved the concept of EBV-MCU. However, we determined that all of the cases could be considered EBV-MCU. This is supported by the report of Yamakawa et al. that 42% of MTX-LPD patients and 13% of elderly LPD patients among all LPD patients are rediagnosed as having EBV-MCU [9]. We also previously reported that cases diagnosed as MTX-LPD in the oral mucosa were highly likely to be EBV-MCU because such cases had a higher rate of EBV infection, a lower rate of ectopic cases, and a better prognosis than MTX-LPD at other sites in the body [22]. Therefore, we considered that most of the LPDs with EBV infection that develop in the oral mucosa of patients using MTX are likely to be EBV-MCU. However, despite speculation that various factors are involved in the onset of LPD and that they interact in a complicated manner, few studies pursuing this possibility have been performed. It is a topic worthy of future research.\n\n5. Conclusions\n\nAll the patients we encountered were being treated for RA using MTX and were positive for EBV infection. In addition, all patients had a good prognosis with the withdrawal of immunosuppressive drugs. We consider that EBV-positive LPD in the oral mucosa of a patient using MTX is likely to be EBV-MCU.\n\nAuthor Contributions\n\nConceptualization, K.O. (Kyoichi Obata) and T.O.; data curation, K.O. (Kyoichi Obata), K.U., S.R., M.Y. and N.Y.; formal analysis, K.O. (Kyoichi Obata), S.O. and K.O. (Kisho Ono); funding acquisition, K.O. (Kyoichi Obata); supervision, T.O., S.I. and A.S.; writing-original draft, K.O. (Kyoichi Obata); writing-review and editing, K.O. (Kyoichi Obata), T.O. and S.I. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis work was partly supported by a Grant-in-Aid for Early-Career Scientists (JP20K18668 to Obata K.) from the Japan Society for the promotion of Sciences, Japan.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences (protocol No: 2108-002, 24 June 2021).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nAll supporting data are provided in the current manuscript.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAbbreviations\n\nCT\tcomputed tomography\t\nEBER-ISH\tEpstein-Barr virus-encoded small RNA in situ hybridization\t\nEBNA\tEpstein-Barr virus nuclear antigen\t\nEBV\tEpstein-Barr virus\t\nEBV-MCU\tEpstein-Barr virus-positive mucocutaneous ulcer\t\nEBV-VCA\tEpstein-Barr virus capsid antigen\t\nFDG-PET/CT\tfluorodeoxyglucose-positron emission tomography/computed tomography\t\nLPD\tlymphoproliferative disorders\t\nMTX\tmethotrexate\t\nMTX-LPD\tmethotrexate-associated lymphoproliferative disorders\t\nPSL\tprednisolone\t\nRA\trheumatoid arthritis\t\nsIL-2R\tsoluble interleukin-2 receptor\t\nSUVmax\tmaximum standardized uptake value\t\nTAC\ttacrolimus\t\n\nFigure 1 Case 1. (A) Pre-treatment intraoral photograph: necrotic bone was exposed in the right mandibular first molar extraction wound with redness and ulceration in the surrounding gingiva. (B) Coronal CT: bone destruction of the mandible. (C) Horizontal FDG-PET/CT: positive uptake around the lesion. (D) Post-treatment intraoral photograph: the wound where the necrotic bone was removed became epithelialized and the lesion completely disappeared. (E) Hematoxylin and eosin staining showing diffuse proliferation of atypical lymphocytes in the subepithelium. (F–H) Immunochemistry staining showing positivity for CD20 (F), a high Ki-67 labeling index (G), and positivity for EBER-ISH (H).\n\nFigure 2 Case 5. (A) Pre-treatment intraoral photograph (mirror image): a painless ulceration with bone exposure on the palatal side of the maxillary left first molar. (B) Coronal CT: cortical bone destruction on the palatal side. (C) Horizontal FDG-PET/CT: positive uptake around the lesion. (D) Post-treatment intraoral photograph (mirror image): The ulceration has disappeared and become epithelization. (E–H) Histopathological findings: Hematoxylin and eosin staining showed diffuse proliferation of atypical lymphocytes with a background of inflammatory cell infiltration (E); the lymphocytes were large with prominent nucleoli (F). These cells were positive for CD20 (G) and EBER-ISH (H).\n\ndiagnostics-11-01375-t001_Table 1 Table 1 Characteristics of patients and course with MTX-LPD or EBV-MCU occurring in the oral mucosa.\n\nNo\tAge\tSex\tAutoimmune Disease\tImmunosuppressive Therapy\t\nRA\tOther\tDuration\n(Year)\tMTX\tDose\n(mg/week)\tDuration\n(Year)\tOther\t\n1\t75\tM\t+\t-\t40\t+\t8\t>20\tPSL\t\n2\t80\tM\t+\t-\tN/A\t+\t6–8\t6\t-\t\n3\t58\tF\t+\t-\t10\t+\t2–4\t10\tPSL\t\n4\t67\tF\t+\t-\t28\t+\tN/A\t25\tPSL\t\n5\t73\tF\t+\t-\t11\t+\t14\t6\tTAC\t\n6\t74\tF\t+\tIP\t12\t+\t10\t11\tTAC\t\n7\t77\tF\t+\t-\t24\t+\t10\t11\tBUC\t\n8\t79\tF\t+\t-\t40\t+\t2.5\t30\tPSL\t\n9\t81\tF\t+\t-\t5\t+\t8\t5\tPSL\t\n10\t87\tF\t+\t-\t10\t+\t6\t10\t-\t\nPrimary\nSite\tMultiple\nSite\tEBV\nInfection\tImmunophenotype\tHistology\tTherapy\nand\nResponse\tFollow Up\nPeriod\n(Month)\t\nPositive\tNegative\t\nMandibular\ngingiva\t-\t+\tCD20\tCD3, 5\tDLBCL\tWM\n-> CR\t24\t\nMaxillary\ngingiva\t-\t+\tCD20\tN/A\tDLBCL\tWM\n-> CR\t92\t\nMaxillary\ngingiva\t+ (lung)\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t36\t\nMaxillary\ngingiva\t-\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t30\t\nMaxillary\ngingiva\t-\t+\tCD20, 30\tCD3\tDLBCL\tWM\n-> CR\t27\t\nMandibular\ngingiva\t-\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t20\t\nMandibular\ngingiva\t-\t+\tCD20, 79a\tCD3, 5\tDLBCL\tWM\n-> CR\t13\t\nMandibular\ngingiva\t-\t+\tCD20, 79a\tCD3, 5\tDLBCL\tWM\n-> CR\t7\t\nMaxillary\ngingiva\t-\t+\tCD20, 79a\tCD3, 5\tDLBCL\tWM\n-> CR\t31\t\nMandibular\ngingiva\t-\t+\tCD20\tCD3, 5, 10\tDLBCL\tWM\n-> CR\t12\t\nBUC = bucillamine, CR = complete remission, DLBCL = diffuse large B-cell lymphoma, EBV = Epstein-Barr virus, IP = interstitial pneumonia, MTX = methotrexate, PSL = prednisolone, RA = rheumatoid arthritis, TAC = tacrolimus, WM = withdrawal of MTX.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Pittaluga S. Jaffe E.S. EBV Positive Mucocutaneous Ulcer—A study of 26 cases associated with various sources of immunosuppression Am. J. Surg. Pathol. 2010 34 405 417 10.1097/PAS.0b013e3181cf8622 20154586\n11. Gaulard P. Swerdlow S.H. Harris N.L. Sundstrom C. Jaffe E. EBV-positive mucocutaneous ulcer World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues Swerdlow S.H. Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Harald S. Jurgen T. IARC Publications Lyon, France 2017 307 308\n12. Sinit R.B. Horan K.L. Dorer R.K. Aboulafia D.M. Epstein-Barr Virus–Positive Mucocutaneous Ulcer: Case Report and Review of the First 100 Published Cases Clin. Lymphoma Myeloma Leuk. 2019 19 e81 e92 10.1016/j.clml.2018.10.003 30442566\n13. Hasserjian R.P. Chen S. Perkins S.L. de Leval L. Kinney M.C. Barry T.S. Said J. Lim M.S. Finn W.G. Medeiros L.J. Immunomodulator agent-related lymphoproliferative disorders Mod. Pathol. 2009 22 1532 1540 10.1038/modpathol.2009.131 19767727\n14. Ichikawa A. Arakawa F. Kiyasu J. Sato K. Miyoshi H. Niino D. Kimura Y. Takeuchi M. Yoshida M. Ishibashi Y. Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: Histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression Eur. J. Haematol. 2013 91 20 28 10.1111/ejh.12116 23560463\n15. Kataoka Y. Matsue T. Katagiri H. Hashiba T. Hanzawa M. Tsunoda R. A case of Epstein-Barr virus-positive mucocutaneous ulcer arising in the lower gingiva Jpn. J. Oral Maxillofac. Surg. 2020 66 157 161 10.5794/jjoms.66.157\n16. Kim H.-J. Ko Y.H. Kim J.E. Lee S.-S. Lee H. Park G. Paik J.H. Cha H.J. Choi Y.-D. Han J.H. Epstein-barr virus-associated lymphoproliferative disorders: Review and update on 2016 WHO classification J. Pathol. Transl. Med. 2017 51 352 358 10.4132/jptm.2017.03.15 28592786\n17. Dugan J.P. Coleman C.B. Haverkos B. Opportunities to target the life cycle of Epstein-Barr Virus (EBV) in EBV-associated lymphoproliferative disorders Front. Oncol. 2019 9 127 10.3389/fonc.2019.00127 30931253\n18. McGinness J.L. Spicknall K.E. Mutasim D.F. Azathioprine-induced EBV-positive mucocutaneous ulcer J. Cutan. Pathol. 2012 39 377 381 10.1111/j.1600-0560.2011.01829.x 22236092\n19. Rotondo J.C. Bononi I. Puozzo A. Govoni M. Foschi V. Lanza G. Gafà R. Gaboriaud P. Touzé F.A. Selvatici R. Merkel cell carcinomas arising in autoimmune disease affected patients treated with biologic drugs including anti-TNF Clin. Cancer Res. 2017 23 3929 3934 10.1158/1078-0432.CCR-16-2899 28174236\n20. Fraenkel L. Bathon J.M. England B.R. Clair E.W.S. Arayssi T. Carandang K. Deane K.D. Genovese M. Huston K.K. Kerr G. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis Arthritis Rheumatol. 2021 73 1108 1123 10.1002/art.41752 34101376\n21. Satou A. Banno S. Hanamura I. Takahashi E. Takahara T. Nobata H. Katsuno T. Takami A. Ito Y. Ueda R. EBV-positive mucocutaneous ulcer arising in rheumatoid arthritis patients treated with methotrexate: Single center series of nine cases Pathol. Int. 2019 69 21 28 10.1111/pin.12745 30615240\n22. Obata K. Okui T. Kishimoto K. Ibaragi S. Sasaki A. Methotrexate-Associated Lymphoproliferative Disorder Developed Ectopically in the Maxillary Gingiva and Bilateral Lungs Case Rep. Med. 2020 2020 5 9 10.1155/2020/4814519 32411253\n\n", "fulltext_license": "CC BY", "issn_linking": "2075-4418", "issue": "11(8)", "journal": "Diagnostics (Basel, Switzerland)", "keywords": "Epstein-Barr virus; lymphoproliferative disorders; methotrexate; mucocutaneous ulcer; rheumatoid arthritis", "medline_ta": "Diagnostics (Basel)", "mesh_terms": null, "nlm_unique_id": "101658402", "other_id": null, "pages": null, "pmc": null, "pmid": "34441310", "pubdate": "2021-07-30", "publication_types": "D002363:Case Reports", "references": "20154586;30442566;24334644;19767727;30615240;34101376;30931253;22313647;15901903;24246254;1787499;21044440;28174236;23560463;32411253;22236092;30243154;28592786", "title": "Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review.", "title_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review" }

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Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics-(Basel) 2021;11(8):1-10.. 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220218", "receivedate": "20220218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20489087, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001457", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, ONCE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "20", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "801", "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GOLIMUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MILLIGRAM, ONCE A MONTH", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "801", "medicinalproduct": "GOLIMUMAB" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484227, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001456", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 TO 8 MG PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "6", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel).. 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220221", "receivedate": "20220221", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20494698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326913", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": "30", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001453", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, ONCE A WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "11", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484226, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326907", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "6", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K et al. Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review. Diagnostics. 2021;11(8):1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220324", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20509326, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326915", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "14 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "14", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucocutaneous ulceration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;Jul 30; 11(8):1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505009, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238052", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUCILLAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUCILLAMINE" } ], "patientagegroup": "6", "patientonsetage": "77", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811629, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-ACCORD-238053", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326906", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505012, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326919", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": "10", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppressant drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20504682, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238046", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CHANGED MTX TO TAC", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GOLIMUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GOLIMUMAB" } ], "patientagegroup": "6", "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N,IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19810572, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001455", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (FOR 25 YEARS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484220, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326912", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "25", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K et al. Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review. Diagnostics. 2021;11:1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20505010, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-MYLANLABS-2022M1012454", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "090596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics-(Basel) 2021;11(8):1-10.. 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220218", "receivedate": "20220218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20489085, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238050", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "14", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19810575, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001449", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6 MILLIGRAM PER WEEK (FOR 10 YEARS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "87", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484225, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-ACCORD-238051", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811631, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-STRIDES ARCOLAB LIMITED-2022SP001450", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM PER WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diffuse large B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al.. Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484221, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326910", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2-4 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucocutaneous ulceration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. Diagnostics (Basel). 2021;11(8):1375 (1-10)", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20509323, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "JP-ACCORD-238048", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "6?8 MG/WEEK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "6", "patientonsetage": "80", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19810573, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326914", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "8 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": "5", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mucocutaneous ulceration", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K, et al. Comparative Study on Epstein-Barr Virus-Positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review. 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Comparative study on epstein-barr virus-positive mucocutaneous ulcer and methotrexate-associated lymphoproliferative disorders developed in the oral mucosa: A case series of 10 patients and literature review.. Diagnostics-(Basel). 2021;11(8):1-10.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220217", "receivedate": "20220217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20484223, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-326917", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Rheumatoid arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "11", "drugtreatmentdurationunit": "801", "medicinalproduct": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Immunosuppression", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS" } ], "patientagegroup": null, "patientonsetage": "74", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Obata K, Okui T, Ono S, Umemori K, Ryumon S, Ono K et al. Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review. Diagnostics. 2021;11:1375", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220223", "receivedate": "20220223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 20504993, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "JP-ACCORD-238054", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "8", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": "6", "patientonsetage": "81", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphoproliferative disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Epstein Barr virus positive mucocutaneous ulcer", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OBATA K, OKUI T, ONO S, UMEMORI K, RYUMON S, ONO K, YAO M, YOSHIOKA N, IBARAGI S, SASAKI A. COMPARATIVE STUDY ON EPSTEIN?BARR VIRUS?POSITIVE?MUCOCUTANEOUS ULCER AND METHOTREXATE?ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS DEVELOPED IN THE ORAL MUCOSA: A CASE SERIES OF 10 PATIENTS AND LITERATURE REVIEW. DIAGNOSTICS (BASEL). 2021 JUL 30?11(8):1375.", "literaturereference_normalized": "comparative study on epstein barr virus positive mucocutaneous ulcer and methotrexate associated lymphoproliferative disorders developed in the oral mucosa a case series of 10 patients and literature review", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19811633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Transcatheter aortic valve implantation is a feasible therapeutic option for selected patients with severe aortic stenosis and high or prohibitive risk for standard surgery. Lung transplant recipients are often considered high-risk patients for heart surgery because of their specific transplant-associated characteristics and comorbidities. We report a case of successful transfemoral transcatheter aortic valve replacement in a lung transplant recipient with a symptomatic severe aortic stenosis, severe left ventricular dysfunction, and end-stage renal failure 9 years after bilateral lung transplantation.", "affiliations": "Department of Pulmonary Medicine, University Hospital and University of Bern, Bern, Switzerland; Academic Department of Sleep and Breathing, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom. Electronic address: [email protected].;Cardiology, Cardiovascular Department, University Hospital and University of Bern, Bern, Switzerland.;Service de Pneumologie et Centre Transplantation, University Hospital and University of Lausanne, Lausanne, Switzerland.;Cardiology, Cardiovascular Department, University Hospital and University of Bern, Bern, Switzerland.;Department of Pulmonary Medicine, University Hospital and University of Bern, Bern, Switzerland.", "authors": "Brill|Anne-Kathrin|AK|;Gloekler|Steffen|S|;Aubert|John-David|JD|;Wenaweser|Peter M|PM|;Geiser|Thomas|T|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4975", "issue": "97(6)", "journal": "The Annals of thoracic surgery", "keywords": null, "medline_ta": "Ann Thorac Surg", "mesh_terms": "D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D006328:Cardiac Catheterization; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "15030100R", "other_id": null, "pages": "e159-60", "pmc": null, "pmid": "24882332", "pubdate": "2014-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Transcatheter aortic valve implantation in a lung transplant recipient.", "title_normalized": "transcatheter aortic valve implantation in a lung transplant recipient" }

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TRANSCATHETER AORTIC VALVE IMPLANTATION IN A LUNG TRANSPLANT RECIPIENT. ANN-THORAC-SURG. 2014;97(6):E159-E160", "literaturereference_normalized": "transcatheter aortic valve implantation in a lung transplant recipient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20150404", "receivedate": "20150404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10985122, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "The viral infection causing COVID-19 most notably affects the respiratory system but can result in extrapulmonary clinical manifestations as well. Rhabdomyolysis-associated acute kidney injury (AKI) in the setting of COVID-19 is an uncommon complication of the infection. There is significant interest in this viral infection given its global spread, ease of transmission, and varied clinical manifestations and outcomes. This case report and literature review describes the symptoms, laboratory findings, and clinical course of a patient who developed AKI secondary to rhabdomyolysis and COVID-19, which will help clinicians recognize and treat this condition.", "affiliations": "Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.;Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.;Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.;Department of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA.", "authors": "Chetram|Vishaka K|VK|https://orcid.org/0000-0003-4375-389X;Ahmad|Akram I|AI|;Farid|Saira|S|;Sood|Tanuj|T|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2021/5528461", "fulltext": "\n==== Front\nCase Rep Nephrol\nCase Rep Nephrol\nCRIN\nCase Reports in Nephrology\n2090-6641\n2090-665X\nHindawi\n\n34367704\n10.1155/2021/5528461\nCase Report\nAcute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review\nhttps://orcid.org/0000-0003-4375-389X\nChetram Vishaka K. [email protected]\n\nAhmad Akram I.\nFarid Saira\nSood Tanuj\nDepartment of Internal Medicine, Washington Hospital Center, Washington, DC 20010, USA\nAcademic Editor: Bernard G Jaar\n\n2021\n2 8 2021\n2021 552846128 2 2021\n26 7 2021\nCopyright © 2021 Vishaka K. Chetram et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nThe viral infection causing COVID-19 most notably affects the respiratory system but can result in extrapulmonary clinical manifestations as well. Rhabdomyolysis-associated acute kidney injury (AKI) in the setting of COVID-19 is an uncommon complication of the infection. There is significant interest in this viral infection given its global spread, ease of transmission, and varied clinical manifestations and outcomes. This case report and literature review describes the symptoms, laboratory findings, and clinical course of a patient who developed AKI secondary to rhabdomyolysis and COVID-19, which will help clinicians recognize and treat this condition.\n\nMedStar Health\n==== Body\n1. Introduction\n\nThe novel coronavirus which emerged in late 2019, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and responsible for COVID-19, has infected more than 85 million people worldwide and has grown into a global pandemic. The incubation period, disease severity, initial presentation, and laboratory findings are varied [1–4]. Multiorgan complications include respiratory failure, cardiac arrhythmias, cardiomyopathy, encephalopathy, thromboembolic events, and acute kidney injury (AKI) [5–7].\n\nKidney involvement in the setting of COVID-19 manifests as hematuria, proteinuria, and/or an AKI, which is associated with increased mortality and more severe infections [8, 9]. Estimates of the incidence of AKI range from 17% to 37% and between 5–15% require kidney replacement therapy [8, 10]. The etiology of kidney dysfunction remains unexplored and may be the result of direct viral infection, cytokine release, altered hemodynamics, or multifactorial, including rhabdomyolysis. Characterized as a clinical syndrome of muscle weakness, myalgia, tea-coloured urine, and muscle swelling, rhabdomyolysis is defined with a creatine kinase value greater than 1000 IU/L or higher than 5 times the upper limit of normal [11]. Rhabdomyolysis occurs due to trauma, drugs, electrolyte abnormalities, and also rarely, viral infections such as influenza A and B, coxsackievirus, Epstein–Barr, herpes simplex, parainfluenza, adenovirus, echovirus, HIV, cytomegalovirus, and most recently, COVID-19 [12, 13]. Thus, our aim in this case report is to present the symptoms, laboratory findings, and clinical course of a patient who presented with AKI secondary to rhabdomyolysis and COVID-19 and provide a literature review of the reported cases.\n\n2. Case Report\n\nA 62 year-old-African American male patient presented to the emergency department with a 3-day history of general feeling of malaise, poor appetite, decreased urine output, and blood in his urine. His comorbidities include hypertension, morbid obesity (BMI of 39.6), and suboptimally controlled type II diabetes. He was socially distancing alone at home and reported no known sick contacts. He denied taking any anticoagulation medication and had no symptoms of urinary urgency or dysuria. He also denied recent strenuous activity, alcohol ingestion, or taking any over-the-counter supplements. Home medications included aspirin 81 mg, glargine 25 units daily, hydrochlorothiazide-lisinopril 12.5mg–20 mg daily, pioglitazone 30 mg, and simvastatin 20 mg daily.\n\nOn presentation, he was febrile to 38.1°C with a heart rate of 103, respiratory rate of 20, blood pressure of 91/58 mmHg, and saturating well on room air. Physical examination yielded a patient with a large body habitus and mild respiratory distress. Pertinent initial laboratory findings revealed a sodium of 132 mmol/L, potassium 4.5 mmol/L, magnesium 2.0 mg/dL, phosphorus 8.9 mg/dL, corrected calcium 4.4 mg/dL, BUN 54 mg/dL, creatinine 4.90 mg/dL (baseline of 1.1 mg/dL), glucose 372 mg/dL, aspartate aminotransferase (AST) 1077 units/L (baseline of 16 units/L), alanine aminotransferase (ALT) of 158 units/L (baseline of 24 units/L), alkaline phosphatase 45 units/L, total bilirubin 0.4 mg/dL, glomerular filtration rate (GFR) 14 mL/min, and lactic acid of 2.1 mmol/L. Urine albumin-to-creatinine ratio one month prior to presentation was 30 mg/g. Creatinine kinase was 327, 629 units/L, and peaked on presentation. Hemoglobin A1C glycosylated was 12.9%. D-dimer was 2.01 mcg/mL FEU. Arterial blood gas showed a pH of 7.35, CO2 of 31 mmHg, and bicarbonate of 17.1 mmol/L. C-reactive protein (CRP) was 136.39 mg/L, and thyroid-stimulating hormone (TSH) was 1.397 uIU/mL. Hepatitis viral panel was obtained and negative. Urine toxicology was negative. Urine analysis showed a moderate amount of blood and 19/hpf red blood cells. The progression of creatinine and creatinine kinase is depicted in Figure 1, respectively.\n\nPoint-of-care ultrasound of the bladder showed <100 mL of urine. Ultrasound of the abdomen showed hepatomegaly with fatty infiltration and no acute cholecystitis or choledocholithiasis, as well as no hydronephrosis. The initial chest radiograph was significant for multifocal patchy airspace disease suggestive of atypical pneumonia or viral infection including COVID-19 (Figure 2).\n\nInitial COVID-19 RNA PCR was negative. Respiratory viral panel for influenza and respiratory syncytial virus (RSV) was also negative. He was given a bolus of 2 L lactated ringer (LR) and started on maintenance LR at 200 mL/hour as well as sevelamer 2400 mg three times a day. For the first 48 hours, he was anuric. He also received ceftriaxone and azithromycin for community-acquired pneumonia coverage. His anion gap and metabolic acidosis resolved shortly after administration of IV fluids. Following the first 48 hours, his urine output increased to 600 mL over 24 hours on the third day and was red tinged. Urine output decreased to 210 mL and 150 mL per 24 hours on hospitalization days four and five, respectively. On the third day of his hospitalization, given the elevated D-dimer and concerning chest radiograph findings, COVID-19 PCR was repeated and found to be positive.\n\nDespite his positive test, the patient did not have respiratory symptoms and continued to oxygenate well on room air. On day 3, continuous renal replacement therapy (CRRT) was initiated due to persistent low urine output, worsening kidney indices, and volume overload. He received 3 consecutive days of CRRT while maintenance fluids were continued at 100 mL per hour. His urine output gradually increased, and CRRT was interrupted. By day 5, his creatine kinase downtrended to 57, 074 units/L with improved serum creatinine to 5.46 mg/dL. At the end of the first week of his hospitalization, his urine appeared clear and total 24-hour output was 700 mL. Given his improvement in urine output and downward trend in creatinine, CRRT was stopped.\n\nOn day 8 of his hospitalization, his oxygen levels desaturated to 87% while walking to the bathroom and he was placed on 2 L supplemental oxygen via a nasal cannula. Maintenance fluids were also discontinued at this time, and he developed a fever to 38.1°C. Chest X-ray showed worsening bilateral infiltrates (Figure 3).\n\nAt this point in his clinical course, his blood pressures remained elevated, ranging from 170/80 to 200/90, and antihypertensive medication doses were progressively increased up to amlodipine 10 mg daily and hydralazine 100 mg thrice a day. On day 12, the patient went into acute hypoxic respiratory failure, developed tachycardia with a heart rate of 120s beats per minute and tachypnea with a respiratory rate of 30. An arterial blood gas (ABG) was obtained which showed a pH of 7.41, CO2 29 mmHg, bicarbonate 18.4 mmol/L, and PaO2 of 82 mmHg. He was placed on BiPAP at 60% FiO2, broad-spectrum antibiotics for pneumonia coverage, and heparin drip for suspected pulmonary embolism and was transferred to the intensive care unit (ICU).\n\nIn the ICU, he was started on a 10-day course of dexamethasone and weaned to a high-flow nasal cannula after 2 days. Remdesevir was never given due to kidney dysfunction. He was also intermittently treated with diuretics. By day 14 of his hospitalization, his daily urine output was 2.9 L and clear in color. He received an echocardiogram which showed an ejection fraction of 65–70% with no valvular or diastolic dysfunction. Ultrasound of the lower extremities was negative for deep vein thrombosis. As his respiratory status improved, he was weaned to 6 L supplemental oxygen via a nasal cannula and was transferred out of the ICU. The patient gradually improved as he completed the 10-day course of dexamethasone, and at the time of discharge, 26 days after his presentation, his creatinine gradually decreased to 1.16 mg/dL and he was sent home, on room air.\n\n3. Discussion\n\nCOVID-19-related kidney dysfunction occurs in a number of ways [14] and can manifest as (1) prerenal AKI from volume depletion or cardiorenal syndrome, (2) acute tubular injury in the setting of circulatory collapse, (3) thrombotic microangiopathy secondary to hypercoagulation, (4) collapsing glomerulopathy in APOL1 gene variants, and (5) myoglobin cast nephropathy due to rhabdomyolysis. Emerging literature has connected COVID-19 to the development of rhabdomyolysis and acute kidney injury, but only few cases have been reported (Table 1) and the physiology link remains unknown.\n\nThe proposed hypotheses include direct invasion of muscle tissue, release of toxic cytokines, namely, TNF-alpha, and destruction of muscle cell membranes by circulating toxins [25]. Approximately 5% of hospitalized COVID-19 patients develop an AKI [26], and up to 40% of those are admitted to the ICU [27]. Studies have indicated that the development of stage II or III AKI incurs a poor prognosis with mortality rates as high as 70% in those requiring kidney replacement therapy [26, 28, 29]. The patient in this case report developed stage III AKI secondary to his rhabdomyolysis which was the presenting symptom of COVID-19. Although he required kidney replacement therapy, he fortunately obtained complete recovery despite a prolonged hospital course and also requiring ICU level of care.\n\nRhabdomyolysis has been described as a late complication of COVID-19 [30], but in our case, it was the presenting clinical manifestation even before respiratory symptoms developed and in light of a negative initial COVID-19 test. Of the reported cases, the classic triad of weakness, myalgia, and tea-coloured urine was not seen in any patients and only 7 of 16 reported one symptom, most commonly myalgia. In this case report, the patient presented with tea-coloured urine, decreased urine output, and general malaise and weakness. Myalgia is a common complaint of viral infections, including influenza. Thus, in patients presenting with myalgia and respiratory symptoms or high suspicion of COVID-19, we recommend evaluating serum creatine kinase and serum creatinine and closely monitoring urine output. The development of rhabdomyolysis and AKI does not appear to have a predilection in patients with certain comorbidities or age. Additionally, it appears that peak creatinine kinase is not associated with in-hospital mortality. In this case, peak creatine kinase was 327, 629 units/L, the second highest of the reported cases, and the patient recovered completely. This contrasts with the cases reported by Singh et al. where peak creatinine kinase was less than <10,000 units/L and patients died during their hospitalization.\n\nThe favourable outcome of our patient may be linked to early identification and IV fluid therapy.\n\nRegarding management of rhabdomyolysis, the mainstay continues to be correction of intravascular volume depletion and prevention of intratubular cast formation with fluid resuscitation. The initial recommended rate is 1 L/hour followed by 500 mL/hour thereafter with either isotonic saline or lactate ringers, although there is no strong evidence supporting either of these IV fluid formulations [31]. The goal of therapy is increased urine output; however, clinicians should be cognizant of volume overload in the setting of oliguria [32]. Additionally, electrolyte abnormalities such as hyperkalemia, hyperphosphatemia, and hypercalcemia or hypocalcaemia should be monitored closely and addressed quickly. Further evidence is needed on target therapies to prevent rhabdomyolysis-associated AKI [33].\n\nA potential limitation to this report is that the patient was taking 20 mg simvastatin as a home medication, a notable cause of myopathy and rhabdomyolysis. Statin-induced rhabdomyolysis is rare and occurs in <0.1% of cases [34]. Furthermore, in larger, follow-up studies, rhabdomyolysis-associated acute kidney failure only developed when statins were used in combination with cyclosporine, gemfibrozil, protease inhibitors, niacin, digoxin, and some antimicrobials [35], none of which this patient was taking at the time. Lastly, although myopathy can occur at any time during treatment with a statin, the onset of symptoms is usually within months of initiation of therapy. Approximately 2/3 of patients experience myopathy in the first six months of starting therapy [36], and the patient in this case report had been on statin therapy for eighteen months without changes in dose. Pioglitazone has been associated with rhabdomyolysis [37], although it appears to be at higher doses (75 mg/day) and rare. Risk factors for thiazolidinedione-induced rhabdomyolysis include concomitant therapy with fibrate, alcohol abuse, and asymptomatic mild creatinine phosphokinase elevation prior to initiating therapy. The patient in this report was on a lower dose of pioglitazone (30 mg/day) and had no further additional risk factors. Other causes of rhabdomyolysis were excluded with thyroid function tests and urine toxicology.\n\nIn summary, this is a unique presentation and complication of COVID-19 in a patient who initially tested negative for the virus. This case was unique in that the patient had a favourable prognosis and although being being admitted to the ICU, recovered completely. Most described cases presented with respiratory symptoms or were diagnosed with COVID-19 and were subsequently found to have rhabdomyolysis and kidney dysfunction, unlike the case in this report. This case report also details the clinical presentation, hospital course, and treatment which adds to the existing literature on the phenomenon. It is imperative for clinicians to be aware of the potential for COVID-19 patients to develop rhabdomyolysis, initiate early treatment, and minimize the kidney dysfunction.\n\nAcknowledgments\n\nThis work was funded by MedStar Health.\n\nConsent\n\nWritten informed consent was obtained prior to the preparation of this manuscript.\n\nDisclosure\n\nThe funder was not involved in the manuscript writing, editing, approval, or decision to publish.\n\nConflicts of Interest\n\nThe authors have no conflicts of interest to declare.\n\nFigure 1 Trend of creatinine kinase and creatinine.\n\nFigure 2 Chest X-ray showing multifocal patchy airspace disease, COVID-19.\n\nFigure 3 Chest X-ray on day 14 showing worsening bilateral infiltrates.\n\nTable 1 Summary of the reported cases.\n\n \tDemographics\tClinical Presentation\tComorbidities\tPertinent labs\tClinical course and outcome\t\nTaxbro et al. [15]\t38-year-old male\t1 week of fever, myalgia, nausea, emesis, dry cough, dyspnea, and abdominal pain\tType 2 diabetes\nGout\tCRP: 145 mg/dL\nCreatinine: 51 mmol/L\nD-dimer: 0.19 mg/dL\nNo reported CK\tComplete recovery after ICU admission requiring intubation\nLOS: 23 days\t\nValente-Acosta et al. [16]\t71-year-old male\t1 week of dry coughing, mild dyspnoea and fever, and myalgia and arthralgia, predominantly in his legs\tBenign prostatic hyperplasia\tCRP: 2.9 mg/dL\nCreatinine: 1.68 mg/dL\nLDH: 541 U/L\nD-dimer: 983 ng/mL\nCK peak: 8,720 U/L\tComplete recovery after ICU admission requiring intubation\nLOS: 16 days\t\nSingh et al. [17]\t34-year-old male\tFever, cough, dyspnea, and weakness\tPrediabetes\t—\nCreatinine 0.89 mg\\dl\n—\n—\nCK peak: 5,454 U/L\tDied in hospital\nLOS: not reported\t\n71-year-old male\tFever, cough, and dyspnea\tHypertension\nSchizophrenia\nSeizures\t—\nCreatinine: 4.1 mg/dL\n—\n—\nCK peak: 10,247 U/L\tDied in hospital\nLOS: not reported\t\n88-year-old male\tConfusion\tDiabetes\nHypertension\t—\nCreatinine: 2.25 mg/dL\n—\n—\nCK peak: 2,628 U/L\tDied in hospital\nLOS: not reported\t\n36-year-old male\tFever, cough, and dyspnea\tNone\t—\nCreatinine: 1.03 mg/dL\n—\n—\nCK peak: 5,531 U\\L\tDied in hospital\nLOS: not reported\t\n39-year-old male\tMyalgias, fever, cough, and dyspnea\tHypertension\t—\nCreatinine: 3.8 mg/dL\n—\n—\nCK peak: 4,330 U/L\tDied in hospital\nLOS: not reported\t\n\t\nHusain et al. [18]\t38-year-old male\tSever, cough, dyspnea, and myalgia\tNot reported\tCRP: 98.3 mg/dL\nCreatinine: 1.5 mg/dL\nLDH: 398 U/L\n—\nCK peak: 33,000 U/L\tComplete recovery after ICU admission\nLOS: 3 months\t\nChedid et al. [19]\t51-year-old male\t2 days of diffuse myalgias, dry cough, and mild chills\tHypertension\nType 2 diabetes OSA\nCKD II\tCRP: 98.3 mg/dL\nCreatinine: 2.48 mg/dL\nLDH: 2150 U/L\n—\nCK peak: 464,000 U/L\tDialysis as outpatient\nLOS: not reported\t\nSingh et al. [20]\t67-year-old male\tFever and dyspnea\tHypertension\t—\nCreatinine: 1.16 mg/dL\nLDH: 459 U/L\nD-dimer: 0.62 ng/mL\nCK peak: 19,773 U/L\tDied in hospital\nLOS: 21 days\t\n39-year-old male\tFever, myalgia, dyspnea, and altered mental status\tHypertension\tCRP: 98.3 mg/dL\nCreatinine: 3.8 mg/dL\nLDH: 907 U/L\nD-dimer: 1.92 ng/mL\nCK: 4,330 U/L\tDied in hospital\nLOS: 1 day\t\n\t\nAlejandro et al. [21]\t89-year-old male\tDyspnea, fever, cough, and malaise\tHypertension, coronary artery disease, and heart failure with preserved ejection fraction\tCreatinine: 2.0 mg/dL\nLDH: 805 U/L\n—\nCK: 2,751 U/L\tComplete recovery\nLOS: 12 days\t\nPellegrini et al. [22]\t34-year-old male\t2 days of emesis, sore throat, nonproductive cough, and dyspnea\tNot reported\tCRP: 3.3 mg/dL\nCreatinine: 1.4 mg/dL\nLDH: 854 U/L\n—\nCK: 73,922 U/L\tComplete recovery\nLOS: 8 days\t\nChong and Saha [23]\t37-year-old male\t2 days of dyspnea and fatigue\tNot reported\t—\nCreatinine: 5.0 mg/dL\n—\n—\nCK peak: 35,000 U/L\tDied in hospital\nLOS: 12 day\t\nChan et al. [24]\t75-year-old female\t4 days of weakness and decrease in appetite\tCoronary artery disease, hypertension, and GERD\t—\nCreatinine: 1.2 mg/dL\n—\n—\nCK: 2,767 U/L\tComplete recovery\nLOS: not reported\t\n71-year-old male\tGeneralized weakness and leg twitching\tHypertension, seizure, CKD, and overactive bladder\t—\nCreatinine: 5.6 mg/dL\n—\n—\nCK: 1,859 U/L\tHospitalized as inpatient\nLOS: undetermined\t\n\t\nChetram et al., 2021 (this manuscript)\t62-year-old male\t3-day history of general feeling of malaise, poor appetite, decreased urine output, and blood in his urine\tHypertension, type II diabetes, obesity\tCRP: 136.39 mg/L\nCreatinine: 4.9 mg/dL\n—\nD-dimer: 2.01 mcg/dL\nCK peak: 327,629 U/L\tComplete recovery\nLOS: 26 days\n==== Refs\n1 Wu Z. McGoogan J. M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China JAMA 2020 323 13 p. 1239 10.1001/jama.2020.2648\n2 Zhou F. Yu T. Du R. 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Pioglitazone-induced acute rhabdomyolysis Diabetes Care 2009 32 7 p. e84 10.2337/dc09-0593 2-s2.0-67650070836\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-665X", "issue": "2021()", "journal": "Case reports in nephrology", "keywords": null, "medline_ta": "Case Rep Nephrol", "mesh_terms": null, "nlm_unique_id": "101598418", "other_id": null, "pages": "5528461", "pmc": null, "pmid": "34367704", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "19564463;8729203;19328397;33125416;33005556;25043142;32878841;30644084;15572716;33824868;33308501;32416116;33022818;32587121;32690987;32555134;32091533;32414522;32671722;32031570;33059350;32109013;32320003;32171076;16344427;27301374;30617905;32247631;32775814;33016619;12622602;32771219;33252915;32197060", "title": "Acute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review.", "title_normalized": "acute kidney injury secondary to rhabdomyolysis and covid 19 a case report and literature review" }

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"activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZITHROMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": 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"Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "011", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXYGEN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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Acute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review. 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"drugauthorizationnumb": "077210", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "30 MILLIGRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "Type 2 diabetes mellitus", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "30", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIOGLITAZONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "76052", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM DAILY; FOR LAST 18 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "087668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COVID-19", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": "10", "drugtreatmentdurationunit": "804", "medicinalproduct": "DEXAMETHASONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", 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"drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN GLARGINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE\\LISINOPRIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE\\LISINOPRIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDRALAZINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "THRICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Hypertension", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDRALAZINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HEPARIN SODIUM" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Drug therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HEPARIN" } ], "patientagegroup": "5", "patientonsetage": "62", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute respiratory failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metabolic acidosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Chetram VK, Ahmad AI, Farid S, Sood T. Acute Kidney Injury Secondary to Rhabdomyolysis and COVID-19: A Case Report and Literature Review. Case-Rep-Nephrol 2021;:.", "literaturereference_normalized": "acute kidney injury secondary to rhabdomyolysis and covid 19 a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211122", "receivedate": "20211111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20059490, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20220304" } ]

{ "abstract": "Pulmonary infiltrates in immunosuppressed patients are common. Yields from bronchoscopy with bronchoalveolar lavage (BAL) has been reported to be between 31 and 65%. The clinical impact of pneumocystis and viral Polymerase chain reaction (PCR) testing on BAL has not been extensively evaluated in a mixed immunosuppressed patient population.\n\n\n\nWe performed a retrospective chart review of immunosuppressed adults with pulmonary infiltrates who underwent BAL at the University of Rochester Medical Center. Only one BAL per patient was included. We compared the rate of positive PCR testing to conventional testing. We then investigated factors associated with positive PCR testing. Finally, we assessed for changes in antimicrobial therapy after bronchoscopy.\n\n\n\nThree hundred and fifty-nine patients underwent BAL with 249 patients having pneumocystis PCR testing and 142 having viral PCR testing. Pneumocystis identification occurred in 43 patients and viral species identification occurred in 56 patients. PCR testing increased pneumocystis identification compared to microscopy, 14% vs. 5%, p = 0.01, and viral identification compared to culture, 25% vs. 6%, p = 0.0001. Of the patients with positive pneumocystis PCR testing 49% had antibiotics stopped, 66% were started on anti-pneumocystis therapy, and only 6% did not receive treatment. There was no difference in the number of patients with antibiotics stopped based on viral PCR testing results.\n\n\n\nPCR testing increases BAL yield in immunosuppressed patients compared to conventional testing. Pneumocystis identified by PCR only may cause a self-limited infection and may not require antimicrobial therapy. PCR testing should be included in the evaluation of pulmonary infiltrates in immunosuppressed patients.", "affiliations": "Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA. Electronic address: [email protected].;Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.;Wegmans School of Nursing, St. John Fisher College, Rochester, NY, USA.;Department of Microbiology and Immunology, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.;Division of Transplant Infectious Disease, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA; Division of Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.;Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center/Strong Memorial Hospital, Rochester, NY, USA.", "authors": "Lachant|Daniel J|DJ|;Croft|Daniel P|DP|;McGrane Minton|Heather|H|;Hardy|Dwight J|DJ|;Prasad|Paritosh|P|;Kottmann|R Matthew|RM|", "chemical_list": "D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000998:Antiviral Agents", "country": "England", "delete": false, "doi": "10.1016/j.rmed.2018.10.021", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-6111", "issue": "145()", "journal": "Respiratory medicine", "keywords": "BAL; Immunosuppressed; PCR; Pneumocystis; Viral", "medline_ta": "Respir Med", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000998:Antiviral Agents; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008875:Middle Aged; D011010:Pneumocystis; D016720:Pneumocystis Infections; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "8908438", "other_id": null, "pages": "35-40", "pmc": null, "pmid": "30509714", "pubdate": "2018-12", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "20837876;23509331;8610948;10524989;15135373;23990137;22814461;9508424;9383232;2817582;12114367;16061360;14769756;8265840;22491773;16652305;17803871;28382762;18576286;15819805;23922610;25009050;25062720;25122864;15752442;15072757;19265086;9154883;26378282;18024536;25448310;15190141;19684637", "title": "The clinical impact of pneumocystis and viral PCR testing on bronchoalveolar lavage in immunosuppressed patients.", "title_normalized": "the clinical impact of pneumocystis and viral pcr testing on bronchoalveolar lavage in immunosuppressed patients" }

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{ "abstract": "The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.", "affiliations": "Department of Neurosurgery, Shunan Memorial Hospital.", "authors": "Anda|Takeo|T|;Honda|Masaru|M|;Ishihara|Tokuhiro|T|;Kamei|Toshiaki|T|", "chemical_list": "D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D009570:Nitriles; D011974:Receptors, LH; D014105:Tosyl Compounds; D007987:Gonadotropin-Releasing Hormone; C053541:bicalutamide; D016729:Leuprolide", "country": "Japan", "delete": false, "doi": "10.2176/nmc.cr2012-0417", "fulltext": "\n==== Front\nNeurol Med Chir (Tokyo)Neurol. Med. Chir. (Tokyo)NMCNeurologia medico-chirurgica0470-81051349-8029The Japan Neurosurgical Society 2420110010.2176/nmc.cr2012-0417nmc-54-327Case ReportProgression of Intracranial Meningioma during Luteinizing Hormone-Releasing Hormone Agonist Treatment for Prostate Cancer: Case Report ANDA Takeo 1HONDA Masaru 1ISHIHARA Tokuhiro 2KAMEI Toshiaki 31 Department of Neurosurgery, Shunan Memorial Hospital, Kudamatsu, Yamaguchi;2 Department of Pathology, Tokuyama Medical Association Hospital, Shunan, Yamaguchi;3 Department of Pathology, Yamaguchi Grand Medical Center, Hofu, YamaguchiAddress reprint requests to: Takeo Anda, MD, Department of Neurosurgery, Shunan Memorial Hospital, 1-10-1 Ikunoyaminami, Kudamatsu, Yamaguchi 744-0033, Japan. e-mail: [email protected] of Interest Disclosure\n\nNone. Two authors who are the members of Japan Neuro-surgical Society have already submitted the conflict of interest self-declaration to the society.\n\n4 2014 8 11 2013 54 4 327 330 6 12 2012 6 2 2013 © 2014 The Japan Neurosurgical Society2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/The authors describe a male patient who developed a large intracranial meningioma during the hormone therapy for pre-existing prostate cancer. A 70-year-old man received a brain check-up, and no intracranial abnormality was detected. Five months later, prostate cancer was diagnosed, and he underwent prostatectomy. Leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist, was subsequently administered to the patient once a month for 3 years. After that he presented with a large parasagittal mass, which was excised. The tumor was histologically diagnosed as meningothelial meningioma, and LH-RH receptors were verified immunohistochemically in the cytoplasm of the tumor cells. Leuprorelin acetate may accelerate the rapid growth of meningioma in this patient.\n\nmeningiomaluteinizing hormone-releasing hormone receptorleuprorelin acetateprostate cancer\n==== Body\nIntroduction\nSome sex hormone receptors have been verified in meningioma cells, and several hormones have been reported to affect the growth of meningioma. In this report, the authors present a patient with meningioma whose tumor growth could have been related to a luteinizing hormone-releasing hormone (LH-RH) agonist administration.\n\nCase Report\nI. History\nA 70-year-old man underwent gastrectomy for early stage gastric cancer, and remained well after that for 7 years. He received a brain check-up at another hospital in November 2007, and no intracranial abnormalities were detected (Fig. 1). In April 2008, early stage prostate cancer (T1C, N0, M0) was detected. Prostatectomy was performed, and leuprorelin acetate and bicalutamide were administered prophylactically to the patient. Monthly treatment was then maintained. In December 2010, he suffered from headache and a brain magnetic resonance imaging (MRI) at another hospital demonstrated an intracranial mass lesion. He was referred to our hospital on January 31, 2011.\n\nII. Examination\nNo neurological deficits were observed. Brain MRI revealed a large extraaxial parasagittal mass near the bregma which compressed bilateral frontal lobes and extended into the falx and skull. It showed iso-intense on T1-weighted images (WI) and high-intense on T2WI, and was homogeneously enhanced after intravenous injection of contrast materials. The diameter of the tumor reached 5 cm (Fig. 2). Hyperostosis of the skull near the mass was identified by skull X-ray. Many feeding arteries originating from bilateral pial arteries and branches of external carotid arteries were recognized on cerebral angiogram. The superior sagittal sinus (SSS) was segmentally occluded near the bregma. Prostate-specific antigen (PSA) was 0 ng/ml, carcinoembryonic antigen (CEA) was 1.8 ng/ml, and Ca19-9 was 9.7 U/ml. The tumor was regarded as a parasagittal meningioma invading the falx, SSS, and skull. An operation was performed on March 14, 2011.\n\nIII. Operation\nUnder general anesthesia, the medial frontoparietal bone was removed in a divided manner. At the same time, a part of the tumor which invaded the skull was also removed. Then, the dura around the tumor was cut, and the border between the tumor and its dural attachment was separated, and the tumor surface was dissected from the brain while interrupting the pial supply. The tumor was pinkish and fragile and tended to bleed. Internal decompression was suitably done, and the tumor was removed in a piecemeal manner. Almost all the tumor attachment, affected falx, and SSS were removed. A part of the attachment near the intact cortical bridging vein was left as it was coagulated. The extent of tumor removal was judged as Simpson grade 2. Dural plasty using Goatex, and cranioplasty using a titanium plate were performed. The tumor was histopathologically proved to be a meningothelial meningioma without atypical or anaplastic features. The molecular immunology borstel-1 (MIB-1) staining index was 5% or less. Cytoplasmic immunoreactivity for the luteinizing hormone-releasing hormone (LH-RH) receptor was detected (Fig. 3). The used primary antibody was mouse monoclonal anti-LH-RH receptor antibody (Thermo, Fremont, California, USA).\n\nIV. Postoperative course\nThere were no perioperative events, and no neurological deficits were recognized. Administration of leuprorelin acetate was ceased. On July 11, 2012, sixteen months after the operation, brain MRI demonstrated no tumor recurrence (Fig. 4).\n\nDiscussion\nThis patient's intracranial tumor was histologically diagnosed as meningothelial meningioma and it showed no evidence of malignant features. It is very rare for a small benign meningioma not detected by MRI to grow into a large mass 5 cm in diameter, and invade the falx and SSS and skull in the course of less than 3 years. Because bony and dural sinus invasion by meningioma is reportedly not related to its biological malignancy,1–3) the rapid tumor progression in such a short time in this patient is not consistent with typical benign meningiomas. The authors suspect that maintenance of hormone treatment for prostate cancer led to rapid growth of the meningioma.\n\nThere are many reports referring to sex steroid hormone receptors in meningiomas. Meningioma occurs in females twice as frequently as in males. Progesterone receptors were found in 83% of meningiomas,4) and discontinuation of a progesterone agonist induced regression of meningioma.5) Antiprogestational therapy showed efficacy for unresectable meningioma.6)\n\n\nReceptors of gonadotropin-releasing hormone, namely LH-RH were identified immunohistochemically in the cytoplasm of 95.1% of meningiomas resected.7) Another report demonstrated that LH-RH increased proliferation of meningioma cells in vitro.8)\n\n\nLeuprorelin acetate, an LH-RH agonist, exhibits antiandrogenic effect if administered to males, so it is often used for patients with prostate cancer. The authors found a few reports referring to leuprorelin acetate administered and a meningioma developing in patients with prostate cancer. Fallanca et al. reported two cases. A 70-year-old man had undergone hormonal therapy with leuprorelin (7.5 mg/month) and bicalutamide (150 mg/day) for 3 years after radical prostatectomy and radiotherapy for prostate cancer. Subsequently, abnormal tracer uptake in the lumboaortic lymph nodes and lumbosacral vertebral body and the posterior cranial fossa were found by a (11C) choline positron emission tomography/computed tomography (PET/CT) scan. The lesions in the skeletal bone and lymph nodes were thought to be metastasis, but the latest was highly suggestive of meningioma on enhanced MRI. Hormonal treatment was discontinued and chemotherapy with docetaxel was started. After two cycles of chemotherapy, PET/CT showed that the intensity of abnormal tracer uptake in the metastatic lesion was increasing but was stable in the posterior cranial fossa meningioma.9) This article quoted other two cases described in a case report written by Lee and Terris.10) Both patients developed neurological symptoms during LH-RH agonist treatment after surgery for prostate cancer. In one patient, meningioma was found on radiological imaging, and in the other, who had undergone surgery for meningioma, tumor recurrence was documented.\n\nBicalutamide is an androgen receptor antagonist, and is often administered to patients with prostate cancer. An effect of this drug on the development of meningioma is regarded as unlikely.\n\nAs mentioned above, leuprorelin acetate, an LH-RH agonist, could conceivably play a role in the rapid growth of meningioma. This hypothesis is consistent with the immunoreactivity for the LR-RH receptor in the tumor cells of this patient. Nevertheless, there have been only a few reports of this kind. This may be because there may be very few male patients with prostate cancer who have meningioma simultaneously as it predominantly occurs in females. Also, PSA, a strong tumor marker for prostate cancer at present, was not popular before. So, some patients with prostate cancer in early stage might be overlooked. Further clinical experience and investigation are needed.\n\nConclusion\nThe authors documented a 70-year-old man with prostate cancer whose meningioma had grown to 5 cm in diameter over 3 years during hormone treatment for prostate cancer. In this patient, leuprorelin acetate, an LH-RH agonist, could have contributed to the rapid growth of meningioma.\n\nThe authors thank the laboratory technician, Ms. Tomoko Hayaki, for her assistance in the immunohistochemistory of the tumor specimen.\n\nFig. 1 A: T2-weighted axial magnetic resonance (MR) imaging demonstrating no apparent intracranial abnormalities. B: MR sagittal scout imaging demonstrating no apparent abnormalities.\n\nFig. 2 A: Gadolinium-enhanced T1-weighted coronal magnetic resonance imaging (MRI) demonstrating an extramedullary homogenously enhanced tumor at the parasagittal region expanding into the falx and skull bone. B: Gadolinium-enhanced T1-weighted sagittal MRI.\n\nFig. 3 Photomicrographs of the resected tumor. A: Whorl arrangements are seen in places. Necrosis is not identified. Hematoxylin and eosin (H&E) staining, original magnification ×200. B: Tumor cells are largely uniform and have oval nuclei. Mitoses are not identified. H&E staining, original magnification ×400. C: Molecular immunology borstel (MIB)-1 staining index is 5%. Immunohistochemical stain for Ki-67, original magnification ×400. D: The cytoplasm of tumor cells is immunopositive for the LH-RH receptor. Immunohistochemical stain for the LH-RH receptor, original magnification ×400. LH-RH: luteinizing hormone-releasing hormone.\n\nFig. 4 No recurrent tumor is identified 16 months after the operation. A: Gadolinium-enhanced T1-weighted coronal magnetic resonance imaging (MRI). B: Gadolinium-enhanced T1-weighted sagittal MRI.\n==== Refs\nReferences\n1) \nDiMeco F Li KW Casali C Ciceri E Giombini S Filippini G Broggi G Solero CL : \nMeningiomas invading the superior sagittal sinus: surgical experience in 108 cases . \nNeurosurgery \n55 : \n1263 –\n1272 ; \ndiscussion 1272–1274 , \n2004 \n15574208 \n2) \nMoon HS Jung S Jung TY Cao VT Moon KS Kim IY : \nPossible role of matrix metalloproteinase in osteolytic intracranial meningiomas . \nJ Korean Neurosurg Soc \n47 : \n11 –\n16 , \n2010 \n20157372 \n3) \nRaza SM Gallia GL Brem H Weingart JD Long DM Olivi A : \nPerioperative and long-term outcomes from the management of parasagittal meningiomas invading the superior sagittal sinus . \nNeurosurgery \n67 : \n885 –\n893 ; \ndiscussion 893 , \n2010 \n20802356 \n4) \nHsu DW Efird JT Hedley-Whyte ET : \nProgesterone and estrogen receptors in meningiomas: prognostic considerations . \nJ Neurosurg \n86 : \n113 –\n120 , \n1997 \n8988089 \n5) \nShimizu J Matsumoto M Yamazaki E Yasue M : \nSpontaneous regression of an asymptomatic meningioma associated with discontinuation of progesterone agonist administration . \nNeurol Med Chir (Tokyo) \n48 : \n227 –\n230 , \n2008 \n18497498 \n6) \nGrunberg SM : \nRole of antiprogestational therapy for meningiomas . \nHum Reprod \n9 (Suppl 1 ): \n202 –\n207 , \n1994 \n7962466 \n7) \nHirota Y Tachibana O Uchiyama N Hayashi Y Nakada M Kita D Watanabe T Higashi R Hamada J Hayashi Y : \nGonadotropin-releasing hormone (GnRH) and its receptor in human meningiomas . \nClin Neurol Neurosurg \n111 : \n127 –\n133 , \n2009 \n18980792 \n8) \nDurmaz R Deliorman S Isiksoy S Uyar R Tel E : \nLuteinizing hormone releasing hormone increases proliferation of meningioma cells in vitro . \nArchives Physiol Biochem \n107 : \n286 –\n291 , \n1999 \n\n9) \nFallanca F Giovacchini G Picchio M Bettinardi V Messa C Fazio F : \nIncidental detection by [11C]choline PET/CT of meningiomas in prostate cancer patients . \nQ J Nucl Med Mol Imaging \n53 : \n417 –\n421 , \n2009 \n19282812 \n10) \nLee KL Terris MK : \nLuteinizing hormone-releasing hormone agonists and meningioma: a treatment dilemma . \nUrology \n62 : \n351 , \n2003\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0470-8105", "issue": "54(4)", "journal": "Neurologia medico-chirurgica", "keywords": null, "medline_ta": "Neurol Med Chir (Tokyo)", "mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000726:Androgen Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005743:Gastrectomy; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D016729:Leuprolide; D008279:Magnetic Resonance Imaging; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D009363:Neoplasm Proteins; D009376:Neoplasms, Hormone-Dependent; D016609:Neoplasms, Second Primary; D009570:Nitriles; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D011974:Receptors, LH; D013274:Stomach Neoplasms; D014105:Tosyl Compounds", "nlm_unique_id": "0400775", "other_id": null, "pages": "327-30", "pmc": null, "pmid": "24201100", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "12893358;20157372;10779825;7962466;8988089;19282812;20802356;18497498;15574208;18980792", "title": "Progression of intracranial meningioma during luteinizing hormone-releasing hormone agonist treatment for prostate cancer: case report.", "title_normalized": "progression of intracranial meningioma during luteinizing hormone releasing hormone agonist treatment for prostate cancer case report" }

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{ "abstract": "BACKGROUND Several cases of herpes simplex virus type 1 meningoencephalitis (HSVE) have been reported in patients receiving steroids, but the exact contribution of steroids to the disorder remains unclear because other risk factors, such as chemotherapy, brain radiation, or surgery, were present in almost all cases. CASE REPORT We report the case of a 76-year-old man who developed HSVE following the administration of pulse-dose steroids. The patient had occupational asbestos exposure and a chronic interstitial lung disease of unclear etiology (sarcoidosis versus hypersensitivity pneumonitis) and was admitted for acute-on-chronic respiratory failure requiring mechanical ventilation. After a negative infectious workup and several days of antibiotics without improvement, pulse-dose steroids were administered. In the following days, the patient developed a fever and worsening encephalopathy. A lumbar puncture showed elevated nucleated cells and positive polymerase chain reaction for herpes simplex virus 1 in the cerebrospinal fluid, confirming the diagnosis of HSVE. Acyclovir treatment was initiated, but the patient later died as a result of persistent severe encephalopathy and respiratory failure with an inability to wean mechanical ventilation. CONCLUSIONS Clinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids, taking into account associated factors of immunosuppression. A high level of awareness should be especially maintained in critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.", "affiliations": "Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.;Division of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA.", "authors": "Horn|Jeffrey|J|;Mullholand|Jon B|JB|;Ashraf|Saad|S|;Shore|David|D|;Van de Louw|Andry|A|", "chemical_list": "D000212:Acyclovir; D008775:Methylprednisolone", "country": "United States", "delete": false, "doi": "10.12659/AJCR.933847", "fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34716288\n10.12659/AJCR.933847\n933847\nArticles\nHerpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review\nHorn Jeffrey A B C D E F\nMullholand Jon B. A B C D E F\nAshraf Saad A B F\nShore David A B C D\nVan de Louw Andry A B C D E F\nDivision of Pulmonary and Critical Care Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA\nCorresponding Author: Andry Van de Louw, e-mail: [email protected]\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nFinancial support: None declared\n\nConflict of interest: None declared\n\n2021\n30 10 2021\n22 e933847-1e933847-6\n03 7 2021\n11 9 2021\n01 10 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 76-year-old\n\nFinal Diagnosis: Herpes simplex virus type 1 (HSV-1) encephalitis\n\nSymptoms: Encephalopathy\n\nMedication: —\n\nClinical Procedure: Lumbar puncture\n\nSpecialty: Critical Care Medicine\n\nObjective:\n\nUnusual or unexpected effect of treatment\n\nBackground:\n\nSeveral cases of herpes simplex virus type 1 meningoencephalitis (HSVE) have been reported in patients receiving steroids, but the exact contribution of steroids to the disorder remains unclear because other risk factors, such as chemotherapy, brain radiation, or surgery, were present in almost all cases.\n\nCase Report:\n\nWe report the case of a 76-year-old man who developed HSVE following the administration of pulse-dose steroids. The patient had occupational asbestos exposure and a chronic interstitial lung disease of unclear etiology (sarcoidosis versus hypersensitivity pneumonitis) and was admitted for acute-on-chronic respiratory failure requiring mechanical ventilation. After a negative infectious workup and several days of antibiotics without improvement, pulse-dose steroids were administered. In the following days, the patient developed a fever and worsening encephalopathy. A lumbar puncture showed elevated nucleated cells and positive polymerase chain reaction for herpes simplex virus 1 in the cerebrospinal fluid, confirming the diagnosis of HSVE. Acyclovir treatment was initiated, but the patient later died as a result of persistent severe encephalopathy and respiratory failure with an inability to wean mechanical ventilation.\n\nConclusions:\n\nClinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids, taking into account associated factors of immunosuppression. A high level of awareness should be especially maintained in critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.\n\nKeywords:\n\nCritical Care\nEncephalitis, Herpes Simplex\nSteroids\n==== Body\npmcBackground\n\nHerpes simplex virus (HSV) is the most common infectious cause of sporadic encephalitis worldwide, with HSV-1 being the most common strain to cause HSV encephalitis (HSVE) [1]. After primary mucocutaneous infection, HSV remains latent in sensory ganglia and 60–90% of the world’s population is estimated to be seropositive for HSV [1]. Possible pathogenic mechanisms for HSVE include reactivation of latent HSV in the trigeminal ganglia, with subsequent spread of infection to the temporal and frontal lobes, primary central nervous system (CNS) infection, and perhaps reactivation of latent virus within the brain parenchyma itself [1]. The introduction of acyclovir has decreased mortality rates from 70% to 15% [2], but early diagnosis and treatment initiation are major determinants of mortality [2].\n\nImmunocompromised individuals seem to be at higher risk for severe HSV infections including meningoencephalitis [3], but the precise contribution of steroids remains unclear. Owing to their anti-inflammatory and immunomodulatory effects, glucocorticoids might in theory increase the rate of viral replication, but experimental animal models have yielded conflicting results regarding their effect on replication and clearance of HSV in the CNS [4,5]. Case reports have shown temporal associations between steroids and HSVE, but the relative contribution of steroids remains unclear because other factors, such as concomitant chemotherapy [6,7] or direct insult to the CNS (radiation [8], surgery [9,10]) or close structures (eye [11,12]), may have contributed to the HSVE in most of these cases. Here, we present a case of HSV-1 meningoencephalitis that developed following pulse-dose steroids for the treatment of interstitial lung disease in a patient with no history of chemotherapy or CNS insult. This case highlights the potential risk of pulse-dose steroids in patients with associated risk factors (age, critical illness immune paralysis, lymphopenia) and the need to rule out CNS infection in case of persistent, unexplained encephalopathy in critically ill patients. Informed consent for publication was obtained from the patient’s next of kin.\n\nCase Report\n\nA 76-year-old man was admitted with acute-on-chronic hypoxic respiratory failure. He had a past medical history of ischemic cardiomyopathy with reduced ejection fraction, atrial fibrillation, and ventricular tachycardia requiring a pacemaker and amiodarone, and he was on home oxygen owing to chronic hypoxic respiratory failure. The patient had a significant smoking history and occupational asbestos exposure. A year prior to admission he underwent the following procedures for dyspnea: (1) a pulmonary function test that showed normal spirometry, decreased lung volumes, and severely impaired diffusion capacity, consistent with restrictive lung disease; (2) a chest computed tomography (CT) scan that revealed perilymphatic nodular opacities (some calcified), ground glass opacities, and lower lobe predominant septal thickening; and (3) unre-markable bronchoscopy and broncho-alveolar lavage. A repeat chest CT a month prior to admission revealed worsening inter-stitial lung disease concerning for sarcoidosis versus chronic hypersensitivity pneumonitis. On admission, the patient was afebrile with a normal neurological exam. Significant laboratory values included white blood cell count 11.4×109/L (lymphocytes 0.66×109/L), procalcitonin 0.15 ng/mL, C-reactive protein 10.3 mg/dL, and brain natriuretic peptide 5374 pg/ mL. A chest CT showed no acute pulmonary embolus, but new ground glass and consolidative opacities were observed in both upper lobes. The patient was started on antibiotics for presumed community-acquired pneumonia and diuretics for heart failure exacerbation. He required intubation and mechanical ventilation on day 3 for worsening acute hypoxic respiratory failure. An extensive infectious workup, including 2 bronchoscopies with broncho-alveolar lavage, was entirely negative (bacterial and fungal cultures, multiplex polymerase chain reaction (PCR) for respiratory viral panel performed on a nasal swab and broncho-alveolar lavage fluids, Pneumocystis jirovecii PCR, acid fast bacillus cultures). Serum levels of immunoglobulins were normal for IgA and IgM and elevated for IgE (388 IU/mL, normal values <100 IU/mL) and IgG (1631 IU/mL, normal values 700–1600 IU/mL). An echocardiogram showed an ejection fraction of 45%, which was unchanged from prior examination. On day 5, given the lack of respiratory improvement after several days of antibiotics and diuretics, methylprednisolone at 46 mg/d was started to treat possible cryptogenic organizing pneumonia versus amiodarone-induced lung toxicity versus sarcoidosis. No improvement was subsequently observed and on day 11 steroid dosage was increased to 1000 mg/d for 3 days.\n\nOn day 13, the patient became febrile with worsening hyper-leukocytosis; urine culture was positive for Candida albicans, blood culture for Candida parapsilosis, and sputum culture for methicillin-sensitive Staphylococcus aureus. The patient was started on caspofungin.\n\nWithin the next few days, attempts to wean sedation and mechanical ventilation were unsuccessful. The patient was intermittently following commands during sedation holidays, but he was very tachypneic with patient/ventilator dyssynchrony, requiring sedation to be maintained. On day 18, the patient was noted to be minimally responsive to commands, which was a worsening of his mental status from previous days. He was febrile again and his white blood cell count was 20.1×109/L. A head CT scan was unremarkable, but a brain MRI could not be obtained due to the pacemaker. A lumbar puncture was performed, and cerebrospinal fluid studies were significant for nucleated cells of 36/μL (92% neutrophils), red blood cells of 8000/μL, glucose 73 mg/dL (normal 40–70 mg/dL), protein 46 mg/dL (normal 15–45 mg/dL), and lactate 2.8 mmol/L (normal 1.1–2.4 mmol/L). Bacterial cultures were negative, but PCR results for HSV-1 were positive.\n\nThe patient was started on acyclovir 10 mg/kg every 8 h for HSV-1 meningoencephalitis. Steroids were tapered and eventually discontinued. The patient’s mental status did not improve, and severe patient/ventilator dyssynchrony persisted with an inability to wean mechanical ventilation. The patient was transitioned to comfort care and died on day 25. Of note, he had remained significantly lymphopenic during the entire Intensive Care Unit (ICU) stay (lymphocyte count consistently below 0.8×109/L with a nadir of 0.01×109/L) with a CD4 count of 66/mm3 and a CD4/CD8 ratio of 1.84. Screening for HIV and viral hepatitis yielded negative results.\n\nAn autopsy was performed, and significant lung findings included interstitial fibrosis most compatible with silicosis, pulmonary congestion, acute bronchopneumonia in the right lower lobe, and subacute infarction with necrosis and cavitation in left upper lobe. The neuropathology did not reveal any acute process.\n\nDiscussion\n\nThis case illustrates how important and challenging the discussion of the benefit/risk ratio is prior to administering pulse-dose steroids in critically ill patients. Steroids were administered in our patient, with the dosage subsequently being increased because of the lack of improvement after treatment of presumed pneumonia and heart failure exacerbation. The steroid treatment was also used because diagnoses of sarcoidosis or hypersensitivity pneumonitis were considered based on previous medical history and chest imaging. However, the autopsy ruled out these diagnoses.\n\nThe risk of developing severe HSV infection after high-dose steroids is difficult to ascertain. In patients with systemic lupus erythematosus treated with various immunosuppressive drugs, the risk of severe HSV infection is increased [3]; steroids have been specifically associated with increased rates of opportunistic infections and herpes zoster infection in this population. The hypothesis of an increased risk of HSV infection due to steroids is therefore reasonable, but it has not been conclusively proven so far. Multiple cases of steroid-associated HSVE have been reported and are summarized in Table 1 [6–8,10–24]. In almost all cases, the presence of other potential triggers of HSVE, such as immunosuppressive drugs or direct CNS injury (surgery, radiation, eye injury), prevents any definite conclusion regarding a specific effect of steroids.\n\nOur patient did not have a history of chemotherapy administration or direct CNS injury, but his lymphopenia on presentation was another potential risk factor for HSVE and makes a causal link between steroids and HSVE difficult to assert.\n\nThe lymphopenia consistently present in our patient throughout his admission and very low CD4 count may have indeed increased his risk of developing HSVE. Its cause remains unclear. HIV screening was negative, and the lymphopenia was ascribed on admission to possible sarcoidosis; however, the autopsy did not confirm that diagnosis. After inoculation of HSV in experimental models, antilymphocyte serum allowed the development of viremia and fatal meningoencephalitis [25]. Lymphopenia has been associated with increased risk of infection in general in patients with systemic lupus erythematosus [26], and HSVE complicating drug-induced lymphopenia has been reported [27]. Lymphopenia was present in our patient even before steroid administration, but steroids are known to decrease circulating lymphocyte count and function, especially T cells and the CD4 subset [28], and may have further altered our patient’s immune system.\n\nCritical illness and sepsis per se are associated with lymphopenia, monocyte deactivation, and immune paralysis [29]. Lymphopenia in our patient was not secondary to sepsis because it was present prior to his admission. Pre-existing lymphopenia, critical illness-induced immune paralysis, and steroids may have synergistically led to the development of HSVE. However, despite a high prevalence of lymphopenia and immune paralysis in critically ill patients, regardless of the presence of sepsis [30], the occurrence of ICU-acquired HSVE is very rare [31] and its reality has even been challenged [32]. It is therefore likely that steroids played a key role in our patient even though a causal link with HSVE cannot be proven. Another concern specific to critically ill patients is that alarming neurological signs associated with HSVE may be missed in sedated, mechanically ventilated patients, which could cause delayed diagnosis and increased mortality. From that perspective, implementing daily interruption of sedation in these patients, which has been associated with better outcomes in randomized control trials [33,34], might also allow earlier detection of alarming signs, earlier diagnosis of HSVE, and improved outcome. The presence of fever, reported in 80–90% of patients with HSVE [35], should prompt a lumbar puncture when it is unexplained and associated with persistent altered mental status during sedation interruptions in immunocom-promised patients.\n\nThe fact that our patient also developed a C. parapsilosis fungemia after steroid administration further suggests significant immunosuppression. The patient had several risk factors for candidemia (age, mechanical ventilation, central venous catheter, broad-spectrum antibiotics) [36], and whether steroids may have acted as an independent risk factor remains unclear given previous conflicting results [37,38]. The patient developed candidemia and HSVE a few days apart; the coexistence of HSVE and candidiasis were already reported in 3 HSVE cases by Schiff and Rosenblum [17]. Circulating immune cells of patients with candidemia display a phenotype of immunosuppression with T-cell exhaustion [39], which may have further predisposed our patient to HSVE.\n\nConclusions\n\nIn summary, clinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids in critically ill patients, taking into account factors associated with immuno-suppression. A high level of awareness should be especially maintained for critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.\n\nTable 1. Summary of reported cases of herpes simplex virus meningoencephalitis associated with steroids administration.\n\nAuthor\tYear\tPatient age/sex\tSteroid\tDaily dose, (Prednisone equivalent)\tDuration d\tIndication for steroids\tAssociated risk factors\tHSV-1/2\tLymphopenia\tSurvival\t\nDoherty et al [13]\t2001\t81 y/M\tHydrocortisone\t75 mg\t10\tMyxedema coma\tDirect CNS insult due to myxedema\tN/A\tN/A\tNo\t\nJacobs [8]\t1999\t42 y/F\tDexametha-sone\t50 mg\t30\tBrain metastases (breast)\tWhole brain radiation\tN/A\tN/A\tN/A\t\nJaques et al [9]\t2016\t24 y/M\tDexametha-sone\t50 mg\t8\tBrain tumor\tNeurosurgery\tHSV-1\tN/A\tYes\t\n\t\t53 y/M\tDexametha-sone\t60 mg\t18\tBrain tumor\tNeurosurgery\tHSV-2\tN/A\tYes\t\nTan et al [14]\t2012\t74 y/F\tNot specified\tN/A\tN/A\tPolymyositis\tCyclophosphamide\tN/A\tN/A\tN/A\t\nSermer et al [15]\t2014\t55 y/M\tDexametha-sone\t80 mg\t28\tBrain metastases (lung)\tWhole brain radiation\tHSV-1\tN/A\tYes\t\nBewersdorf et al [16]\t2019\t60 y/F\tPrednisolone\t30 mg\tN/A\tCOPD exacerbation\tIgG deficiency\tHSV-1\tN/A\tYes\t\nSchiff and Rosenblum [17]\t1998\t35 y/F\tDexametha-sone\t120 mg\t21\tCNS lymphoma\tRadiation/neurosurgery\tN/A\tYes\tNo\t\n\t\t24 y/F\tDexametha-sone\t30 mg\t120\tGlioblastoma\tRadiation/neurosurgery/chemotherapy\tHSV-1\tYes\tNo\t\nAlimohamadi et al [6]\t2004\t22 y/F\tPrednisolone\t20 mg\tN/A\tUlcerative colitis\tAzathioprine\tN/A\tNo\tYes\t\nNg et al [24]\t2019\t38 y/F\tNot specified\tN/A\t8\tGlioblastoma\tNeurosurgery\tHSV-1\tNo\tNo\t\nMcLaughlin et al [10]\t2019\t72 y/M\tDexametha-sone\t110 mg\t4\tMeningioma\tNeurosurgery\tHSV-1\tN/A\tYes\t\nOsterman et al [18]\t2020\t48 y/F\tNot specified\tPulse-dose\t5\tSuspected limbic encephalitis\tNone but CSF abnormalities present before steroid administration (HSV PCR negative)\tHSV-1\tN/A\tNo\t\nSilvano et al [19]\t2007\t55 y/M\tDexametha-sone\t50 mg\tN/A\tProphylactic cranial irradiation\tChemotherapy/radiation\tHSV-1\tYes\tNo\t\nRiel-Romero and Baumann [20]\t2003\t15 y/M\tDexametha-sone\t50 mg\tN/A\tGlioma\tTemozolomide/radiation\tHSV-1\tN/A\tN/A\t\nPeng et al [21]\t2007\t61 y/M\tDexametha-sone\t110 mg\t14\tPituitary adenoma\tNeurosurgery/radiation\tN/A\tYes\tYes\t\nWittles et al [12]\t2011\t62 y/F\tPrednisolone\t1 mg/kg/d\t14\tPanuveitis\tAcute retinal necrosis\tN/A\tN/A\tNo\t\nKim et al [11]\t2012\t57 y/M\tMethylpredni-solone\t1250 mg\t5\tRetinal vasculitis\tAcute retinal necrosis\tHSV-1\tN/A\tYes\t\nLizarraga et al [22]\t2013\t32 y/F\tDexametha-sone\t110 mg\t77\tGlomus jugulare paraganglioma\tRadiation\tHSV-1\tN/A\tYes\t\nSaito et al [7]\t2016\t77 y/F\tDexametha-sone\t110 mg\tN/A\tProphylactic antiemetic\tChemotherapy\tHSV-1\tYes\tYes\t\nGraber et al [23]\t2011\t48 y/F\tDexametha-sone\t40 mg\tN/A\tBrain metastases (lung)\tRadiation/chemotherapy\tHSV-2\tNo\tYes\t\n\t\t55 y/M\tDexametha-sone\t80 mg\tN/A\tBrain metastases (melanoma)\tRadiation\tHSV-1\tNo\tNo\t\n\t\t45 y/F\tDexametha-sone\t50 mg\tN/A\tThyroid cancer\tNeurosurgery\tHSV-2\tNo\tNo\t\nCNS – central nervous system; COPD – chronic obstructive pulmonary disease; CSF – cerebrospinal fluid; F – Female; HSV – herpes simplex virus; IgG – immunoglobulin G; M – Male; N/A – not available; PCR – polymerase chain reaction.\n==== Refs\nReferences:\n\n1. Bradshaw MJ Venkatesan A Herpes simplex virus-1 encephalitis in adults: Pathophysiology, diagnosis, and management Neurotherapeutics 2016 13 3 493 508 27106239\n2. Raschilas F Wolff M Delatour F Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: Results of a multicenter study Clin Infect Dis 2002 35 3 254 60 12115090\n3. Li TH Lai CC Wang WH Risk of severe herpes simplex virus infection in systemic lupus erythematosus: Analysis of epidemiology and risk factors analysis in Taiwan Ann Rheum Dis 2019 78 7 941 46 30954968\n4. Baringer JR Klassen T Grumm F Experimental herpes simplex virus encephalitis. Effect of corticosteroids and pyrimidine nucleoside Arch Neurol 1976 33 6 442 46 180935\n5. Thompson KA Blessing WW Wesselingh SL Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal herpes encephalitis J Neurovirol 2000 6 1 25 32 10786994\n6. Alimohamadi SM Malekzadeh R Mirmadjless SH Herpes simplex virus encephalistis during immunosuppressive treatment of ulcerative colitis MedGenMed 2004 6 4 7\n7. Saito M Kiyozaki H Obitsu T Herpes simplex virus-1 encephalitis induced by chemoradiotherapy and steroids in an esophageal cancer patient: A case report BMC Cancer 2016 16 233 26988237\n8. Jacobs DH Herpes simplex virus encephalitis following corticosteroids and cranial irradiation Neurology 1999 52 5 1108 9 10102451\n9. Jaques DA Bagetakou S L’Huillier AG Herpes simplex encephalitis as a complication of neurosurgical procedures: Report of 3 cases and review of the literature Virol J 2016 13 83 27216026\n10. McLaughlin DC Achey RL Geertman R Grossman J Herpes simplex reactivation following neurosurgery: Case report and review of the literature Neurosurg Focus 2019 47 2 E9\n11. Kim SJ Kang SW Joo EY An unusual case of herpes simplex viral encephalitis following acute retinal necrosis after administration of a systemic steroid J Epilepsy Res 2012 2 1 21 24 24649457\n12. Wittles KN Goold LA Gilhotra JS Herpes simplex encephalitis presenting after steroid treatment of panuveitis Med J Aust 2011 195 2 87 88 21770880\n13. Doherty MJ Baxter AB Longstreth WT Jr Herpes simplex virus encephalitis complicating myxedema coma treated with corticosteroids Neurology 2001 56 8 1114 15 11320194\n14. Tan IL McArthur JC Venkatesan A Nath A Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised Neurology 2012 79 21 2125 32 23136265\n15. Sermer DJ Woodley JL Thomas CA Hedlund JA Herpes simplex encephalitis as a complication of whole-brain radiotherapy: A case report and review of the literature Case Rep Oncol 2014 7 3 774 79 25722668\n16. Bewersdorf JP Koedel U Patzig M Challenges in HSV encephalitis: Normocellular CSF, unremarkable CCT, and atypical MRI findings Infection 2019 47 2 267 73 30506479\n17. Schiff D Rosenblum MK Herpes simplex encephalitis (HSE) and the immunocompromised: A clinical and autopsy study of HSE in the settings of cancer and human immunodeficiency virus-type 1 infection Hum Pathol 1998 29 3 215 22 9496822\n18. Osterman A Ruf VC Domingo C Travel-associated neurological disease terminated in a postmortem diagnosed atypical HSV-1 encephalitis after high-dose steroid therapy – a case report BMC Infect Dis 2020 20 1 150 32070282\n19. Silvano G Lazzari G Resta F A herpes simplex virus-1 fatal encephalitis following chemo-radiotherapy, steroids and prophylactic cranial irradiation in a small cell lung cancer patient Lung Cancer 2007 57 2 243 46 17368625\n20. Riel-Romero RM Baumann RJ Herpes simplex encephalitis and radiotherapy Pediatr Neurol 2003 29 1 69 71 13679127\n21. Peng T Blakeley J Cingolani E Herpes simplex encephalitis in a patient with recurrent pituitary adenoma receiving radiation therapy Am J Clin Oncol 2007 30 6 664 65 18091066\n22. Lizarraga KJ Alexandre LC Ramos-Estebanez C Merenda A Are steroids a beneficial adjunctive therapy in the immunosuppressed patient with herpes simplex virus encephalitis? Case Rep Neurol 2013 5 1 52 55 23626565\n23. Graber JJ Rosenblum MK DeAngelis LM Herpes simplex encephalitis in patients with cancer J Neurooncol 2011 105 2 415 21 21637964\n24. Ng S Le Corre M Aloy E Herpes simplex encephalitis shortly after surgery for a secondary glioblastoma: A case report and review of the literature World Neurosurg 2019 129 13 17 31150854\n25. Zisman B Hirsch MS Allison AC Selective effects of anti-macrophage serum, silica and anti-lymphocyte serum on pathogenesis of herpes virus infection of young adult mice J Immunol 1970 104 5 1155 59 4315460\n26. Ng WL Chu CM Wu AK Lymphopenia at presentation is associated with increased risk of infections in patients with systemic lupus erythematosus QJM 2006 99 1 37 47 16371405\n27. Perini P Rinaldi F Puthenparampil M Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient Mult Scler Relat Disord 2018 26 68 70 30227312\n28. Slade JD Hepburn B Prednisone-induced alterations of circulating human lymphocyte subsets J Lab Clin Med 1983 101 3 479 87 6219171\n29. Boomer JS To K Chang KC Immunosuppression in patients who die of sepsis and multiple organ failure JAMA 2011 306 23 2594 605 22187279\n30. Hohlstein P Gussen H Bartneck M Prognostic relevance of altered lymphocyte subpopulations in critical illness and sepsis J Clin Med 2019 8 3 353\n31. Algahtani H Shirah B Hmoud M Subahi A Nosocomial herpes simplex encephalitis: A challenging diagnosis J Infect Public Health 2017 10 3 343 47 27686257\n32. Jouan Y Grammatico-Guillon L Guillon A Nosocomial herpes simplex encephalitis: does it really exist? J Infect Public Health 2018 11 1 142 28209321\n33. Girard TD Kress JP Fuchs BD Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial Lancet 2008 371 9607 126 34 18191684\n34. Kress JP Pohlman AS O’Connor MF Hall JB Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation N Engl J Med 2000 342 20 1471 77 10816184\n35. Whitley RJ Herpes simplex encephalitis: Adolescents and adults Antiviral Res 2006 71 2–3 141 48 16675036\n36. Guery BP Arendrup MC Auzinger G Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis Intensive Care Med 2009 35 1 55 62 18972101\n37. Dimopoulos G Ntziora F Rachiotis G Candida albicans versus nonalbicans intensive care unit-acquired bloodstream infections: differences in risk factors and outcome Anesth Analg 2008 106 2 523 29 18227310\n38. Poissy J Damonti L Bignon A Risk factors for candidemia: A prospective matched case-control study Crit Care 2020 24 1 109 32188500\n39. Spec A Shindo Y Burnham CA T cells from patients with Candida sepsis display a suppressive immunophenotype Crit Care 2016 20 15 26786705\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1941-5923", "issue": "22()", "journal": "The American journal of case reports", "keywords": null, "medline_ta": "Am J Case Rep", "mesh_terms": "D000212:Acyclovir; D000368:Aged; D020803:Encephalitis, Herpes Simplex; D018259:Herpesvirus 1, Human; D006801:Humans; D008297:Male; D008590:Meningoencephalitis; D008775:Methylprednisolone", "nlm_unique_id": "101489566", "other_id": null, "pages": "e933847", "pmc": null, "pmid": "34716288", "pubdate": "2021-10-30", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "18972101;24649457;21637964;26988237;27106239;4315460;27686257;28209321;17368625;21770880;30506479;12115090;18191684;16371405;6219171;30871101;30954968;9496822;16675036;18227310;11320194;180935;25722668;27216026;30227312;32188500;13679127;23136265;26786705;10816184;22187279;15775834;23626565;10786994;18091066;31370030;10102451;32070282;31150854", "title": "Herpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review.", "title_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review" }

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"reactionmeddraversionpt": "24.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Candida infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract candidiasis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. American Journal of Case Reports. 2021;22(e933847):1-6", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211129", "receivedate": "20211129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20124988, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" }, { "companynumb": "US-AUROBINDO-AUR-APL-2021-046672", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, 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"1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MILLIGRAM, ONCE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sarcoidosis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIODARONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Ventricular tachycardia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIODARONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYGEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Respiratory failure", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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Mullholand JB, Ashraf S, Shore D, Van de Louw A.. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review.. 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Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. American Journal of Case Reports. 2021;22(1):10.12659/AJCR.933847", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211124", "receivedate": "20211116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20074286, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "US-JUBILANT CADISTA PHARMACEUTICALS-2021JUB00418", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "46 MG/D", "drugenddate": null, "drugenddateformat": null, "drugindication": "Organising pneumonia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "46", "drugstructuredosageunit": "003", "drugtreatmentduration": "6", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "040189", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/D", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": "3", "drugtreatmentdurationunit": "804", "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": null, "patientonsetage": "76", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Herpes simplex meningoencephalitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A.. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review.. Am J Case Rep. 2021;22(1)", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211119", "receivedate": "20211119", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20092192, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" }, { "companynumb": "US-TEVA-2021-US-1982309", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, 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Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. 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Herpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review. 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Herpes Simplex Virus Meningoencephalitis Following Pulse-Dose Methylprednisolone: A Case Report and Literature Review. 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"801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Horn J, Mullholand JB, Ashraf S, Shore D, Van de Louw A. Herpes simplex virus meningoencephalitis following pulse-dose methylprednisolone: A case report and literature review. Am-J-Case-Rep 2021;22(1):e933847-1-e933847-6.", "literaturereference_normalized": "herpes simplex virus meningoencephalitis following pulse dose methylprednisolone a case report and literature review", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211123", "receivedate": "20211123", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20101673, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "Rothia mucilaginosa (R. mucilaginosa), formerly named Stomatococcus mucilaginosus, is a facultatively anaerobic, encapsulated gram-positive coccus, which forms part of the normal oropharyngeal and is rarely considered to be a pathogen in immunocompetent patients, although it can produce, on rare occasions, serious infections like bacteremia, endocarditis and respiratory infections; such as pneumonia, pleural empyema or superinfection of bronchiectasis. We present the case of a 74-year-old male diagnosed with right basal pneumonia of torpid evolution with a poor initial response to different antibiotics, with clinical and radiological worsening and the appearance of bilateral bronchopneumonia with pseudonodular images. R. mucilaginosa in pure culture was isolated in three sputum cultures and in bronchial suction. The patient was finally treated with Linezolid with a good clinical response and normalisation of the thorax radiography, confirming the disappearance of R. mucilaginosa in subsequent sputum cultures. As there are few documented cases of pneumonia due to R. mucilaginosa, we believe that presenting this case will be of interest.", "affiliations": "Hospital Clínico Universitario Lozano Blesa. [email protected].", "authors": "De Escalante Yangüela|B|B|;Gracia Gutiérrez|A|A|;Gracia Tello|B|B|;Alastrué Del Castaño|V|V|;Bueno Juana|E|E|;Algárate Cajo|S|S|", "chemical_list": null, "country": "Spain", "delete": false, "doi": "10.23938/ASSN.0090", "fulltext": null, "fulltext_license": null, "issn_linking": "1137-6627", "issue": "40(3)", "journal": "Anales del sistema sanitario de Navarra", "keywords": null, "medline_ta": "An Sist Sanit Navar", "mesh_terms": "D000368:Aged; D001996:Bronchopneumonia; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D008835:Micrococcaceae", "nlm_unique_id": "9710381", "other_id": null, "pages": "479-483", "pmc": null, "pmid": "29149111", "pubdate": "2017-12-29", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Bilateral bronchopneumonia due to Rothia mucilaginosa.", "title_normalized": "bilateral bronchopneumonia due to rothia mucilaginosa" }

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BILATERAL BRONCHOPNEUMONIA DUE TO ROTHIA MUCILAGINOSA", "literaturereference_normalized": "bilateral bronchopneumonia due to rothia mucilaginosa", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20190531", "receivedate": "20190531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16379758, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "ES-CIPLA LTD.-2018ES21949", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "076890", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PNEUMONIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Condition aggravated", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE ESCALANTE YANGUELA B, GRACIA GUTIERREZ A, GRACIA TELLO B, ALASTRUE DEL, BUENO JUANA E, ALGARATE CAJO S. BILATERAL BRONCHOPNEUMONIA DUE TO ROTHIA MUCILAGINOSA", "literaturereference_normalized": "bilateral bronchopneumonia due to rothia mucilaginosa", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20181024", "receivedate": "20181024", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15544361, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "Stevens-Johnson Syndrome (SJS) is a rare but severe dermatological condition that typically occurs after the ingestion of medications such as nonsteroidal drugs, antibiotics, and anticonvulsants. Extracutaneous manifestations of the syndrome can occur and may involve the conjunctiva, trachea, buccal mucosa, gastrointestinal tract, and genitourinary tract. Cholestatic liver disease, which may precede the skin manifestations of SJS, has been reported to occur in SJS, but the medical literature has only 10 case reports describing this phenomenon (1-9). We report the case of a 19-year-old female with SJS and cholestatic liver disease. A discussion of the underlying pathophysiology of SJS and its treatment follows.", "affiliations": "Department of Internal Medicine, Section of General Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.", "authors": "Morelli|M S|MS|;O'Brien|F X|FX|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen", "country": "United States", "delete": false, "doi": "10.1023/a:1012351231143", "fulltext": null, "fulltext_license": null, "issn_linking": "0163-2116", "issue": "46(11)", "journal": "Digestive diseases and sciences", "keywords": null, "medline_ta": "Dig Dis Sci", "mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D005260:Female; D006801:Humans; D007052:Ibuprofen; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "7902782", "other_id": null, "pages": "2385-8", "pmc": null, "pmid": "11713940", "pubdate": "2001-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "2064763;8934797;276660;6224935;7477195;7794310", "title": "Stevens-Johnson Syndrome and cholestatic hepatitis.", "title_normalized": "stevens johnson syndrome and cholestatic hepatitis" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METOCLOPRAMIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PIPERACILLIN AND TAZOBACTAM" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatitis cholestatic", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Stevens-Johnson syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary tract infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Morelli MS, O^Brien F. Stevens-Johnson Syndrome and Cholestatic Hepatitis. Digestive Diseases and Sciences. 2001;VOL 46/11:2385 - 2388", "literaturereference_normalized": "stevens johnson syndrome and cholestatic hepatitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220330", "receivedate": "20220316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20601933, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" } ]

{ "abstract": "Minimally invasive therapies for drug-resistant epilepsy (DRE) have been advocated. A study of convection-enhanced delivery (CED) of muscimol, a GABAA receptor agonist, was previously completed in non-human primates.\n\n\n\nTo investigate the safety and anti-epileptic effects of intracerebral muscimol infusion into the epileptic focus of patients with DRE.\n\n\n\nIn this phase 1 clinical trial, 3 adult patients with DRE underwent CED into the seizure focus of artificial CSF vehicle followed by muscimol for 12 to 24 h each using a crossover design. Basic pathophysiology of the epileptic focus was examined by assessing the infusions' effects on seizure frequency, electroencephalogram (EEG) spike-wave activity, and power-spectral EEG frequency.\n\n\n\nInter-ictal neurological function remained normal in all patients. Pathological examination of resected specimens showed no infusion-related brain injuries. Seizure frequency decreased in 1 of 3 patients during muscimol infusion but was unchanged in all patients during vehicle infusion. Mean beta frequencies did not differ significantly before, during, or after infusion periods. Infused fluid provided insufficient MRI-signal to track infusate distribution. In the 2 yr after standard epilepsy surgery, 1 patient had temporary reduction in seizure frequency and 2 patients were seizure-free.\n\n\n\nCED of muscimol into the epileptic focus of patients with DRE did not damage adjacent brain parenchyma or adversely affect seizure surgery outcome. This study did not confirm that intracerebral muscimol infusion effectively suppressed seizures. A surrogate tracer is recommended to track infusion distribution to the epileptic focus and surrounding structures in future studies using CED to suppress the seizure focus.", "affiliations": "Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.;Electroencephalography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.;Electroencephalography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.", "authors": "Heiss|John D|JD|;Argersinger|Davis P|DP|;Theodore|William H|WH|;Butman|John A|JA|;Sato|Susumu|S|;Khan|Omar I|OI|", "chemical_list": "D000927:Anticonvulsants; D009118:Muscimol", "country": "United States", "delete": false, "doi": "10.1093/neuros/nyy480", "fulltext": null, "fulltext_license": null, "issn_linking": "0148-396X", "issue": "85(1)", "journal": "Neurosurgery", "keywords": "Convection; epilepsy; epileptic focus; muscimol", "medline_ta": "Neurosurgery", "mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001921:Brain; D018481:Convection; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D057967:Infusions, Intraventricular; D008279:Magnetic Resonance Imaging; D008297:Male; D009118:Muscimol", "nlm_unique_id": "7802914", "other_id": null, "pages": "E4-E15", "pmc": null, "pmid": "30407567", "pubdate": "2019-07-01", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": "16381190;12700290;9396606;10516265;418955;10507396;27995127;9950503;7539062;7278491;16304999;9322847;152602;8304553;17054693;11240604;1449242;2203963;9652621;10443891;24410126;8134351", "title": "Convection-Enhanced Delivery of Muscimol in Patients with Drug-Resistant Epilepsy.", "title_normalized": "convection enhanced delivery of muscimol in patients with drug resistant epilepsy" }

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GLOBULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RASMUSSEN ENCEPHALITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMMUNOGLOBULINS NOS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMOTRIGINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMOTRIGINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM, TID, EXTENDED-RELEASE CAPSULES", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXCARBAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MILLIGRAM, QD (EVERY MORNING)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBAMAZEPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBAMAZEPINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5 MILLIGRAM, PRN (3 TO 4 TIMES DAILY AS NEEDED)", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISS JD, ARGERSINGER DP, THEODORE WH, BUTMAN JA, SATO S, KHAN OI.. CONVECTION-ENHANCED DELIVERY OF MUSCIMOL IN PATIENTS WITH DRUG-RESISTANT EPILEPSY. NEUROSURGERY. 2019?85 (1):E4 TO E15", "literaturereference_normalized": "convection enhanced delivery of muscimol in patients with drug resistant epilepsy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190920", "receivedate": "20190920", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16830639, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-CIPLA LTD.-2019US06434", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DIVALPROEX SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DIVALPROEX" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076343", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": 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null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GENERALISED TONIC-CLONIC SEIZURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GABAPENTIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "FOCAL DYSCOGNITIVE SEIZURES", "drugintervaldosagedefinition": null, 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Epilepsy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HEISS JD, ARGERSINGER DP, THEODORE WH, BUTMAN JA, SATO S, KHAN OI. CONVECTION-ENHANCED DELIVERY OF MUSCIMOL IN PATIENTS WITH DRUG-RESISTANT EPILEPSY. NEUROSURGERY. 2019?85 (1):E4 TO E15", "literaturereference_normalized": "convection enhanced delivery of muscimol in patients with drug resistant epilepsy", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190923", "receivedate": "20190923", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16837542, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]

{ "abstract": "West Nile virus infection can pose a diagnostic challenge to clinicians, especially in geographic areas where human cases of this disease have never been encountered before. In August 2016, the first human case of West Nile virus infection was diagnosed in Cyprus. An elderly non immunosuppressed patient with a history of recent travel, presented with a clinical picture of rapidly progressing ascending paralysis mimicking Guillain-Barré syndrome. Neuroinvasive West Nile virus disease was diagnosed by detecting West Nile virus nucleic acid in the patient's cerebrospinal fluid. Public health measures were taken raising awareness regarding this disease and its prevention. Clinical vigilance to consider West Nile virus as a possible emerging pathogen in the appropriate clinical setting is warranted and could benefit individual patients.", "affiliations": "Nicosia General Hospital Intensive Care Clinic, Nicosia, Cyprus. Electronic address: [email protected].;Nicosia General Hospital Intensive Care Clinic, Nicosia, Cyprus. Electronic address: [email protected].;Nicosia General Hospital Intensive Care Clinic, Nicosia, Cyprus; Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].;Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].;Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].;Cyprus Institute of Neurology and Genetics, Department of Molecular Virology, 6 International Airport Ave., Agios Dometios, 2379 Nicosia Nicosia, Cyprus. Electronic address: [email protected].", "authors": "Paphitou|Niki I|NI|;Tourvas|Aristomenis|A|;Floridou|Dora|D|;Richter|Jan|J|;Tryfonos|Christina|C|;Christodoulou|Christina|C|", "chemical_list": "D012367:RNA, Viral", "country": "England", "delete": false, "doi": "10.1016/j.jiph.2017.02.003", "fulltext": null, "fulltext_license": null, "issn_linking": "1876-0341", "issue": "10(6)", "journal": "Journal of infection and public health", "keywords": "Cyprus; Emerging diseases; Neuroinvasive disease; Public health; West Nile virus", "medline_ta": "J Infect Public Health", "mesh_terms": "D000368:Aged; D002555:Cerebrospinal Fluid; D003535:Cyprus; D006801:Humans; D008297:Male; D012367:RNA, Viral; D014901:West Nile Fever; D014902:West Nile virus", "nlm_unique_id": "101487384", "other_id": null, "pages": "891-893", "pmc": null, "pmid": "28233724", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "The first human case of neuroinvasive West Nile virus infection identified in Cyprus.", "title_normalized": "the first human case of neuroinvasive west nile virus infection identified in cyprus" }

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{ "abstract": "BACKGROUND\nPseudoaneurysm, the most common complication of femoral artery catheterization, involves the formation of a space between the lumen and the surrounding fibrous tissue through the damaged arterial wall. In patients treated with antiplatelet and anticoagulant agents, the incidence of vascular complications increases with the increasing use of minimally invasive procedures.\nWe experienced 2 cases of procedure-induced pseudoaneurysms. A 79-year-old man with right hemiparesis visited our hospital. Brain magnetic resonance imaging showed acute left middle cerebral artery territory infarction and severe stenosis of the left proximal carotid artery. The patient was prescribed apixaban and underwent carotid stenting through the right femoral artery. Hematoma and tenderness were observed in the right inguinal region after the procedure. The hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL. Another 78-year-old man with left common carotid artery stenosis was admitted. We performed stent implantation through the right femoral artery and administered aspirin and clopidogrel. After the procedure, hematoma and tenderness of the puncture site were observed. The hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL.\n\n\nMETHODS\nEmergency computed tomography confirmed a pseudoaneurysm with a massive hematoma in the right inguinal area. The patients were diagnosed with infection-associated right pseudoaneurysm for which an emergency puncture site repair was performed.\n\n\nMETHODS\nWe performed resection of pseudoaneurysm and repaired puncture site.\n\n\nRESULTS\nThe hemoglobin level was stabilized postoperatively and vital sign remained stable.\n\n\nCONCLUSIONS\nPseudoaneurysm is an important complication of femoral artery puncture. The use of a hemostatic device was not superior to manual compression, and the incidence of this complication was significantly higher in patients who received anticoagulant or antiplatelet agents. A pseudoaneurysm may cause a bad prognosis. Therefore, the early detection of pseudoaneurysm and immediate treatment after femoral arterial puncture are needed.", "affiliations": "Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.;Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonju.", "authors": "Jeon|Seung-Ho|SH|;Kang|Hyun Goo|HG|;Kim|Hong-Jin|HJ|;Seo|Man-Wook|MW|;Shin|Byoung-Soo|BS|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000015309", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31027097MD-D-18-0861510.1097/MD.0000000000015309153095300Research ArticleClinical Case ReportFemoral artery pseudoaneurysm after carotid artery stenting Two case reportsJeon Seung-Ho MDaKang Hyun Goo MD, PhDabKim Hong-Jin MDaSeo Man-Wook MD, PhDabShin Byoung-Soo MD, PhDab∗NA. a Department of Neurology, Chonbuk National University Medical School and Hospital, Jeonjub Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Chonbuk, Republic of Korea.∗ Correspondence: Byoung-Soo Shin, Department of Neurology, Chonbuk National University Medical School and Hospital, 20, Geonji-ro, Jeonju, Chonbuk, 54907, Republic of Korea (e-mail: [email protected]).4 2019 26 4 2019 98 17 e1530928 11 2018 13 3 2019 25 3 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nPseudoaneurysm, the most common complication of femoral artery catheterization, involves the formation of a space between the lumen and the surrounding fibrous tissue through the damaged arterial wall. In patients treated with antiplatelet and anticoagulant agents, the incidence of vascular complications increases with the increasing use of minimally invasive procedures.\n\nPatient concerns:\nWe experienced 2 cases of procedure-induced pseudoaneurysms. A 79-year-old man with right hemiparesis visited our hospital. Brain magnetic resonance imaging showed acute left middle cerebral artery territory infarction and severe stenosis of the left proximal carotid artery. The patient was prescribed apixaban and underwent carotid stenting through the right femoral artery. Hematoma and tenderness were observed in the right inguinal region after the procedure. The hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL. Another 78-year-old man with left common carotid artery stenosis was admitted. We performed stent implantation through the right femoral artery and administered aspirin and clopidogrel. After the procedure, hematoma and tenderness of the puncture site were observed. The hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL.\n\nDiagnosis:\nEmergency computed tomography confirmed a pseudoaneurysm with a massive hematoma in the right inguinal area. The patients were diagnosed with infection-associated right pseudoaneurysm for which an emergency puncture site repair was performed.\n\nInterventions:\nWe performed resection of pseudoaneurysm and repaired puncture site.\n\nOutcomes:\nThe hemoglobin level was stabilized postoperatively and vital sign remained stable.\n\nLessons:\nPseudoaneurysm is an important complication of femoral artery puncture. The use of a hemostatic device was not superior to manual compression, and the incidence of this complication was significantly higher in patients who received anticoagulant or antiplatelet agents. A pseudoaneurysm may cause a bad prognosis. Therefore, the early detection of pseudoaneurysm and immediate treatment after femoral arterial puncture are needed.\n\nKeywords\nangiographyclosure devicepseudoaneurysmstentOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nA pseudoaneurysm, the most common complication caused by femoral artery catheter insertion, occurs when a space forms between the blood vessel lumen and the surrounding fibrous tissue through the damaged artery wall.[1] The occurrence of local vascular complications due to a surgical procedure has recently increased with the use of an antiplatelet or anticoagulant along with femoral artery catheter insertion.[2] In particular, pseudoaneurysm frequently occurs at the puncture site below the head of the femur due to insufficient bone support resulting in angiopressure after catheter removal.[3] However, to our knowledge, only a few studies have reported local complications after cerebral angiography. Here we describe 2 cases of femoral artery pseudoaneurysm after cerebral angiography and a review of the relevant literature.\n\n2 Case presentation\n2.1 Case 1\nA 79-year-old man visited our clinic with a 3-day history of weakness of the right hand. He was taking medication for chronic obstructive pulmonary disease. However, he had no hypertension or diabetes and did not smoke. A neurological examination showed no abnormalities except for weakness in the distal portion of the right upper extremity (Medical Research Council Grade 4+). At the time of the visit, his National Institutes of Health Stroke Scale score was 1 point. Acute cerebral infarction was observed in the left middle cerebral artery territory on brain magnetic resonance imaging (MRI). Moreover, severe stenosis was found in the left proximal internal carotid artery on brain magnetic resonance angiography (MRA). In addition, atrial fibrillation was observed on echocardiography performed during the visit. The patient was prescribed apixaban 10 mg/day and underwent balloon angioplasty and carotid artery stent insertion through the right femoral artery. Moreover, puncture site closure was conducted using an Angio-seal closure device.\n\nThe second day after the procedure, hematoma accompanying ecchymosis and tenderness was observed in the right inguinal area. Although the patient's vital signs were stable, his hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL before the surgical procedure. Emergent computed tomography (CT) was performed to identify the cause of the hemoglobin decrease after a fluid infusion and blood transfusion. We confirmed the presence of pseudoaneurysm accompanying a massive hematoma in the right inguinal area (Fig. 1A, B). After pseudoaneurysm removal and puncture site restoration surgery, the vital signs remained stable and the hemoglobin level normalized.\n\nFigure 1 Axial view and angiography of contrast-enhanced computed tomography with right femoral pseudoaneurysm in 2 patients. (Case 1—A and B. Case 2—C and D) Hematoma (H) and pseudoaneurysm (P) communicate with the right common femoral artery through a pseudoaneurysm neck (N). The white arrow indicated a pseudoaneurysm (P) which is communicated with right common femoral artery.\n\n2.2 Case 2\nA 78-year-old man visited our hospital with stenosis of the left common carotid artery detected on brain MRA during a health check examination. The patient was already on antiplatelet treatment and no abnormalities were found in a neurological examination. Although there were no specific findings on brain MRI, the MRA results showed severe stenosis of the left common carotid artery. The patient was administered aspirin 100 mg/day and clopidogrel 75 mg/day and underwent balloon angioplasty and carotid artery stent insertion through the right femoral artery. Moreover, the puncture site was closed using an MYNXGRIP closure device.\n\nThe patient's vital signs and neurological symptoms were stable after the procedure. However, a mild fever (38.2°C) and hematoma accompanying puncture site tenderness were observed the day after the procedure. A laboratory test showed that the hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL. Moreover, the emergent CT revealed that pseudoaneurysm occurred in the right femoral artery (Fig. 1C, D). The patient was diagnosed with an infection-associated pseudoaneurysm for which an emergent pseudoaneurysm resection and puncture site reconstruction were performed. The patient was stable afterward and then discharged.\n\n3 Discussion\nBoth patients described here experienced pseudoaneurysm accompanying an acute hemoglobin level decrease after undergoing cerebral angiography through the femoral artery while taking anticoagulant or antiplatelet agents. We conducted further evaluations of suspected pseudoaneurysm due to the hematoma accompanying the tenderness that expanded in the inguinal area after the femoral artery catheter insertion.\n\nWhen a hematoma accompanying tenderness while the vibration thrill of the femoral artery is felt or bruit is auscultated, further evaluations of pseudoaneurysm should be performed.[3] Color Doppler ultrasonography, the most common test, is used to confirm the presence of a communicating tract and pseudoaneurysm number and size. When a pseudoaneurysm is large, its location and size can be identified more precisely using contrast-enhanced CT or MRI.[4] It was difficult to conduct ultrasounds for these patients due to severe tenderness at the hematoma site, decrease in hemoglobin level, and rapidly expanding hematoma. Therefore, contrast-enhanced CT was conducted immediately.\n\nThe treatment of pseudoaneurysm may vary depending on its size and symptoms. A pseudoaneurysm <2 cm in diameter that is not expanding can be treated conservatively. Among conservative treatments, ultrasound-guided compression repair (UGCR) can be the first option. A thrombus in the pseudoaneurysm lumen compresses the pseudoaneurysm neck and blocks the blood flow. If UGCR fails, embolization, in which thrombin or multiple small coils are injected into the aneurysm neck, is performed.[5] Surgical treatment can be considered when infection, rapid swelling, non-surgical treatment failure, skin necrosis, compression syndrome such as neuropathy, or claudication occurs.[6] Simple wound suturing after hematoma removal may be sufficient, while surgical reconstruction with a patch can be added as needed.[7] In these cases, conservative treatments such as compression using ultrasonography or a simple procedure could not be conducted due to severe pain and they needed emergency operations because of the rapid hematoma expansion, an abrupt decrease in hemoglobin, and symptoms of infection such as fever.\n\nThe use of an arterial puncture closure device such as the MYNXGRIP compared to manual compression did not affect the occurrence of complications. However, the occurrence of pseudoaneurysm was significantly higher for patients taking anticoagulant or antiplatelet agents.[8] Similarly, our patients’ bleeding was controlled using a hemostasis device while they were taking medications and a pseudoaneurysm occurred. This result suggests that it a future large-scale systematic prospective study of the effects and abnormal responses of a hemostasis device on patients taking anticoagulant or antiplatelet agents will be necessary.\n\nPseudoaneurysm is an important complication of femoral artery puncture that may lead to a poor prognosis for patients such as hematoma and infection. If a patient takes anticoagulant or antiplatelet agents, such as in our cases, it will be necessary to control bleeding using sufficient pressure for a sufficient time after femoral artery puncture. Moreover, it is important to identify the pseudoaneurysm as soon as possible by observing the patient carefully and continuously. Additionally, physicians must pay enough attention to these patients. For example, it is recommended that the hematoma development, puncture site, and fever be checked periodically. Thus, if a pseudoaneurysm is suspected, active treatment such as an emergency operation can be performed efficiently.\n\nAuthor contributions\nConceptualization: Seung-Ho Jeon, Hyun Goo Kang, Hong-Jin Kim, Man-Wook Seo, Byoung-Soo Shin.\n\nFormal analysis: Byoung-Soo Shin.\n\nFunding acquisition: Hyun Goo Kang.\n\nInvestigation: Seung-Ho Jeon.\n\nMethodology: Seung-Ho Jeon, Hyun Goo Kang, Hong-Jin Kim, Man-Wook Seo.\n\nSupervision: Hyun Goo Kang, Byoung-Soo Shin.\n\nWriting – original draft: Seung-Ho Jeon, Hyun Goo Kang, Byoung-Soo Shin.\n\nAbbreviations: CT = computed tomography, MRA = magnetic resonance angiography, MRI = magnetic resonance imaging, UGCR = ultrasound-guided compression repair.\n\nS-HJ and HGK contributed equally to this work.\n\nThe patients have given their consents for this case report.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nAll data and material supporting our findings are contained within the manuscript.\n\nFunding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, NRF-2017R1C1B5017293).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Baird R Doran M \nThe false aneurysm . Canad Med Assoc J \n1964 ;91 :281 –4 .14180533 \n[2] Morgan R Belli A-M \nCurrent treatment methods for postcatheterization pseudoaneurysms . J Vasc Interv Radiol \n2003 ;14 :697 –710 .12817037 \n[3] Gupta P Basheer A Sukumaran G \nFemoral artery pseudoaneurysm as a complication of angioplasty. How can it be prevented . Heart Asia \n2013 ;5 :144 –7 .27326111 \n[4] Ouriel K DeWeese JA \nManagement of peripheral arterial aneurysms. Vascular Surgery . 5th ed. 1994 ;Boston, MA : Springer , 377–383 .\n[5] Kang SS Labropoulos N Mansour MA \nPercutaneous ultrasound guided thrombin injection: a new method for treating postcatheterization femoral pseudoaneurysms . J Vasc Surg \n1998 ;27 :1032 –8 .9652465 \n[6] Webber GW Jang J Gustavson S \nContemporary management of postcatheterization pseudoaneurysms . Circulation \n2007 ;115 :2666 –74 .17515479 \n[7] Tisi PV Callam MJ \nSurgery versus non-surgical treatment for femoral pseudoaneurysms . Cochrane Database Syst Rev \n2009 ;2 :CD004981 .19370614 \n[8] Piedad BT Kronzon I \nIatrogenic femoral artery pseudoaneurysm . Curr Treat Options Cardiovasc Med \n2003 ;5 :103 –8 .12686007\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0025-7974", "issue": "98(17)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000368:Aged; D017541:Aneurysm, False; D017536:Carotid Artery, Common; D002404:Catheterization; D005263:Femoral Artery; D006801:Humans; D008297:Male; D015607:Stents", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e15309", "pmc": null, "pmid": "31027097", "pubdate": "2019-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Femoral artery pseudoaneurysm after carotid artery stenting: Two case reports.", "title_normalized": "femoral artery pseudoaneurysm after carotid artery stenting two case reports" }

[ { "companynumb": "KR-ACCORD-125900", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202925", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIPLATELET THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOPIDOGREL" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vascular pseudoaneurysm", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vessel puncture site haematoma", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "JEON SH, KANG HG, KIM HJ, SEO MW, SHIN BS. FEMORAL ARTERY PSEUDOANEURYSM AFTER CAROTID ARTERY STENTING: TWO CASE REPORTS. MEDICINE (BALTIMORE). 2019 APR?98(17):E15309.", "literaturereference_normalized": "femoral artery pseudoaneurysm after carotid artery stenting two case reports", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20190506", "receivedate": "20190506", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16274558, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]

{ "abstract": "We present a rare case of infantile pyoderma gangrenosum with an extended course and limited response to treatment. Despite extensive examination for an underlying disorder, the case remains idiopathic.", "affiliations": "Jefferson Medical College, Philadelphia, PA.", "authors": "Etzler|Chloe|C|;Cannon|Sarah|S|;Hyde|Patrice|P|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1111/pde.12318", "fulltext": null, "fulltext_license": null, "issn_linking": "0736-8046", "issue": "32(1)", "journal": "Pediatric dermatology", "keywords": null, "medline_ta": "Pediatr Dermatol", "mesh_terms": "D004351:Drug Resistance; D005260:Female; D006801:Humans; D007223:Infant; D017511:Pyoderma Gangrenosum", "nlm_unique_id": "8406799", "other_id": null, "pages": "156-7", "pmc": null, "pmid": "24894462", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Refractory pyoderma gangrenosum in an infant.", "title_normalized": "refractory pyoderma gangrenosum in an infant" }

[ { "companynumb": "US-JNJFOC-20150208978", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PYODERMA GANGRENOSUM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" } ], "patientagegroup": "2", "patientonsetage": "10", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyoderma gangrenosum", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ETZLER C, CANNON S, HYDE P. REFRACTORY PYODERMA GANGRENOSUM IN AN INFANT. PEDIATRIC DERMATOLOGY 2015;32/1:156-157.", "literaturereference_normalized": "refractory pyoderma gangrenosum in an infant", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150218", "receivedate": "20150218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10815114, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150721" } ]

{ "abstract": "Objectives: Acute kidney injury (AKI) at onset of adult systemic lupus erythematosus (SLE) is a risk factor for end stage kidney disease (ESKD). However, data on childhood-onset lupus nephritis (LN) with AKI are scarce.Methods: We retrospectively reviewed the complete files of pediatric SLE patients from 1995 to 2010. All patients underwent kidney biopsy promptly after diagnosis.Results: Thirty-six patients (10 males and 26 females) were enrolled. Mean age at diagnosis and observation period were 11.6 ± 2.4 and 8.1 ± 4.4 years, respectively. Seven patients had AKI at onset of SLE. Compared with those without AKI, patients with AKI had significantly higher proportions of pathologically proliferative LN. Only one patient with AKI progressed to ESKD without complete recovery of renal function. Overall and renal survival rates were 100and 97.2%, respectively. There was no significant difference in estimated glomerular filtration rate at the final visit (85ml/min/1.73 m2 in the AKI group vs. 103.2 ml/min/1.73 m2 in the non-AKI group; p = .11).Conclusion: Our study demonstrated favorable renal outcomes in childhood-onset LN with AKI in the near to midterm period. Inducing complete remission may be important for preserving renal function.", "affiliations": "Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.;Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.;Department of Pediatrics, Kakogawa Central City Hospital, Hyogo, Japan.;Department of Pediatrics, Himeji Red-Cross Hospital, Hyogo, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.;Department of Pediatrics, Ryukyu University Graduate School of Medicine, Okinawa, Japan.;Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, Hyogo, Japan.;Clinical Research Center, Wakayama Medical University, Wakayama, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, Japan.", "authors": "Ishimori|Shingo|S|;Kaito|Hiroshi|H|;Shima|Yuko|Y|;Kamioka|Ichiro|I|;Hamahira|Kiyoshi|K|;Nozu|Kandai|K|;Nakanishi|Koichi|K|;Tanaka|Ryojiro|R|;Yoshikawa|Norishige|N|;Iijima|Kazumoto|K|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/14397595.2018.1532861", "fulltext": null, "fulltext_license": null, "issn_linking": "1439-7595", "issue": "29(6)", "journal": "Modern rheumatology", "keywords": "Acute kidney injury; childhood-onset; lupus nephritis; renal prognosis; systemic lupus erythematosus", "medline_ta": "Mod Rheumatol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008181:Lupus Nephritis; D008297:Male; D012307:Risk Factors; D015996:Survival Rate", "nlm_unique_id": "100959226", "other_id": null, "pages": "970-976", "pmc": null, "pmid": "30289013", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Clinicopathological characteristics and renal outcomes of childhood-onset lupus nephritis with acute kidney injury: A multicenter study.", "title_normalized": "clinicopathological characteristics and renal outcomes of childhood onset lupus nephritis with acute kidney injury a multicenter study" }

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CLINICOPATHOLOGICAL CHARACTERISTICS AND RENAL OUTCOMES OF CHILDHOOD-ONSET LUPUS NEPHRITIS WITH ACUTE KIDNEY INJURY: A MULTICENTER STUDY. MODERN RHEUMATOLOGY. 2019?29(6):970-6", "literaturereference_normalized": "clinicopathological characteristics and renal outcomes of childhood onset lupus nephritis with acute kidney injury a multicenter study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20191216", "receivedate": "20191216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17159562, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "JP-MYLANLABS-2019M1123620", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIZORIBINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIZORIBINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapy non-responder", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ISHIMORI S, KAITO H, SHIMA Y, KAMIOKA I, HAMAHIRA K, NOZU K, ET AL. CLINICOPATHOLOGICAL CHARACTERISTICS AND RENAL OUTCOMES OF CHILDHOOD-ONSET LUPUS NEPHRITIS WITH ACUTE KIDNEY INJURY: A MULTICENTER STUDY. MOD-RHEUMATOL 2019?29(6):970-976.. 2019?29(6):970-976", "literaturereference_normalized": "clinicopathological characteristics and renal outcomes of childhood onset lupus nephritis with acute kidney injury a multicenter study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20191213", "receivedate": "20191213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17151355, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "OBJECTIVE\nTo address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea.\n\n\nMETHODS\nFrom May 2005 to May 2007, cases of DILI (alanine transferase > 3 × upper normal limit or total bilirubin > 2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used.\n\n\nRESULTS\nA total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included \"herbal medications\" (102, 27.5%), \"prescription or non-prescription medications\" (101, 27.3%), \"health foods or dietary supplements\" (51, 13.7%), \"medicinal herbs or plants\" (35, 9.4%), \"folk remedies\" (32, 8.6%), \"combined\" (30, 8.2%), \"herbal preparations\" (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hy's law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM.\n\n\nCONCLUSIONS\nDILI appears to be a highly relevant health problem in Korea. \"Herbal medications\" are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.", "affiliations": "Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea.", "authors": "Suk|Ki Tae|KT|;Kim|Dong Joon|DJ|;Kim|Chang Hoon|CH|;Park|Seung Ha|SH|;Yoon|Jai Hoon|JH|;Kim|Yeon Soo|YS|;Baik|Gwang Ho|GH|;Kim|Jin Bong|JB|;Kweon|Young Oh|YO|;Kim|Byung Ik|BI|;Kim|Seok Hyun|SH|;Kim|In Hee|IH|;Kim|Ju Hyun|JH|;Nam|Soon Woo|SW|;Paik|Yong Han|YH|;Suh|Jeong Ill|JI|;Sohn|Joo Hyun|JH|;Ahn|Byung Min|BM|;Um|Soon Ho|SH|;Lee|Heon Ju|HJ|;Cho|Mong|M|;Jang|Myoung Kuk|MK|;Choi|Sung Kyu|SK|;Hwang|Seong Gyu|SG|;Sung|Ho Taik|HT|;Choi|Jong Young|JY|;Han|Kwang Hyub|KH|", "chemical_list": "D004365:Drugs, Chinese Herbal; D000082:Acetaminophen", "country": "United States", "delete": false, "doi": "10.1038/ajg.2012.138", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9270", "issue": "107(9)", "journal": "The American journal of gastroenterology", "keywords": null, "medline_ta": "Am J Gastroenterol", "mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000368:Aged; D056486:Chemical and Drug Induced Liver Injury; D004365:Drugs, Chinese Herbal; D005260:Female; D006801:Humans; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D063487:Prescription Drug Misuse; D015995:Prevalence; D011446:Prospective Studies; D056910:Republic of Korea", "nlm_unique_id": "0421030", "other_id": null, "pages": "1380-7", "pmc": null, "pmid": "22733303", "pubdate": "2012-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A prospective nationwide study of drug-induced liver injury in Korea.", "title_normalized": "a prospective nationwide study of drug induced liver injury in korea" }

[ { "companynumb": "KR-JNJFOC-20120908845", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "UNSPECIFIED INGREDIENT" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "UNKNOWN MEDICATION" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "019872", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "MORE THAN 4 GM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETAMINOPHEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug-induced liver injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SUK KT, KIM DJ, KIM CH, PARK SH, YOON JH, KIM YS, ET AL. A PROSPECTIVE NATIONWIDE STUDY OF DRUG-INDUCED LIVER INJURY IN KOREA. THE AMERICAN JOURNAL OF GASTROENTEROLOGY SEP-2012;107:1380-1387.", "literaturereference_normalized": "a prospective nationwide study of drug induced liver injury in korea", "qualification": "1", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20150605", "receivedate": "20120927", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8812007, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "The world is facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although kidney transplant recipients are at increased risk for viral infections, the impact of their chronic immunosuppressed status on the risk for acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown.\nAll cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management, and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mammalian target of rapamycin inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients.\n22 COVID-19 infections were diagnosed in our cohort of 1,200 kidney transplant recipients.\nMost common initial symptoms included fever, cough, or dyspnea. 18 (82%) patients required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Computed tomography of the chest at admission (performed in 15 patients) showed mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. 11 patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non-ICU units, 1 was in the ICU, and 2 patients had died.\nSmall sample size and short follow-up.\nThe clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19 infection.", "affiliations": "Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.;Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.", "authors": "Devresse|Arnaud|A|;Belkhir|Leila|L|;Vo|Bernard|B|;Ghaye|Benoit|B|;Scohy|Anaïs|A|;Kabamba|Benoit|B|;Goffin|Eric|E|;De Greef|Julien|J|;Mourad|Michel|M|;De Meyer|Martine|M|;Yombi|Jean-Cyr|JC|;Kanaan|Nada|N|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.xkme.2020.06.001", "fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595\nElsevier\n\nS2590-0595(20)30112-6\n10.1016/j.xkme.2020.06.001\nOriginal Research\nCOVID-19 Infection in Kidney Transplant Recipients: A Single-Center Case Series of 22 Cases From Belgium\nDevresse Arnaud 1\nBelkhir Leila 2\nVo Bernard 1\nGhaye Benoit 3\nScohy Anaïs 4\nKabamba Benoit 4\nGoffin Eric 1\nDe Greef Julien 2\nMourad Michel 5\nDe Meyer Martine 5\nYombi Jean-Cyr 4\nKanaan Nada [email protected]\n1∗\n1 Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n2 Internal Medicine and Infectious Disease, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n3 Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n4 Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n5 Abdominal Surgery and Transplantation, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium\n∗ Address for Correspondence: Nada Kanaan, MD, MSc, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, 1200 Brussels, Belgium. [email protected]\n15 6 2020\nJul-Aug 2020\n15 6 2020\n2 4 459466\n© 2020 The Authors\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nRationale & Objective\n\nThe world is facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although kidney transplant recipients are at increased risk for viral infections, the impact of their chronic immunosuppressed status on the risk for acquiring coronavirus disease 2019 (COVID-19) and disease severity is unknown.\n\nStudy Design\n\nAll cases of COVID-19 infection in our cohort of kidney transplant recipients were prospectively monitored. Clinical features, management, and outcomes were recorded. A standard strategy of immunosuppression minimization was applied: discontinue the antimetabolite drug and reduce trough levels of calcineurin or mammalian target of rapamycin inhibitors. Unless contraindicated, hydroxychloroquine was administered only to hospitalized patients.\n\nSetting & Participants\n\n22 COVID-19 infections were diagnosed in our cohort of 1,200 kidney transplant recipients.\n\nResults\n\nMost common initial symptoms included fever, cough, or dyspnea. 18 (82%) patients required hospitalization. Of those patients, 3 had everolimus-based immunosuppression. Computed tomography of the chest at admission (performed in 15 patients) showed mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1) involvement. Immunosuppression reduction was initiated in all patients. Hydroxychloroquine was administered to 15 patients. 11 patients required supplemental oxygen; 2 of them were admitted to an intensive care unit (ICU) with mechanical ventilation. After a median of 10 days, 13 kidney transplant recipients were discharged, 2 were hospitalized in non-ICU units, 1 was in the ICU, and 2 patients had died.\n\nLimitations\n\nSmall sample size and short follow-up.\n\nConclusions\n\nThe clinical presentation of COVID-19 infection was similar to that reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with 11% mortality among kidney transplant recipients hospitalized with COVID-19 infection.\n\nIndex Words\n\nCOVID-19\ncoronavirus disease 2019\nSars-CoV-2 virus\nkidney transplantation\nimmunosuppression\noutcomes\n==== Body\nPlain-Language Summary\n\nSpecific questions arise for kidney transplant recipients who are facing coronavirus disease 2019 (COVID-19) infection. As with other infections, the risk for acquiring COVID-19 might be increased due to the chronic state of immunosuppression. Also, the disease could present with increased severity with eventually poor outcome. Moreover, handling immunosuppression in that context can be challenging. We report our experience with 22 kidney transplant recipients followed up at our academic center in Belgium, in whom we applied a standard strategy of immunosuppression minimization and treatment. Clinical symptoms were similar to those reported in the general population. Among kidney transplant recipients hospitalized with COVID-19 infection, 11% died. Our study expands the knowledge base of COVID-19 infection in kidney transplant recipients.\n\nSince the first case was diagnosed in Wuhan, China, in December 2019, the world has faced a rapidly growing outbreak of a newly discovered contagious infectious disease: coronavirus disease 2019 (COVID-19). COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and primarily manifests as an acute respiratory illness with interstitial and alveolar pneumonia, but can affect multiple organs, such as heart, kidney, digestive tract, blood, and central nervous system.1 As of April 18, 2020, a total of 2,338,335 cases of COVID-19 infection have been confirmed in more than 185 countries and territories and at least 161,030 deaths have been reported to date.2\n\nIn Belgium, the first case of COVID-19 infection in the general population was diagnosed on February 4, 2020. To date, more than 42,000 cases have been reported, including more than 12,000 hospitalizations.3\n\nSpecific questions arise for transplant recipients who are facing COVID-19 infection. As with other infections, could the risk for acquiring COVID-19 be increased due to the chronic state of immunosuppression? Will the infection be more severe than in patients with normal immunity? Moreover, how should immunosuppressive therapy be handled in that context?\n\nCase reports of COVID-19 infection in kidney transplant recipients4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and limited case series14, 15, 16 with a small number of patients have been published to date. In this study, we report 22 COVID-19 disease cases among our cohort that currently includes 1,200 kidney transplant recipients followed up in our academic institution in Belgium.\n\nMethods\n\nPatient Selection\n\nBefore the outbreak onset, about 1,200 kidney transplant recipients who underwent transplantation and were followed up in our hospital in collaboration with peripheral centers were recorded in our database as alive with a functioning graft. Since the first case of COVID-19 infection was diagnosed in Belgium, we have been prospectively monitoring all cases of proven COVID-19 infection in our cohort of kidney transplant recipients followed up in our academic center. Colleagues from peripheral centers with whom we share routine follow-up and managerial decisions of patients were invited by mail to report on all their patients with COVID-19 infection. To date, 22 kidney transplant recipients have been diagnosed with COVID-19 infection (n = 14 in our transplantation center and n = 8 in peripheral centers). Clinical features, management, and outcomes were recorded.\n\nThe study was approved by the local ethics committee (Comité d'Ethique Hospitalo-Facultaire Saint-Luc- Brussels-Belgium; approval number: B 403). The need for informed consent was waived due to deidentified information.\n\nImpact of COVID-19 on Daily Transplantation Activities\n\nSince the onset of the COVID-19 outbreak in Belgium, daily transplantation activities have been severely affected in the whole country. Kidney transplantation is considered only in patients with “high-urgency” status (ie, imminent lack of access for dialysis or psychiatric contraindication to dialysis) or in hypersensitized patients on the waiting list for more than 5 years. In our center, no kidney transplantations have been performed since March 1, 2020. The activity of the outpatient clinic has also been dramatically reduced. Patients were advised very early to stay at home, avoid public transportation and unnecessary contact, and report every symptom before coming to the outpatient clinic. The vast majority of consultations are made by telephone and patients are asked to come in our center only if they underwent transplantation less than 6 months ago or if they have an unstable clinical situation (increase in serum creatinine level, new-onset proteinuria,…), or newly developed symptoms. In case of COVID-19 infection suspicion, patients were sent to a dedicated COVID unit at the emergency department.\n\nDiagnosis\n\nAll kidney transplant recipients presenting symptoms compatible with COVID-19 infection were tested and fully evaluated by a physician (clinical evaluation, chest x-ray, and/or pulmonary computed tomography [CT] and nasopharyngeal swab for reverse-transcriptase polymerase chain reaction [PCR] laboratory test). The laboratory diagnosis of SARS-CoV-2 infection was confirmed by using the Coronavirus COVID-19 genesig Real-Time PCR assay (Primerdesign Ltd) on a nasopharyngeal swab, targeting the RNA-dependent RNA polymerase (RdRp) gene. The amplification was performed on the LightCycler 480 instrument (Roche Diagnostics) according to the manufacturer’s recommendations. A cycle threshold value less than 40 was defined as a positive test.\n\nAssessment of Pulmonary Involvement Using CT\n\nIn patients in whom CT of the chest was performed at admission, the type of lesion and degree of pulmonary parenchyma involvement were reported using the French Society of Radiology classification.17\n\nPulmonary involvement is classified as mild (<10%), moderate (10%-25%), extensive (25%-50%), severe (50%-75%), or critical (>75%). Figure 1 illustrates 3 CT patterns: mild, moderate and severe patterns, respectively.Figure 1 Images are presented in 3-dimensional volume-rendering technique mode to allow an optimal comparison between patients on a single frontal view. (A) Healthy patient. Only the lung contours and walls of bronchi and pulmonary vessels can be depicted. The normal lung parenchyma containing air appears in black. (B) Patient with mild coronavirus disease 2019 (COVID-19) involvement. Ground glass opacities (GGOs) appear in grey (arrowheads) mostly in the central part of the lungs, while consolidations appear in white in the peripheral and basal parts of both lungs (long arrows). (C) Patient with moderate COVID-19 involvement. The GGO is more extensive than in B, while consolidations are prominent in the right upper area. (D) Patient with severe COVID-19 involvement. Both lungs are involved with extensive central and peripheral GGOs. Consolidations are preferentially seen in the peripheral parts of both lungs.\n\nTreatment and Management of Immunosuppression\n\nKidney transplant recipients receive standard immunosuppression in our center, based on a combination of tacrolimus, mycophenolate, and steroids. Daily mycophenolate and steroid doses are 1 g and 4 mg, respectively. Tacrolimus trough levels are 10 to 13 ng/mL during the first month, 7 to 10 ng/mL for the next 2 months, and then 5 to 7 ng/mL. Everolimus is used in case of history of cancer or calcineurin inhibitor nephrotoxicity with a trough level of 5 to 7 ng/mL. Cyclosporine therapy is continued in patients who underwent transplantation before the use of tacrolimus or because of tacrolimus intolerance with trough levels of 50 to 70 ng/mL. Azathioprine is used at a daily dose of 1 mg/kg in case of mycophenolate intolerance or pregnancy desire.\n\nFor COVID-19–infected kidney transplant recipients, we have designed a standard strategy of immunosuppression minimization and treatment, which was sent to our colleagues from peripheral centers at the onset of the outbreak. In all cases, treatment with the antimetabolite drug (mycophenolate or azathioprine) is stopped; the daily dose of tacrolimus, cyclosporine, or everolimus is reduced to reach trough levels at 3 to 5 ng/mL, 30 to 40 ng/mL, and 3 to 5 ng/mL, respectively. The routine steroid dose is unchanged (4 mg/d of methylprednisolone). In case of life-threatening situations (eg, critical admission in the intensive care unit [ICU]), tacrolimus, cyclosporine, or everolimus treatment is stopped. Adjunctive treatment with corticosteroids has been provided to some patients after careful case-by-case evaluation, considering the extent of respiratory involvement and hyperinflammatory status.\n\nIn all kidney transplant recipients requiring hospitalization, following interim Belgian recommendations,18 hydroxychloroquine can be administered in patients with no cardiac contraindication at the discretion of the physician depending on the patient clinical situation for 5 days (400 mg twice daily day 1 and then 200 mg twice daily up to day 5; for estimated glomerular filtration rates < 30 mL/min/1.73 m2, 400 mg twice daily day 1 and then 200 mg/d up to day 5). Hydroxychloroquine treatment is initiated only if the corrected QT interval on the electrocardiogram is > 500 milliseconds.\n\nResults\n\nBaseline Characteristics\n\nFrom March 14, 2020, to April 15, 2020, a total of 22 COVID-19 infections were diagnosed in our cohort. Four patients were mildly ill and were sent back home after their first clinical evaluation. In all 4 patients, the antimetabolite treatment was stopped. They were called by telephone at least twice a week by a transplant physician. Symptoms rapidly improved in all 4 patients.\n\nEighteen patients required hospitalization. Their baseline characteristics are summarized in Table 1. Except for 2 patients, all had comorbid conditions, including treated hypertension, treated diabetes, history of cardiovascular event, obesity, dementia/intellectual disability, and active metastatic malignancy.Table 1 Characteristics of the 18 Hospitalized COVID-19–Infected Kidney Transplant Recipients\n\nCharacteristics\tPopulation (n = 18)\t\nAge, y\t57 (41-73)\t\nWomen\t10 (56%)\t\nRace\t\t\n White\t11 (61%)\t\n North African\t4 (22%)\t\n Asian\t1 (6%)\t\n Black\t2 (11%)\t\nDelay from KT, mo\t89 (1-402)\t\nACE inhibitor/ARB use\t10 (56%)\t\nComorbid conditions\t\t\n Hypertension\t14 (78%)\t\n Diabetes\t4 (22%)\t\n Cardiovascular\t4 (22%)\t\n Obesity\t4 (22%)\t\n Active malignancy\t1 (6%)\t\n Dementia/intellectual disability\t2 (11%)\t\nImmunosuppression\t\t\n Inductiona\t6 (33%)\t\n Tac/MPA/St\t7 (39%)\t\n Tac/Aza/St\t1 (6%)\t\n Tac/St\t2 (11%)\t\n EVL/MPA/St\t3 (16%)\t\n Csa/MPA/St\t2 (11%)\t\n Csa/Aza/St\t2 (11%)\t\n Csa/St\t1 (6%)\t\nClinical presentation\t\t\n Fever\t14 (78%)\t\n Cough\t12 (67%)\t\n Dyspnea\t7 (39%)\t\n Digestive symptoms\t5 (28%)\t\n Neurologic symptoms\t3 (16%)\t\nRadiological presentation on CTb\t\t\n Mild\t3/15 (20%)\t\n Moderate\t8/15 (53%)\t\n Extensive\t1/15 (7%)\t\n Severe\t2/15 (13%)\t\n Critical\t1/15 (7%)\t\nLaboratory parameters at admission\t\t\n Baseline eGFR, mL/min/1.73 m2\t45 (15-95)\t\n C-Reactive protein, mg/Lc\t56 (1.5-314)\t\n Lymphocyte count, /μLd\t730 (50-1440)\t\nNote: Values for categorical variables are given as number (percent); values for continuous variables are given as median (range).\n\nAbbreviations: ACE, angiotensin-converting-enzyme; ARB, angiotensin II receptor blocker; Aza, azathioprine; COVID-19, coronavirus disease 2019; Csa, cyclosporine; CT, computed tomography; eGFR, estimated glomerular filtration rate; EVL, everolimus; KT, kidney transplantation; MPA, mycophenolate; Tac, tacrolimus; St, steroids.\n\na Antithymocyte globulin (n = 4) or basiliximab (n = 2).\n\nb Available for 15 patients.\n\nc Normal value < 5.0 mg/L.\n\nd Normal value of 800 to 5,000/μL.\n\nClinical, Laboratory, and Radiologic Presentation at Diagnosis\n\nThe clinical, laboratory, and radiologic presentation of the 18 hospitalized patients is summarized in Table 1. Interestingly, patient 18 (Table 2), currently in the ICU, showed the highest C-reactive protein (CRP) level. Fifteen underwent CT of the chest at admission. Pulmonary lesions were classified as mild (n = 3), moderate (n = 8), extensive (n = 1), severe (n = 2), and critical (n = 1), respectively.Table 2 Clinical Features of the 18 Hospitalized COVID-19–Infected Kidney Transplant Recipients\n\nPatient\tLength of Stay, d\tAge, y\tSex\tDelay From KT, mo\tIS\tSymptoms\tCT\tIS Management\tOther Treatment\tO2\tAKI\tICU\tOutcome\t\n1\t13\t50s\tM\t191\tTac-MPA-St\tFever+C+Dig\tSevere\tStop MPA\n↘ Tac\tHC\tNC\tNo\tNo\tHome\t\n2\t10\t60s\tM\t102\tEVL-MPA-St\tD+C+N\tND\tStop MPA\n↘ EVL\tHCa\tNC + IV\tNo\tYes, 2 d\tHome\t\n3\t16\t60s\tF\t1\tTac-MPA-St\tFever+D+C\tModerate\tStop MPA\n↘ Tac\tHC\tNo\tNo\tNo\tHome\t\n4\t16\t60s\tF\t250\tTac-St\tN+Dig\tModerate\t↘Tac\tHC\tNo\tNo\tNo\tHome\t\n5\t17\t50s\tM\t2\tTac-MPA-St\tFever+C\tModerate\tStop MPA\n↘ Tac\tHC +\n↗ steroidsb\tNC\tYes\tNo\tHome\t\n6\t17\t60s\tM\t357\tCsa-St\tFever+C\tMild\tNone\tHC\tNC\tNo\tNo\tHome\t\n7\t2\t60s\tF\t260\tCsa-MPA-St\tFever+D+C+N\tND\tNone\tNo\tNo\tNo\tNo\tDeathc\t\n8\t20\t50s\tF\t101\tTac-Aza-St\tC\tModerate\tStop Aza\n↘ Tac\tHC\tNC\tYes\tNo\tDeathc\t\n9\t26\t60s\tF\t36\tTac-MPA-St\tFever+C\tModerate\tStop MPA\n↘ Tac\tHCd\tNC\tYes\tNo\tHome\t\n10\t3\t50s\tF\t402\tCsA-Aza-St\tFever+Dig\tMild\tStop Aza\tNo\tNC\tNo\tNo\tHome\t\n11\t6\t40s\tF\t268\tCsa-MPA-St\tFever+C+D\tModerate\tStop Aza\n↘ Csa\tHC\tNo\tNo\tNo\tHome\t\n12\tOngoing\t40s\tF\t376\tCsa-Aza-St\tFever+C+Dig\tND\tStop Aza\n↘ Csa\tNo\tNo\tNo\tNo\tNon-ICU COVID unit\t\n13\t7\t40s\tF\t3\tEVL-MPA-St\tFever\tExtensive\tStop MPA\n↘ EVL\tHC\tNo\tNo\tNo\tHome\t\n14\t7\t50s\tM\t74\tTac-MPA-St\tFever+C+D\tMild\tStop MMF\n↘ Tac\tHC\tNC\tNo\tNo\tHome\t\n15\t8\t50s\tM\t48\tTac-St\tAsthenia\tSevere\tNonee\tHC\tNC\tYes\tNo\tHome\t\n16\t10\t70s\tM\t10\tTac-MPA-St\tFever\tModerate\tStop MPA\n↘ Tac\tHC\tNo\tNo\tNo\tHome\t\n17\tOngoing\t60s\tF\t5\tTac-MPA-St\tFever+D\tCritical\tStop MPA\n↘ Tac\tHC\tNC\tNo\tNo\tNon-ICU COVID unit\t\n18\tOngoing\t40s\tM\t77\tEVL-MPA-St\tFever+C+D+Dig\tModerate\tStop MPA\nStop EVL\tHC +\n↗steroidsf\tNC +IV\tYes\tYes, ongoing\tICU, critical\t\nAbbreviations: AKI, acute kidney injury; Aza, azathioprine; C, cough; COVID-19, coronavirus disease 2019; Csa, cyclosporine; CT, computed tomography; D, dyspnea; Dig, digestive symptoms; EVL, everolimus; F, female; HC, hydoxychloroquine; ICU, intensive care unit; IS, immunosuppression; IV, invasive ventilation; KT, kidney transplantation; M, male; MMF, mycophenolate mofetil; MPA, mycophenolate; N, neurologic symptoms; NC, nasal cannula; ND, not done; Tac, tacrolimus; St, steroids.\n\na This patient received 5 days of intravenous cefuroxime for suspected concomitant bacterial infection.\n\nb Three-day course of methylprednisolone, 32 mg/d.\n\nc No ICU because of severe comorbid conditions, death in palliative unit.\n\nd This patient received antibiotics for concomitant acute pyelonephritis.\n\ne Tac already reduced for BK virus viremia.\n\nf Methylprednisolone, 16 mg/d, for 2 days and then 1 mg/kg (ongoing).\n\nManagement of Hospitalized Patients\n\nThe management and outcomes of hospitalized patients are described in Table 2. With the exception of 1 patient (patient 7, discussed later), our local protocol of immunosuppression minimization was applied: the antimetabolite treatment was stopped and the tacrolimus/cyclosporine/everolimus dose was reduced to reach trough level targets, as per protocol. Fifteen of the 18 (83%) hospitalized patients were treated with hydroxychloroquine and 2 (11%) had an increase in steroid doses (Table 2). We did not observe cardiac side effects during hydroxychloroquine treatment. However, we observed an increase in tacrolimus trough levels in 5 patients after the initiation of hydroxychloroquine treatment. One patient (patient 2) also received 5 days of intravenous cefuroxime because of suspected additional pulmonary infection.\n\nEleven (61%) patients received supplemental oxygen during hospitalization. Only 2 patients were transferred to the ICU and received invasive ventilation (patients 2 and 18). Both were receiving everolimus because of a history of cancer. Patient 2 was a man in his 60s with a history of osteosarcoma of the thigh and was known for advanced dementia with Lewy bodies. He was admitted for dyspnea and worsening confusion. Chest x-ray findings were compatible with COVID-19 infection that was confirmed by reverse-transcriptase PCR in a nasopharyngeal swab. Oxygen saturation level was normal at admission, but his neurologic status deteriorated within hours, associated with severe hypercapnia. He was admitted to the ICU and rapidly intubated. Nevertheless, the clinical situation improved promptly and invasive ventilation was stopped after 48 hours. He was sent back home 10 days after admission.\n\nPatient 18 was a man in his 40s with a history of Hodgkin cervical lymphoma at age 15 years. He was admitted for fever, dyspnea, dry cough, and diarrhea. Clinical workup showed mild hypoxemia requiring oxygen at 2 L/min using a nasal cannula. CT of the chest showed bilateral pneumonia classified as moderate. Mycophenolate treatment was stopped and hydroxychloroquine treatment was started. However, oxygen needs increased progressively. Five days after admission, the patient showed signs of severe respiratory distress with hypoxemia. He was admitted to the ICU and rapidly intubated. Everolimus treatment was stopped and steroid dosages were increased at 16 mg/d of methylprednisolone for 2 days and then at 1 mg/kg (80 mg) per day because he did not improve. At the time of writing of this report, his condition remains critical, requiring invasive ventilation with a high level of oxygen (fraction of inspired oxygen of 100%).\n\nFive cases of acute kidney injury (defined as plasma creatinine increase > 50% from baseline or plasma creatinine increase ≥ 0.3 mg/dL)19 were observed during hospitalization (28%). However, acute kidney injury rapidly resolved with intravenous hydration, and no patient required dialysis. Overall, kidney function remained stable in the hospitalized patients (Table 2). Baseline estimated glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) before COVID-19 infection was 45 (range, 15-95) mL/min/1.73 m2 versus 38 (range, 15-101) mL/min/1.73 m2 at last follow-up. One patient (patient 9) presented with an acute pyelonephritis associated with bacteremia during hospitalization, but rapidly responded to antibiotic treatment.\n\nOutcomes\n\nAfter a median follow-up of 18 (range, 5-30) days, 13 (72%) of the 18 hospitalized patients recovered and were sent home (no readmissions to date) after a median of 10 (range, 2-26) days. Three (17%) patients are still currently hospitalized in our institution, and 2 (11%) have died. Both patients (patients 7 and 8) who died from COVID-19 infection also presented with very severe comorbid conditions: the first had metastatic uterine carcinoma and was terminally ill, and the second had severe active scleroderma associated with very impaired general health status, which had been deteriorating during the past months. Both patients were considered terminally ill and died in palliative care units. The rate of death of hospitalized COVID-19–infected kidney transplant recipients in our cohort is 11.1% (2/18).\n\nThe severity of pulmonary parenchyma involvement on CT performed at admission did not seem to influence outcome. For example, both patients who showed the most severe involvements on CT (patients 15 and 17) had rapidly favorable clinical evolutions (the first patient was dismissed from the hospital after 8 days and the second patient, though still hospitalized, no longer requires supplemental oxygen). Conversely, patient 18, who is currently intubated in the ICU, needing very high levels of oxygen, had moderate pulmonary involvement on CT at admission.\n\nDiscussion\n\nBecause of their chronic immunosuppressed status, kidney transplant recipients are at increased risk for many viral infections (cytomegalovirus, herpes zoster, norovirus infections…).20,21 Thus, higher rates of infection with COVID-19 and/or increased severity of the disease in our transplant population was feared. However, in past epidemics with Middle East respiratory syndrome (MERS) and SARS-CoV-1, this increased risk was not observed.22\n\nAs in the general population,1 the most common symptoms in our cohort of kidney transplant recipients with COVID-19 infection were fever, dry cough, and dyspnea. As reported,5,23,24 we also observed some atypical presentations with predominant digestive symptoms and acute confusion. Interestingly, the severity of pulmonary involvement on CT of the chest at admission was not associated with worse clinical outcome. Some patients with images of severe pulmonary involvement recovered well, whereas the only patient currently in the ICU had moderate involvement at admission with subsequent dramatic evolution. This suggests that CT of the chest at admission is useful for diagnosis but does not provide prognostic information. However, other factors may affect the severity of the pulmonary involvement on the first CT of the chest, such as the interval between the onset of symptoms and the CT and the presence of underlying chronic pulmonary diseases. Little is known about early markers that may predict the clinical evolution. Tan et al25 recently showed that CRP level increased early in severe COVID-19 infection, before CT findings, suggesting that the initial evolution of CRP levels might provide more prognostic information than early CT. In line with this hypothesis, patient 18 (Table 1) showed a rapid increase in CRP level from 90 mg/L on the day of admission to 304 mg/L on the day of transfer to the ICU (6 days after).\n\nThe current management of COVID-19 disease in kidney transplant recipients still remains ill-defined despite guidelines provided by many scientific societies.26, 27, 28 All these guidelines suggest drastically reducing immunosuppression, especially in clinical situations requiring admittance to the ICU. Of course, no randomized controlled trials have been conducted to assess how immunosuppression should be reduced and how to resume it after remission.\n\nOne important question is the optimal management of kidney transplant recipients who are receiving a mammalian target of rapamycin inhibitor (mTORi)-based regimen. Though mTORis are known to reduce the risk for developing cytomegalovirus or BK virus infections after kidney transplantation,29 their impact on SARS-CoV-2 is currently unknown. mTORis are believed to lead to a proinflammatory status by increasing the production of some cytokines, including interleukin 12 (IL-12), IL-6, IL-1, and IL-23), and tumor necrosis factor α. Thus, the mTORi capacity to boost the deleterious inflammatory response involved in COVID-19 infection is an important yet unresolved question. In this context, some guidelines26,27 have advocated withdrawing mTORis in all COVID-19–infected kidney transplant recipients requiring hospitalization. In our cohort, 3 (16.6%) of the 18 hospitalized kidney transplant recipients had mTORi-based immunosuppression. mTORi treatment was reduced, but maintained, in 2 patients (patients 2 and 13) who finally recovered. By contrast, mTORi treatment was stopped the day patient 18 was admitted to the ICU. He is to date the only patient who has developed such a severe pulmonary illness. Factors associated with worse respiratory outcomes still need to be identified. In patient 18, besides mTORi, comorbid conditions and history of cancer might have put him at risk for untoward evolution. Genetic background such as HLA antigen polymorphisms or angiotensin-converting enzyme polymorphism could also be implicated in the individual response to infection; their precise identification will probably shed some light on how to better handle infection in high-risk populations.30,31\n\nEighty-three percent of our hospitalized kidney transplant recipients received hydroxychloroquine. Early reports suggest a role for hydroxychloroquine in reducing the viral load.32 However, the impact of hydroxychloroquine on the clinical outcome of COVID-19–infected patients is largely unknown and highly debated. Even if hydroxychloroquine was safely used in our cohort, we cannot draw any conclusion regarding its efficacy because of the absence of a control group. The currently recruiting DISCOVERY and SOLIDARITY trials (NCT04315948 and NCT04321616, respectively) will provide some answers regarding treatment efficacy in the general population. The results of these trials will then need to be extrapolated to the kidney transplant recipient population.\n\nNone of our patient received the antivirals currently in the pipeline33 or promising specific anti-inflammatory drugs such as the anti–IL-6 tocilizumab34 because of their unavailability outside of a clinical trial. Interesting data regarding the use of tocilizumab were reported by Alberici et al15 in 6 kidney transplant recipients with severe pneumonia: 3 patients experienced reduction in oxygen requirements and 2 showed improvement in radiologic findings. Two patients eventually died and 1 was discharged from the hospital 9 days after tocilizumab administration.15\n\nIn our cohort, the kidney function outcome was satisfactory. Although 28% of hospitalized patients experienced acute kidney injury, none required hemodialysis. Moreover, kidney function rapidly stabilized after appropriate hydration. To date, we have not observed any acute rejection episodes, but the current follow-up of our patients is short. Because there is a correlation between immunosuppression reduction and increased risk for acute rejection,35 appropriate monitoring of kidney function should be continued and reintroduction of immunosuppressive drugs should be tailored after infection recovery.\n\nAt the time of writing this report, 2 kidney transplant recipients from our cohort died of COVID-19 infection. However, as mentioned, both patients had very severe comorbid conditions and were terminally ill. Italian and Spanish teams have reported higher mortality rates of 27.8% and 25% in the former and latter studies, respectively.14,15 Closer to our findings, a British team reported a 14% mortality rate in their series that included 7 kidney transplant recipients.16\n\nLarger data from US centers have been recently published. Pereira et al36 recently reported a 2-center experience of 90 solid-organ transplant recipients with COVID-19 infection, including 46 kidney transplant recipients. Among the kidney transplant recipients, 12 had severe disease defined as a need for mechanical ventilation, ICU admission, or death. The general management was similar to ours with immunosuppression reduction (88%) and the use of hydroxychloroquine (91%). Sixteen patients from the entire cohort (24%) had died by the end of follow-up. Although this report provides a broad picture of COVID-19 infection in solid-organ transplant recipients, it does not focus on kidney transplant recipients, making it difficult to compare with our population.\n\nAkalin et al37 also published a US case-series including 36 kidney transplant recipients with 28 (78%) requiring hospitalization. Management was not uniform as in our series because immunosuppression reduction and hydroxychloroquine treatment were used in 86%, and patients also received azithromycin (46%), the CCR5 inhibitor leronlimab (21%), and tocilizumab (7%). Interestingly, although kidney transplant recipients from this cohort seem similar to ours regarding comorbid conditions, the outcome appears more severe, with 11 (39%) kidney transplant recipients requiring mechanical ventilation and 6 (21%) requiring kidney replacement therapy. The mortality rate was also higher at the end of follow-up (28% vs 11% in our patients). A possible explanation might be the ethnic origin of the patients in that cohort because 39% and 42% were black and Hispanic, respectively, which differs from our population. These differences in disease severity and outcomes between centers and countries will need to be closely analyzed in larger cohorts with longer follow-up.\n\nIn conclusion, we report our experience of 22 kidney transplant recipients with COVID-19 infection, of whom 18 required hospitalization. Clinical symptoms were similar to those reported in the general population. A standard strategy of immunosuppression minimization and treatment was applied, with a mortality rate for kidney transplant recipients hospitalized for COVID-19 infection of 11%. Further studies with a higher number of patients and longer follow-up are required to better assess the optimal management and outcomes of kidney transplant recipients with COVID-19 infection.\n\nArticle Information\n\nAuthors’ Full Names and Academic Degrees\n\nArnaud Devresse, MD, Leila Belkhir, MD, PhD, Bernard Vo, MD, Benoit Ghaye, MD, PhD, Anaïs Scohy, PharmD, MSc, Benoit Kabamba, MD, PhD, Eric Goffin, MD, Julien De Greef, MD, Michel Mourad, MD, PhD, Martine De Meyer, MD, Jean-Cyr Yombi, MD, and Nada Kanaan, MD, MSc.\n\nAuthors’ Contributions\n\nResearch idea, study design, data analysis: AD, NK; data acquisition: AD, BV; providing and interpreting CT scans images: BG; performed PCR analysis: AS, BK; patient care: AD, BV, NK, EG, MM, MDM, JCY, JDG, LB. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.\n\nSupport\n\nNone.\n\nFinancial Disclosure\n\nThe authors declare that they have no relevant financial interests.\n\nPeer Review\n\nReceived April 27, 2020. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form June 3, 2020.\n\nComplete author and article information provided before references.\n==== Refs\nReferences\n\n1 Wang D. Hu B. Hu C. 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Incidence, risk factors and clinical consequences of neutropenia following kidney transplantation: a retrospective study Am J Transplant 9 8 2009 1816 1825 19538494\n36 Pereira M.R. Mohan S. Cohen D.J. COVID-19 in solid organ transplant recipients: initial report from the US epicenter Am J Transplant 20 2020 1800 1808 32330343\n37 Akalin E. Azzi Y. Bartash R. Covid-19 and kidney transplantation N Engl J Med 382 2020 2475 2477 32329975\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2590-0595", "issue": "2(4)", "journal": "Kidney medicine", "keywords": "COVID-19; Sars-CoV-2 virus; coronavirus disease 2019; immunosuppression; kidney transplantation; outcomes", "medline_ta": "Kidney Med", "mesh_terms": null, "nlm_unique_id": "101756300", "other_id": null, "pages": "459-466", "pmc": null, "pmid": "32775986", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "32279418;32302078;32181990;25073040;32273181;32031570;32243672;31027892;32354634;32282991;32198834;32330343;32090448;32205204;32292866;32301155;32233067;32354637;32253759;32299017;32281668;32329975;22977217;32220422;32301198;32243690;19538494;32282977", "title": "COVID-19 Infection in Kidney Transplant Recipients: A Single-Center Case Series of 22 Cases From Belgium.", "title_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium" }

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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. 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COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191948, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197167", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "211688", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191946, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197179", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "090253", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191749, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197178", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Polyomavirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191469, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197176", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191272, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197174", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191622, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197170", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191632, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197168", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFUROXIME" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFUROXIME." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191945, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-TEVA-2020-BE-1824880", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "2", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" } ], "patientagegroup": "5", "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory distress", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "COVID-19 pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B, ET AL. COVID-19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE-CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY-MED 2020?2(4):459-466.", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20201020", "receivedate": "20200907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18237395, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210113" }, { "companynumb": "BE-ACCORD-197173", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "2020", "drugenddateformat": "602", "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191621, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197172", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CICLOSPORIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18191633, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-ACCORD-197181", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY MED. 2020 JUN 15?2(4):459?466", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200825", "receivedate": "20200825", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18189823, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "BE-TEVA-2020-BE-1824882", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "65457", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM DAILY;", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" } ], "patientagegroup": "6", "patientonsetage": "7", "patientonsetageunit": "800", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neurological decompensation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypercapnia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "COVID-19", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DEVRESSE A, BELKHIR L, VO B, GHAYE B, SCOHY A, KABAMBA B, ET AL. COVID?19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE?CENTER CASE SERIES OF 22 CASES FROM BELGIUM. KIDNEY?MED 2020?2(4):459?466.", "literaturereference_normalized": "covid 19 infection in kidney transplant recipients a single center case series of 22 cases from belgium", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200907", "receivedate": "20200907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 18237423, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20201103" } ]

{ "abstract": "We describe the compassionate use of high dose insulin dextrose (HID) for life threatening metformin associated lactic acidosis (MALA) in four patients admitted to intensive care.\nPatients presenting with refractory lactic acidosis believed to be secondary to metformin poisoning were included.High dose insulin dextrose at 0.5units/kg/hour was infused in 50% dextrose. Frequent blood gas analysis allowed titration of therapy. All patients also received continuous veno-venous haemofiltration.\nAll four patients recovered to normal or near normal lactate and pH between 10 and 24 hours of therapy. Two patients had significant separation in time between initiation of HID and haemofiltration to suggest an independent effect of HID on improving pH and lactate.All patients had at least one episode of hypoglycaemia below 4.0 mmol/L with the lowest glucose in any patient during therapy being 3.0 mmol/L. All episodes were corrected with a dextrose infusion without sequelae.\nOur study demonstrates that HID therapy appears to be safe in patients with suspected metformin poisoning. It also appears to work to drive down lactate, improve pH and patients' clinical condition. Further evidence is required to assess the effectiveness of HID therapy in the context of MALA.", "affiliations": "Newham University Hospital, London, United Kingdom.;Newham University Hospital, London, United Kingdom.;Newham University Hospital, London, United Kingdom.;Newham University Hospital, London, United Kingdom.", "authors": "Young|Theodore|T|;Cevallos|Joaquim|J|;Napier|James|J|;Martin-Lazaro|Juan|J|", "chemical_list": null, "country": "Lithuania", "delete": false, "doi": "10.6001/actamedica.v26i1.3958", "fulltext": null, "fulltext_license": null, "issn_linking": "1392-0138", "issue": "26(1)", "journal": "Acta medica Lituanica", "keywords": "acidosis; insulin; lactate; metformin", "medline_ta": "Acta Med Litu", "mesh_terms": null, "nlm_unique_id": "9442465", "other_id": null, "pages": "72-78", "pmc": null, "pmid": "31281219", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "10617608;11602624;1504710;15898827;18945920;19556031;20345411;20577053;21545617;21563902;23549904;24713415;24847880;25283255;25538310;29069937;29291990;29343628;29617642;9205542;9802770", "title": "Metformin poisoning treated with high dose insulin dextrose therapy: a case series.", "title_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series" }

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METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?VOL. 26. NO. 1:72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16418517, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-BAUSCH-BL-2019-018048", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. 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METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MED LITU. 2019?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190720", "receivedate": "20190720", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16600306, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-035763", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. 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METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190621", "receivedate": "20190621", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16465349, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "GB-MYLANLABS-2019M1093842", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26 (1):72-8", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191014", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16898609, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-MYLANLABS-2019M1093836", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26 (1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191016", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16898612, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-INDICUS PHARMA-000604", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "079148", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MED LITU. 2019?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190725", "receivedate": "20190725", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16629630, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "GB-BAUSCH-BL-2019-017584", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "78", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190621", "receivedate": "20190621", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16465350, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" }, { "companynumb": "GB-MYLANLABS-2019M1094655", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191017", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16900190, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-036188", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26 (1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190628", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16489100, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-MYLANLABS-2019M1093831", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075973", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191015", "receivedate": "20191009", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16898615, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-TEVA-2019-GB-1062047", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16418665, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-036181", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA.. 2019?26 (1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190628", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16493435, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-AUROBINDO-AUR-APL-2019-036190", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77095", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 GRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T.. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES.. ACTA MEDICA LITUANICA.. 2019?26(1):72-78", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190628", "receivedate": "20190628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16491911, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-TEVA-2019-GB-1062044", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190611", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16414641, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-TEVA-2019-GB-1062048", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "075979", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019 MAR 26?26(1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190612", "receivedate": "20190612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16419371, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190711" }, { "companynumb": "GB-BAUSCH-BL-2019-018047", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021748", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METFORMIN" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lactic acidosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YOUNG T, CEVALLOS J, NAPIER J, MARTIN-LAZARO J. METFORMIN POISONING TREATED WITH HIGH DOSE INSULIN DEXTROSE THERAPY: A CASE SERIES. ACTA MEDICA LITUANICA. 2019?26 (1):72-78.", "literaturereference_normalized": "metformin poisoning treated with high dose insulin dextrose therapy a case series", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190625", "receivedate": "20190625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16474983, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "BACKGROUND\nDabigatran etexilate (dabigatran) is a direct thrombin inhibitor anticoagulant agent. There is limited information about the changes in coagulation profile and outcomes in overdose. A monoclonal antibody has been developed to neutralize the anticoagulant effect of dabigatran. Case reports describe enhanced clearance of dabigatran by haemodialysis as an intervention to prevent haemorrhagic complications - however, the threshold for initiating haemodialysis is not well defined in an asymptomatic patient with normal renal function.\n\n\nMETHODS\nTwo patients presented following deliberate dabigatran overdoses. A 55-year-old woman ingested 10 × 150 mg dabigatran. A 21-year-old woman with a history of systemic lupus erythematosus and pulmonary embolus ingested 100 × 110 mg dabigatran. Both were admitted to the intensive care unit and managed expectantly. Serial coagulation tests normalized over 60 h. The half-life of dabigatran was not prolonged following overdose, being calculated between 7 and 11 h in each case. There was positive correlation between international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT) with plasma dabigatran levels.\n\n\nCONCLUSIONS\nThere is limited experience with dabigatran overdoses. Normal aPTT, PT and INR assays 12 h following deliberate ingestion indicate that the drug concentration is not high. Individual risk assessment of bleeding risk needs to be formulated for each patient and expectant management is reasonable in the presence of normal renal function and absent risk factors for bleeding.", "affiliations": "a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia ;;a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia ;;b Intensive Care Unit, Joondalup Hospital , Perth , Australia.;a Emergency Department , Sir Charles Gairdner Hospital , Perth , Australia ;", "authors": "Vlad|Ioana|I|;Armstrong|Jason|J|;Ridgley|James|J|;Pascu|Ovidiu|O|", "chemical_list": "D000925:Anticoagulants; D000069604:Dabigatran", "country": "England", "delete": false, "doi": "10.3109/15563650.2015.1126287", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-3650", "issue": "54(3)", "journal": "Clinical toxicology (Philadelphia, Pa.)", "keywords": "Anticoagulant; coagulation test; dabigatran; overdose", "medline_ta": "Clin Toxicol (Phila)", "mesh_terms": "D000437:Alcoholism; D000925:Anticoagulants; D001780:Blood Coagulation Tests; D003422:Critical Care; D000069604:Dabigatran; D062787:Drug Overdose; D005260:Female; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D008991:Monitoring, Physiologic; D011655:Pulmonary Embolism; D012307:Risk Factors; D055815:Young Adult", "nlm_unique_id": "101241654", "other_id": null, "pages": "286-9", "pmc": null, "pmid": "26735702", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring.", "title_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring" }

[ { "companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2022-00293", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "208040", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 ? 110 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anticoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE MESYLATE" } ], "patientagegroup": null, "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Vlad L, Armstrong J, Ridgley J, Pascu O et al. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila). 2016;54(3):286-9", "literaturereference_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20220330", "receivedate": "20220330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20656118, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220423" }, { "companynumb": "AU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-02838BI", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 TABLETS X 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VLAD I,ARMSTRONG J,RIDGLEY J,PASCU O. DABIGATRAN DELIBERATE OVERDOSE: TWO CASES AND SUGGESTIONS FOR LABORATORY MONITORING. JOURNAL OF TOXICOLOGY. CLINICAL TOXICOLOGY 2016?.", "literaturereference_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring", "qualification": "3", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "AU", "receiptdate": "20160223", "receivedate": "20160223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12105971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160526" }, { "companynumb": "AU-ALKEM LABORATORIES LIMITED-AU-ALKEM-2022-00292", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "208040", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 ? 150 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "Anticoagulant therapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN ETEXILATE MESYLATE" } ], "patientagegroup": null, "patientonsetage": "55", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Vlad L, Armstrong J, Ridgley J, Pascu O et al. Dabigatran deliberate overdose: two cases and suggestions for laboratory monitoring. Clin Toxicol (Phila). 2016;54(3):286-9", "literaturereference_normalized": "dabigatran deliberate overdose two cases and suggestions for laboratory monitoring", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20220330", "receivedate": "20220330", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20656121, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 2, "transmissiondate": "20220423" } ]

{ "abstract": "Vancomycin is used in the treatment of infections caused by gram-positive bacteria resistant to beta-lactam antibiotics. It is also used in the treatment ofenterococci, although this use has been limited due to resistance. The authors report the clinical and pathological presentations of 5 different vancomycin hypersensitivity reactions, including morbilliform eruption, erythroderma, acute generalized exanthematous pustulosis, linear immunoglobulin A bullous dermatosis, and toxic epidermal necrolysis. With the increased prevalence of beta-lactam-resistant bacteria, reliance on vancomycin continues to increase; thus, the recognition of reactions to this drug will be helpful in caring for patients who require this medication in the future.", "affiliations": "Department of Dermatology, Drexel University College of Medicine, 219 North Broad Street, Philadelphia, PA 19107, USA.", "authors": "O'Brien|Meghan|M|;Shah|Avnee|A|;Allen|Herbert B|HB|", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1540-9740", "issue": "9(4)", "journal": "Skinmed", "keywords": null, "medline_ta": "Skinmed", "mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000293:Adolescent; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003873:Dermatitis, Exfoliative; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012872:Skin Diseases, Vesiculobullous; D013262:Stevens-Johnson Syndrome; D014640:Vancomycin; D028761:Withholding Treatment", "nlm_unique_id": "101168327", "other_id": null, "pages": "225-9", "pmc": null, "pmid": "21980707", "pubdate": "2011", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A pentad of vancomycin reactions.", "title_normalized": "a pentad of vancomycin reactions" }

[ { "companynumb": "US-PFIZER INC-2011316213", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "062911", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RESPIRATORY FAILURE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HCL" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ALLEN, H.. A PENTAD OF VANCOMYCIN REACTIONS. SKINMED. 2011?9 (4):225?229", "literaturereference_normalized": "a pentad of vancomycin reactions", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200821", "receivedate": "20120105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8322378, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "A 7-year-old girl with an unremarkable medical history presented to a local paediatric emergency department with a 7-day history of fever, sore throat and vomiting, and a 1-day history of rash. She was admitted to the hospital, with presumed Kawasaki disease. A few hours after admission, the patient had sudden onset of two witnessed tonic-clonic seizures and subsequent decreased mental status. She was transferred to the paediatric intensive care unit and started on broad-spectrum antibiotics. On hospital day 2, cerebral spinal fluid cultures and blood cultures grew Streptococcus pyogenes, and repeat physical examination was consistent with acute streptococcal pharyngitis. On hospital day 3, the patient developed left-sided hemiparesis and had another witnessed seizure. A CT scan was obtained and revealed a subdural abscess. She was transferred to a tertiary care centre and underwent craniotomy with evacuation of her subdural abscess. Surgical cultures eventually grew S. pyogenes.", "affiliations": "Department of Family Medicine, University of North Carolina Chapel Hill, Greensboro, North Carolina, USA.;Cone Health Family Medicine Residency, Greensboro, North Carolina, USA.;Cone Health Family Medicine Residency, Greensboro, North Carolina, USA.", "authors": "Walden|Jeffrey Howard|JH|;Hess|Bryan|B|;Rigby|Michael|M|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2015()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D002648:Child; D013354:Empyema, Subdural; D005260:Female; D006801:Humans; D010291:Paresis; D010612:Pharyngitis; D012640:Seizures; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26385939", "pubdate": "2015-09-18", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11889374;18635385;7442993;24300473;10069590;15173504;15629962", "title": "Streptococcal pharyngitis: an uncommon cause of subdural empyema.", "title_normalized": "streptococcal pharyngitis an uncommon cause of subdural empyema" }

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{ "abstract": "The prevalence of chronic myeloid leukemia and multiple myeloma has increased in recent years partly because of an improved therapeutic armamentarium for both conditions. Likewise, understanding the complexity inherent in designing combination treatment strategies will become increasingly prescient in the coming years. We describe, to the best of our knowledge, the first reported patient to be treated with second-generation tyrosine kinase inhibitor therapy while on novel therapy for myeloma. The combination was well tolerated and effective for the treatment of chronic myeloid leukemia and concurrent myeloma.", "affiliations": "Departments of aOncology bOncology Pharmacy, Kaiser Permanente, Santa Clara, California cJohn Theurer Cancer Center, Hackensack UMC, Hackensack, New Jersey, USA.", "authors": "Katzel|Jed A|JA|;Lee-Ma|Annette|A|;Vesole|David H|DH|", "chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D001897:Boronic Acids; D011719:Pyrazines; D011743:Pyrimidines; D000069286:Bortezomib; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases", "country": "England", "delete": false, "doi": "10.1097/CAD.0000000000000262", "fulltext": null, "fulltext_license": null, "issn_linking": "0959-4973", "issue": "26(8)", "journal": "Anti-cancer drugs", "keywords": null, "medline_ta": "Anticancer Drugs", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D011505:Protein-Tyrosine Kinases; D011719:Pyrazines; D011743:Pyrimidines", "nlm_unique_id": "9100823", "other_id": null, "pages": "907-9", "pmc": null, "pmid": "26111050", "pubdate": "2015-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Safety of a second-generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma.", "title_normalized": "safety of a second generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma" }

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{ "abstract": "The introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in BRAF-mutant intracranial metastatic melanoma, most tumors will eventually progress. This demonstrates a gap in addressing the best management in such patients. Here, we present a case demonstrating our approach in this patient population.", "affiliations": "Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.;Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA.", "authors": "Khaddour|Karam|K|https://orcid.org/0000-0001-6697-3516;Johanns|Tanner M|TM|;Ansstas|George|G|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.2217/mmt-2020-0022", "fulltext": "\n==== Front\nMelanoma Manag\nMelanoma Manag\nMMT\nMelanoma Management\n2045-0885\n2045-0893\nFuture Medicine Ltd London, UK\n\n10.2217/mmt-2020-0022\nCase Report\nBRAF-MEK inhibitors as steroid-sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma\nhttps://orcid.org/0000-0001-6697-3516\nKhaddour Karam 1\nJohanns Tanner M 1\nAnsstas George *1\n1 Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, Saint Louis, MO 63110, USA\n* Author for correspondence: [email protected]\n15 2 2021\n6 2021\n15 2 2021\n8 2 MMT5510 11 2020\n21 1 2021\n15 2 2021\n© 2021 George Ansstas\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License\n\nThe introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in BRAF-mutant intracranial metastatic melanoma, most tumors will eventually progress. This demonstrates a gap in addressing the best management in such patients. Here, we present a case demonstrating our approach in this patient population.\n\nTweetable abstract\n\nManagement of symptomatic BRAF-mutated intracranial melanoma.\n\nKeywords: \n\nBRAF-MEK\nbrain\nimmune checkpoint blockade\nintracranial\nipilimumab\nmetastatic melanoma\nnivolumab\nsteroids\nsymptomatic\ntargeted therapy\n==== Body\nPractice points\n\nStandard of care is lacking regarding the best approach in treating patients with symptomatic intracranial BRAF-mutated melanoma.\n\nSymptomatic patients with intracranial metastatic melanoma are often treated with dexamethasone to control brain edema.\n\nThe use of steroids at baseline can decrease the antitumor efficacy of immune checkpoint blockade (ICB) and lead to poor outcomes.\n\nObjective response to ICB in symptomatic metastatic intracranial melanoma is low and is associated with short duration of response.\n\nObjective response rate to combined BRAF-MEK inhibitors in BRAF-mutated intracranial melanoma is high, albeit short duration of response prior to progression.\n\nPresence of mutations such as CDKN2A is associated with a shorter duration of response to BRAF-MEK inhibitors in patients with BRAF-mutated melanoma.\n\nPreclinical and clinical data suggest the efficacy of ICB might be compromised in patients who receive ICB after progressing during treatment with BRAF-MEK inhibitors.\n\nUsing BRAF-MEK inhibitors (short course) in BRAF-mutated symptomatic intracranial metastatic melanoma might allow the discontinuation of steroids and lead to higher intracranial response. This might optimize the effect of ICB if started prior to progression of the disease.\n\nMelanoma brain metastases represent a unique spectrum of metastatic melanoma due to high associated morbidity and mortality. This is of importance as a high proportion of patients (∼36%) have evidence of intracranial metastases at the time of diagnosis [1]. Survival has improved significantly with the introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors. However, some patients have a high disease burden (defined as ≥3 intracranial lesions), and often demonstrate neurological symptoms. These cases represent a challenge in clinical practice as most clinical trials excluded patients with symptomatic brain metastases. Moreover, the immunosuppressive state caused by baseline use of dexamethasone, which is used to relieve neurological symptoms and brain edema, can attenuate the response to ICB and lead to poorer responses and outcomes [2–5]. Furthermore, despite the high efficacy of targeted treatment with combination BRAF and MEK inhibitors in intracranial metastatic BRAF-mutated melanoma, most tumors will eventually progress due to acquired resistance. Genomic alterations such as the loss of expression of CDKN2A can contribute to acquired resistance leading to a short-lived response to targeted therapy [6,7]. Therefore, the heterogenous molecular nature of melanoma could further compromise the duration of response to targeted therapy. Here, we report the case of a patient successfully treated with planned sequential BRAF-MEK inhibitors followed by ICB after presenting with high-burden, symptomatic intracranial metastatic melanoma requiring high dose dexamethasone. The patient had detectable BRAFV600E and CDKN2A mutations. The treatment course included administration of BRAF-MEK inhibitors for 8 weeks while discontinuing dexamethasone followed by ipilimumab-nivolumab administration. The patient had a near-complete radiological resolution of intracranial disease after initiating ICB with an ongoing durable response at 8 months of follow-up.\n\nCase presentation\n\nA 50-year old female presented with new left arm weakness, headache, slurred speech and vision disturbance. Her past medical history was significant for stage IA melanoma in the left chest wall diagnosed 5 years prior for which she underwent wide local excision. She had another lesion in the left lower extremity 2 years later consistent with malignant melanoma (Stage IB: T1bN0M0), which was treated with wide local excision and sentinel lymph node biopsy. The patient underwent brain magnetic resonance imaging (MRI) due to presence of neurological symptoms which showed numerous scattered lesions (30 lesions) involving the supratentorial and infratentorial compartments bilaterally, consistent with metastatic disease (Figure 1A). The patient was started on dexamethasone (4 mg orally, three-times daily) due to symptomatic vasogenic edema (Figure 2A). Chest computed tomography (CT) revealed a 3 cm right upper lobe pulmonary mass which was biopsied and confirmed malignant melanoma. Next-generation sequencing revealed presence of a BRAFV600E mutation (VAF 41.1%), CDKN2A copy number loss, and tumor mutation burden of 11.1 mutation per megabase (Tempus xT assay). The patient completed whole brain radiation WBRT (total of 30 Gy over 10 fractions) prior to referral to our hospital for further evaluation and management. Repeat brain MRI confirmed persistence of intracranial metastatic lesions. We tapered off dexamethasone within 3-week period after starting treatment with BRAF inhibitor (encorafenib 300 mg once daily orally) and MEK inhibitor (binimetinib 45 mg twice daily orally) as a bridge to control the symptomatic brain lesions prior to initiation of ICB. There were no side effects noted during treatment, and brain MRI after 8 weeks demonstrated partial response in several lesions without new neurological symptoms (Figure 1B). There was also continued resolution of brain edema after starting targeted therapy (Figure 2B). CT showed partial response in pulmonary metastatic lesion. Encorafenib and binimetinib were discontinued 8 weeks after their initiation despite no evidence of progressive disease, and the patient switched to ICB combination therapy including ipilimumab (3 mg/kg intravenously) and nivolumab (1 mg/kg intravenously) every three weeks. Given the risk of rebound disease and flare-up after the discontinuation of targeted therapy, the patient was closely monitored in the clinic but did not demonstrate any concerning signs or symptoms. After the second cycle of ICB, there was near-complete resolution noted on brain MRI. In addition, repeat CT demonstrated complete resolution of the pulmonary metastatic lesion. The patient developed hepatitis (immune related adverse event grade 3) which required holding off ICB and a treatment with 4-week course of high-dose prednisone taper (started 1 mg/kg/day). The patient later started maintenance ICB therapy with nivolumab (480 mg intravenously every 4 weeks). She remains without neurological symptoms and brain MRI continues to show a durable response in intracranial brain metastases after 8 months of initiating treatment (Figure 1C).\n\nFigure 1. Brain MRI demonstrating intracranial metastatic changes during treatment of the patient in the case report.\n\n(A) Axial section of brain MRI in T1 post contrast phase prior to treatment with BRAF-MEK inhibitors which demonstrates 30 scattered enhancing lesions in the supratentorial and infratentorial compartments bilaterally with associated edema. (B) Demonstrates reduction in the size and the number of several lesions 8 weeks after treatment with BRAF-MEK inhibitors and prior to administration of immunotherapy. (C) Marked decrease in the size of bilateral cerebral and cerebellar metastatic lesions with near-complete resolution of several lesions after 6 months of treatment with ICB.\n\nICB: Immune checkpoint blockade.\n\nFigure 2. Brain MRI demonstrating with FLAIR signal demonstrating brain edema.\n\n(A) Axial section of brain MRI with FLAIR signal showing large diffuse signal abnormality throughout the brain prior to treatment with steroids. (B) Significant reduction of the signal abnormality at end of treatment with BRAF-MEK inhibitors.\n\nDiscussion\n\nThe integration of ICB into the treatment paradigm of patients with intracranial metastatic melanoma has substantially improved overall survival compared with the pre-immunotherapy era based on data collected from the national cancer database [1]. Further prospective trials have corroborated the high and durable efficacy of ICB in intracranial metastatic melanoma. One such example is the CheckMate-204 Phase II open-label trial, which prospectively evaluated combination ICB (ipilimumab and nivolumab) followed by maintenance nivolumab in 94 patients with asymptomatic intracranial metastases [8]. This trial demonstrated a high intracranial response rate of 57% (including complete and partial responses) which was similar to the extracranial metastatic response rate. Moreover, the estimated overall survival rate was 81.5% at 1-year which further substantiated the evidence of the intracranial durable response attained through treatment with ICB [8]. Nevertheless, the evidence supporting the use of ICB in patients with high burden symptomatic intracranial metastatic melanoma and those who are treated with a high dose of steroids at baseline is lacking as most clinical trials have excluded patients with the previous characteristics. This stems from the notion that immunosuppression at baseline (including the use of steroids) could reduce the antitumor efficacy of ICB and lead to short-lived response. To this end, another cohort of the CheckMate-204 study addressed this issue by evaluating the efficacy of ipilimumab and nivolumab in 18 patients with symptomatic melanoma brain metastases of which 39% had three or more brain lesions and 61% were on dexamethasone (4 mg or less) [9]. The results demonstrated an objective response rate (ORR) of 22% which was inferior to the response rate observed in patients with asymptomatic brain metastases and those who are not receiving steroids at baseline (ORR = 57%) [9].\n\nInterestingly, BRAF-MEK inhibitors have an advantage over ICB given the high response rates in patients with both asymptomatic and symptomatic intracranial metastatic melanoma whose tumors harbor BRAFV600 mutations (>50 and 59%, respectively) [10]. Nevertheless, the high response rates in intracranial metastases are temporary, as the majority of patients treated with targeted therapy progress eventually, which is likely secondary to acquired resistance mechanisms [10,11]. The presence of CDKN2A copy number loss has been suggested to contribute to resistance to BRAF-MEK inhibitors in melanoma and lead to a shorter duration of response and inferior outcomes [6,7,12]. In addition, the duration of response in intracranial melanoma metastases is shorter compared with extracranial disease [10,13,14]. Of importance, one concern upon discontinuation of BRAF-MEK inhibitors is the rebound effect caused by reactivation of the BRAF kinase which could result in a flare-up and worsening of the metastatic disease [15]. Collectively, the previous evidence supports the high efficacy of BRAF-MEK inhibitors in patients with BRAFV600E melanoma brain metastases, albeit short duration of response with early progression during treatment and the concern of possible flare-up upon discontinuation of targeted therapy.\n\nOur case highlights the challenge often encountered in clinical practice when making a decision to treat patients with BRAF-mutated and symptomatic intracranial metastatic melanoma who are receiving baseline high dose steroids. The use of ICB as a front-line therapy in these patients is expected to be associated with low efficacy and short durable response based on the available evidence. As such, BRAF-MEK inhibitors in these patients can offer an advantage in obtaining high response as their efficacy is not compromised by steroids. However, the obtained response with targeted therapy is sustained for a short period prior to progression. Therefore, we followed an approach using BRAF-MEK inhibitors as a bridge to allow the discontinuation of glucocorticoid and to obtain a response in the intracranial metastatic disease prior to initiating ICB (evidenced by the partial radiological response, decrease in intracranial lesion numbers and control of neurological symptoms). We hypothesized such an approach would allow the resolution of the immunosuppressive effect of steroids and optimize the response to ICB. The presence of CDKN2A copy number loss further supported our rationale to use BRAF-MEK inhibitors temporarily given the short duration of response associated with this genetic alteration [6,7]. It should be noted that whole-brain radiotherapy could have contributed to the response obtained in the intracranial disease, however, we believe that most of the benefit obtained in the intracranial disease in our case was secondary to the use of BRAF-MEK inhibitors given the depth of response.\n\nRecently, there has been an increased interest in evaluating the use of BRAF-MEK inhibitors with ICB in the treatment of metastatic melanoma. These efforts are assessing several approaches in clinical trials including combination targeted and immunotherapy or the sequential use of BRAF-MEK inhibitors followed by ICB and is summarized in Table 1 [16–21]. This is based on the role of BRAF-MAPK pathway in the modulation of the tumor biology in melanoma. Preclinical research supports this notion as BRAFV600E mutant melanoma is associated with immunosuppressive tumor microenvironment leading to diminished antigen presentation and decreased CD8+ T cells [22]. As such, inhibition of the BRAF-MAPK pathway can alter tumor microenvironment favoring an immune permissive effect, which can facilitate the action of ICB [23]. To this end, the concurrent use of BRAF-MEK inhibitors and ICB or the sequenced use could favor a higher response with improved survival and is currently under investigation. Of importance, it has been suggested that when using an approach utilizing targeted therapy followed by ICB, waiting until progression while on BRAF-MEK inhibitors prior to starting immunotherapy could lead to an immunosuppressive environment and downregulation of effector T cells, which could negatively impact the efficacy of ICB [24]. This further supports our approach of switching BRAF-MEK inhibitors to ICB prior to an evidence of progressive disease in our patient.\n\nTable 1. Selected studies of sequenced or combined targeted therapy with immune checkpoint blockade in metastatic melanoma.\n\nStudy (year)\tStudy design\tPatients (n)\tModality of treatment\tPresence of intracranial metastases\tPrimary end point\tSurvival results\tRef.\t\nGutzmer et al. (2020)\tProspective randomized double blinded Phase III\t256\tCombination atezolizumab, vemurafenib and cobimetinib\tYes (5 patients in the study arm)\tPFS\t15.1 vs 10.6 months\t[16]\t\nPuzanov et al. (2020)\tPost hoc Pooled analysis of three clinical trials\t271\tPreviously treated with BRAFi with or without MEKi and later were treated with pembrolizumab\tYes (46 patients in the study arm)\tORR, PFS, OS\tLower ORR, PFS and OS†\t[17]\t\nDummer et al. (2020)\tSingle arm safety run in from Phase III COMBI-I trial\t36\tCombination spartalizumab, dabrafenib, trametinib\tNot included\tDose limiting toxicity\nbiomarker analysis‡\t24 months PFS was 41%\t[18]\t\nBurton et al. (2019)\tSingle arm Phase II\t24\tCombination nivolumab, dabrafenib, trametinib\tIncluded\tSafety and ORR§\tNot provided\t[19]\t\nRibas et al. (2015)\tPhase I\t50\tCombination durvalumab, dabrafenib, trametinib\tNot included\tSafety\tNot provided\t[20]\t\nAmin et al. (2016)\tPhase II\t46\tVemurafenib followed by ipilimumab\tNot included\tSafety\tmPFS was 4.5 months\t[21]\t\n† Baseline characteristics were significantly different in the compared subgroups.\n\n‡ PFS was a secondary end point in the study.\n\n§ ORR was 89% in 19 evaluable patients.\n\nBRAFi: BRAF inhibitor; MEKi: MEK inhibitor; PFS: Progression-free survival; ORR: Objective response rate; OS: Overall survival.\n\nThe preclinical evidence of the compromised outcome with ICB treatment in patients who progressed on BRAF-MEK inhibitors has been echoed by a recent Phase-II trial (ABC trial), which evaluated the efficacy of ICB in 76 patients with melanoma brain metastases [25]. This study included a cohort of 16 patients with symptomatic or leptomeningeal brain metastases of which 75% received ICB treatment after they progressed while on BRAF-MEK inhibitors, and were found to have low response rates (ORR = 6%, progressive disease 81%) [25].\n\nConclusion\n\nThis report describes a patient with BRAF-mutant symptomatic intracranial metastatic melanoma who was successfully treated with BRAF-MEK inhibitors as a bridge to allow discontinuation of steroids prior to ICB therapy. The patient had significant clinical and radiographic response ongoing at 8 months after initiating therapy. Our observation with the previous reported literature suggest: treatment with BRAF-MEK inhibitors may allow the discontinuation of steroids in patients with symptomatic BRAF mutant intracranial metastatic melanoma; bridging temporarily with BRAF-MEK inhibitors prior to evidence of progressive disease may optimize the efficacy of ICB and lead to a durable response; and; integration of tumor molecular characteristics such as CDKN2A copy number loss can aid in planning treatment (favoring a short course with targeted therapy and considering other treatments prior to disease progression). While this case report provides proof-of-concept, further clinical trials are needed to confirm stated conclusions.\n\nFuture perspective\n\nTo date, the management of patients with metastatic intracranial melanoma and symptomatic disease remains challenging with very limited therapeutic options. The use of steroids to relieve symptom associated morbidity might hinder the efficacy of ICB. The role of targeted therapy in such patients with BRAF-mutated melanoma is a possible avenue to circumvent the use of steroids. Research is currently ongoing to investigate the efficacy and safety of and approach combining versus sequencing BRAF-MEK inhibitors and ICB in metastatic melanoma which will offer further insight on the possible role of utilizing short-term targeted therapy prior to ICB in patients with symptomatic intracranial melanoma.\n\nAuthor contributions\n\nThis case report was conceptualized by K Khaddour and G Ansstas. K Khaddour reviewed the literature, wrote the manuscript and created Table 1. K Khaddour, G Ansstas and TM Johanns reviewed the manuscript.\n\nFinancial & competing interests disclosure\n\nThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\n\nNo writing assistance was utilized in the production of this manuscript.\n\nEthical conduct of research\n\nThe authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.\n\nOpen access\n\nThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/\n==== Refs\nReferences\n\nPapers of special note have been highlighted as: • of interest; •• of considerable interest\n\n1. Iorgulescu JB, Harary M, Zogg CK Improved risk-adjusted survival for melanoma brain metastases in the era of checkpoint blockade immunotherapies: results from a National Cohort. Cancer Immunol. 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Burton EM, Amaria RN, Glitza IC Safety and efficacy of TRIplet combination of nivolumab (N) with dabrafenib (D) and trametinib (T) [TRIDeNT] in patients (pts) with BRAF-mutated metastatic melanoma (MM): a single center Phase II study [abstract 1312PD]. Poster presented at: European Society for Medical Oncology Congress. European Society for Medical Oncology Congress. Barcelona, Spain, 27 September–1 October 1, 2019.\n20. Ribas A, Butler M, Lutzky J Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma [abstract 3003]. Oral presentation at: American Society of Clinical Oncology Annual Meeting Chicago, IL, USA, 29 May–2 June, 2015.\n21. Amin A, Lawson DH, Salama AK Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma. J. Immunother. Cancer 4 , 44 (2016).27532019\n22. Bradley SD, Chen Z, Melendez B BRAFV600E co-opts a conserved MHC Class I internalization pathway to diminish antigen presentation and CD8+ T-cell recognition of melanoma. Cancer Immunol. Res. 3 (6 ), 602–9 (2015). 25795007\n••Study shows that BRAF-mutated melanoma is associated with immunosuppressive tumor microenvironment.\n\n23. Frederick DT, Piris A, Cogdill AP BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19 (5 ), 1225–31 (2013). 23307859\n• Study shows that BRAF inhibition counteract the immunosuppressive effect mediated through BRAF mutation.\n\n24. Dummer R, Ascierto PA, Nathan P Rationale for immune checkpoint inhibitors plus targeted therapy in metastatic melanoma: a review. JAMA Oncol. (Epub ahead of print).\n•• Comprehensive review suggests reduced efficacy of immune checkpoint blockade when administered in melanoma patients after progressing while on BRAF-MEK inhibitors.\n\n25. Long GV, Atkinson V, Lo S Long-term outcomes from the randomized Phase II study of nivolumab (nivo) or nivo + ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets): anti-PD1 brain collaboration (ABC). Ann. Oncol. 30 (Suppl. 5 ), 13110 (2019).\n• Prospective study shows that response rate and survival to immunotherapy are worse in patients with intracranial metastatic melanoma who previously had disease progression while being treated with BRAF-MEK inhibitors.\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2045-0885", "issue": "8(2)", "journal": "Melanoma management", "keywords": "BRAF-MEK; brain; immune checkpoint blockade; intracranial; ipilimumab; metastatic melanoma; nivolumab; steroids; symptomatic; targeted therapy", "medline_ta": "Melanoma Manag", "mesh_terms": null, "nlm_unique_id": "101649842", "other_id": null, "pages": "MMT55", "pmc": null, "pmid": "34084449", "pubdate": "2021-02-15", "publication_types": "D002363:Case Reports", "references": "31936151;25795007;33020648;26037941;32007138;27687304;28592387;32970096;25500362;23290787;25018652;32534646;26433819;30125216;30002157;32120803;32672795;27532019;30134131;23307859", "title": "BRAF-MEK inhibitors as steroid-sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma.", "title_normalized": "braf mek inhibitors as steroid sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma" }

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{ "abstract": "Respiratory syncytial virus (RSV) infection can cause lower respiratory tract disease and mortality in pediatric hematopoietic stem cell transplant (HSCT) recipients. We report two children who underwent HSCT and developed RSV infection simultaneously at the Bone Marrow Transplant Unit. The treatment with intravenous palivizumab was provided and sequential viral loads were measured in nasopharyngeal (NP) and whole blood samples. To our knowledge, this is the first report where RSV loads were measured in parallel (NP and blood), before and after palivizumab, in correlation with a favorable clinical outcome in both cases.", "affiliations": "Department of Pediatrics, Division of Pediatric Infectious Diseases, Hospital Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago, Chile.;Department of Pediatrics and Pediatric Surgery, Hospital Roberto del Río and Virology Program, Facultad de Medicina, Universidad de Chile, Santiago, Chile.;Transplant Unit, Hospital Luis Calvo Mackenna, Santiago, Chile.;Department of Pediatrics, Division of Pediatric Infectious Diseases, Hospital Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago, Chile.;Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, OH.", "authors": "Torres|Juan Pablo|JP|;Tapia|Lorena I|LI|;Catalán|Paula|P|;De la Maza|Verónica|V|;Mejías|Asunción|A|", "chemical_list": "D000998:Antiviral Agents; D000069455:Palivizumab", "country": "United States", "delete": false, "doi": "10.1002/pbc.26667", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(12)", "journal": "Pediatric blood & cancer", "keywords": "children; hematopoietic stem cell transplant; palivizumab; respiratory syncytial virus", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D000069455:Palivizumab; D018357:Respiratory Syncytial Virus Infections", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "28598593", "pubdate": "2017-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children.", "title_normalized": "intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children" }

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"actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": "12", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower respiratory tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Respiratory syncytial virus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Upper respiratory tract infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytomegalovirus chorioretinitis", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bacterial infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TORRES JP, TAPIA LI, CATALAN P, DE LA MAZA V, MEJIAS A. INTRAVENOUS PALIVIZUMAB IN RESPIRATORY SYNCYTIAL VIRUS INFECTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN CHILDREN. 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{ "abstract": "Patients with leptomeningeal disease (LMD) from melanoma have very poor outcomes and few treatment options. We present a case of intrathecal (i.t.) administration of autologous tumor-infiltrating lymphocytes (TIL) in a patient with LMD from metastatic melanoma. The patient developed LMD after previous treatments with surgery, high-dose bolus interleukin-2 (HD IL2), and systemic TIL infusion and experienced radiographic progression after intrathecal IL2 (i.t. IL2) therapy. The patient received weekly treatment with increasing numbers of i.t. TIL followed by twice-weekly i.t. IL2. The patient received three i.t. TIL infusions and did not experience any toxicities beyond those expected with i.t. IL2 therapy. Analysis of cerebrospinal fluid demonstrated increased inflammatory cytokines following the i.t.\n\n\nMETHODS\nSubsequent imaging demonstrated disease stabilization, and neurological deficits also remained stable. The patient expired 5 months after the initiation of i.t. TIL therapy with disease progression in the brain, liver, lung, and peritoneal and retroperitoneal lymph nodes, but without LMD progression. These results demonstrate the safety of i.t. administration of TIL in melanoma patients with LMD and support the feasibility of conducting a prospective clinical trial to determine this therapy's clinical benefit among these patients.", "affiliations": "Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. [email protected].;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.;Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.", "authors": "Glitza|Isabella C|IC|;Haymaker|Cara|C|;Bernatchez|Chantale|C|;Vence|Luis|L|;Rohlfs|Michelle|M|;Richard|Jessie|J|;Lacey|Carol|C|;Mansaray|Rahmatu|R|;Fulbright|Orenthial J|OJ|;Ramachandran|Renjith|R|;Toth|Christopher|C|;Wardell|Seth|S|;Patel|Sapna P|SP|;Woodman|Scott E|SE|;Hwu|Wen-Jen|WJ|;Radvanyi|Laszlo G|LG|;Davies|Michael A|MA|;Papadopoulos|Nicholas E|NE|;Hwu|Patrick|P|", "chemical_list": "D016207:Cytokines", "country": "United States", "delete": false, "doi": "10.1158/2326-6066.CIR-15-0071", "fulltext": null, "fulltext_license": null, "issn_linking": "2326-6066", "issue": "3(11)", "journal": "Cancer immunology research", "keywords": null, "medline_ta": "Cancer Immunol Res", "mesh_terms": "D016207:Cytokines; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007278:Injections, Spinal; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma; D055756:Meningeal Carcinomatosis; D008875:Middle Aged", "nlm_unique_id": "101614637", "other_id": null, "pages": "1201-6", "pmc": null, "pmid": "26216417", "pubdate": "2015-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "23358426;20960525;23160697;23032743;16939963;12173336;1737371;21498393;9420067;18287337;11300492;22527228;22594466", "title": "Intrathecal Administration of Tumor-Infiltrating Lymphocytes Is Well Tolerated in a Patient with Leptomeningeal Disease from Metastatic Melanoma: A Case Report.", "title_normalized": "intrathecal administration of tumor infiltrating lymphocytes is well tolerated in a patient with leptomeningeal disease from metastatic melanoma a case report" }

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"reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoaesthesia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GLITZA IC, HAYMAKER C, BERNATCHEZ C, VENCE L, ROHLFS M, RICHARD J ET AL.. INTRATHECAL ADMINISTRATION OF TUMOR-INFILTRATING LYMPHOCYTES IS WELL TOLERATED IN A PATIENT WITH LEPTOMENINGEAL DISEASE FROM METASTATIC MELANOMA: A CASE REPORT. CANCER IMMUNOLOGY RESEARCH. 2015?3 (11):1201-6", "literaturereference_normalized": "intrathecal administration of tumor infiltrating lymphocytes is well tolerated in a patient with leptomeningeal disease from metastatic melanoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160308", "receivedate": "20160308", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12161399, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "We describe the first case of a FLT-3 mutated AML in a healthy donor, 3years after recombinant human granulocyte colony stimulating factor (rhG-CSF)-mobilized peripheral blood stem cell (PBSC) harvest. The patient had a myeloablative (MA) matched unrelated donor (MUD) stem cell transplant (SCT) for refractory AML. However, he experienced a secondary graft failure. He had a second non myeloablative (NMA) on day +75 from a second MUD. He achieved a complete neutrophil and platelet engraftment. After 4years of follow up, he is alive in complete remission with full second donor chimerism.", "affiliations": "Staten Island University Hospital, Staten Island, NY 10305, USA.;Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.;Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: [email protected].", "authors": "Haddad|Housam|H|;Wungjiranirun|Manida|M|;Gergis|Usama|U|", "chemical_list": "D016179:Granulocyte Colony-Stimulating Factor", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": null, "issue": "9(3)", "journal": "Hematology/oncology and stem cell therapy", "keywords": "Filgrastim; Peripheral blood stem cell; Recombinant human granulocyte colony-stimulating factor; Stem cell donor", "medline_ta": "Hematol Oncol Stem Cell Ther", "mesh_terms": "D000328:Adult; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation; D014019:Tissue Donors", "nlm_unique_id": "101468532", "other_id": null, "pages": "123-5", "pmc": null, "pmid": "26173032", "pubdate": "2016-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Acute myeloid leukemia developing in a granulocyte colony-stimulating factor-mobilized stem cell donor: A case report and review of the literature.", "title_normalized": "acute myeloid leukemia developing in a granulocyte colony stimulating factor mobilized stem cell donor a case report and review of the literature" }

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ACUTE MYELOID LEUKEMIA DEVELOPING IN A GRANULOCYTE COLONY-STIMULATING FACTOR-MOBILIZED STEM CELL DONOR: A CASE REPORT AND REVIEW OF THE LITERATURE. HEMATOL ONCOL STEM CELL THER (2016)9, 123-25. 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUDARABINE" } ], "patientagegroup": "5", "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Trisomy 9", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute myeloid leukaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dyspnoea exertional", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Graft versus host disease", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WUNGJIRANIRUN M. ACUTE MYELOID LEUKEMIA DEVELOPING IN A GRANULOCYTE COLONY-STIMULATING FACTOR-MOBILIZED STEM CELL DONOR: A CASE REPORT AND REVIEW OF THE LITERATURE. HEMATOLOGY/ONCOLOGY + STEM CELL THERAPY. 2016;9(3):123-125", "literaturereference_normalized": "acute myeloid leukemia developing in a granulocyte colony stimulating factor mobilized stem cell donor a case report and review of the literature", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160926", "receivedate": "20160926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12780941, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" }, { "companynumb": "US-ASPEN PHARMA TRADING LIMITED US-AG-2017-000236", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HADDAD H, WUNGJIRANIRUN M, GERGIS U. ACUTE MYELOID LEUKEMIA DEVELOPING IN A GRANULOCYTE COLONY-STIMULATING FACTOR-MOBILIZED STEM CELL DONOR. A CASE REPORT AND REVIEW OF THE LITERATURE. HEMATOL ONCOL STEM CELL THER. 2016;9:123-125.", "literaturereference_normalized": "acute myeloid leukemia developing in a granulocyte colony stimulating factor mobilized stem cell donor a case report and review of the literature", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170127", "receivedate": "20170127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13157603, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "BACKGROUND\nTransrectal ultrasound-guided prostate biopsies (TRUSBx), in spite of being one of the most frequently performed urological office procedures, are associated with a spectrum of complications, most significantly including infection. The aim of the study is to evaluate the prevalence of fluoroquinolone-resistant bacteria in rectal swabs from our local population prior to TRUSBx and to identify risk factors among a patient population harboring fluoroquinolone-resistant organisms.\n\n\nMETHODS\nWe prospectively included 541 men who were submitted for TRUSBx in our center from March 2011 to June 2015. The indications for TRUSBx were an elevated prostate-specific antigen level and/or abnormal digital rectal exam. All patients were randomly divided into two groups: Group 1 (n = 279 cases) who received standard empirical prophylactic antibiotics and Group 2 who received targeted prophylaxis based on a rectal swab culture and susceptibility result. Differences in risk factors between quinolone-resistant and nonresistant patients were compared. Univariate and multivariate analyses were performed to identify independent potential risk factors associated with fluoroquinolone-resistant rectal flora.\n\n\nRESULTS\nSixteen out of 271 men developed infectious complications after TRUSBx in the group receiving standard empirical prophylaxis (5.7%). No men in the group who received targeted prophylactic antibiotic guided by rectal swab developed infectious complications. Among the 262 patients who underwent prebiopsy rectal swab cultures, 76 men (29%) displayed fluoroquinolone-resistant rectal flora (29%). In the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with an increased risk of fluoroquinolone resistance.\n\n\nCONCLUSIONS\nDetermining the prevalence of fluoroquinolone resistance in rectal flora has important implications in the selection of targeted prophylactic antibiotic regimens. Antimicrobial profiles guided by rectal swabs may prove useful to optimize prophylaxis prior to TRUSBx; this strategy is effective at reducing the rates of infectious complications, including sepsis, especially in men at higher risk of infectious complications.", "affiliations": "Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.;Urology Department, Alexandria University, Alexandria, Egypt.", "authors": "Fahmy|Ahmed|A|;Rhashad|Hazem|H|;Mohi|Mohamed|M|;Elabbadie|Ahmed|A|;Kotb|Ahmed|A|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.1016/j.prnil.2016.06.001", "fulltext": "\n==== Front\nProstate IntProstate IntProstate International2287-88822287-903XAsian Pacific Prostate Society S2287-8882(16)30027-710.1016/j.prnil.2016.06.001Original ArticleOptimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound-guided prostate biopsies: A prospective randomized study Fahmy Ahmed [email protected]∗Rhashad Hazem Mohi Mohamed Elabbadie Ahmed Kotb Ahmed Urology Department, Alexandria University, Alexandria, Egypt∗ Corresponding author. Urology Department, Alexandria University, 41 St. Abdelmoneam Sanad, Kamp Sizar, Alexandria, Egypt. [email protected] 7 2016 9 2016 01 7 2016 4 3 113 117 25 5 2016 10 6 2016 14 6 2016 Copyright © 2016 Asian Paciﬁc Prostate Society, Published by Elsevier.2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nTransrectal ultrasound-guided prostate biopsies (TRUSBx), in spite of being one of the most frequently performed urological office procedures, are associated with a spectrum of complications, most significantly including infection. The aim of the study is to evaluate the prevalence of fluoroquinolone-resistant bacteria in rectal swabs from our local population prior to TRUSBx and to identify risk factors among a patient population harboring fluoroquinolone-resistant organisms.\n\nMethods\nWe prospectively included 541 men who were submitted for TRUSBx in our center from March 2011 to June 2015. The indications for TRUSBx were an elevated prostate-specific antigen level and/or abnormal digital rectal exam. All patients were randomly divided into two groups: Group 1 (n = 279 cases) who received standard empirical prophylactic antibiotics and Group 2 who received targeted prophylaxis based on a rectal swab culture and susceptibility result. Differences in risk factors between quinolone-resistant and nonresistant patients were compared. Univariate and multivariate analyses were performed to identify independent potential risk factors associated with fluoroquinolone-resistant rectal flora.\n\nResults\nSixteen out of 271 men developed infectious complications after TRUSBx in the group receiving standard empirical prophylaxis (5.7%). No men in the group who received targeted prophylactic antibiotic guided by rectal swab developed infectious complications. Among the 262 patients who underwent prebiopsy rectal swab cultures, 76 men (29%) displayed fluoroquinolone-resistant rectal flora (29%). In the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with an increased risk of fluoroquinolone resistance.\n\nConclusion\nDetermining the prevalence of fluoroquinolone resistance in rectal flora has important implications in the selection of targeted prophylactic antibiotic regimens. Antimicrobial profiles guided by rectal swabs may prove useful to optimize prophylaxis prior to TRUSBx; this strategy is effective at reducing the rates of infectious complications, including sepsis, especially in men at higher risk of infectious complications.\n\nKeywords\nBiopsyProphylactic antibioticProstate biopsyTransrectal\n==== Body\n1 Introduction\nTransrectal ultrasound-guided prostate biopsies (TRUSBx), in spite of being a frequently performed urological procedure, are associated with a spectrum of complications, most significantly including infection, which affects up to 5% of patients.1 In the most severe cases, infection leads to sepsis, which poses significant morbidity to patients with inpatient hospital stays, intensive care requirements, and even death. Escherichia coli is the pathogen most commonly associated with infections after TRUSBx.2, 3, 4\n\nAntibiotic prophylaxis with fluoroquinolones (FQ) is currently used on a regular routine basis for preventing sepsis after TRUSBx because of its broad spectrum activity against gram-positive and gram-negative organisms and the convenience of using an oral agent with a high sustained concentration in urine and prostate tissue;5, 6, 7 however, there is growing evidence that the infection rate after TRUSBx is on the rise and it continues to be a problem, frequently caused by an increasing prevalence of FQ-resistant organisms.8, 9, 10, 11, 12\n\nIn an attempt to reduce the rate of infectious complications, there are an increasing number of publications citing different prophylaxis regimens.13, 14, 15 The aim of this study is to evaluate the prevalence of FQ-resistant bacteria in rectal swabs from men presented to the outpatient department at Alexandria University Hospital, Egypt, prior to TRUSBx and to identify the risk factors among a patient population harboring FQ-resistant organisms.\n\n2 Materials and methods\nWe prospectively included 541 men who were submitted for TRUSBx in our center from March 2011 to June 2015. All patients were randomly divided into two groups: Group 1 (n = 279 cases) who received standard empirical prophylactic antibiotic with oral ciprofloxacin 500 mg and metronidazole 500 mg at least 1 hour before biopsy and continued this twice daily for 3 days (a total of 6 doses of each antibiotic) and Group 2 who received targeted prophylaxis based on a rectal swab culture and susceptibility results performed 1 week before TRUSBx provided in a 3-day regimen on the day before the biopsy, the day of the biopsy, and the day after the biopsy (Fig. 1).\n\nSealed opaque envelopes were used as the method of randomization which were placed into a box and mixed. Allocation concealment was achieved using an independent person (“biopsy nurse”) who selected one of the sealed opaque envelopes blindly. Thus patients were randomly allocated to Group 1 or Group 2 before the procedure. The study was approved through the Institutional Review Board.\n\nDemographic data were obtained for all patients, as well as diabetic status, recurrent urinary tract infections (UTI), presence of a urinary catheter, prior FQ exposure within 6 months before the biopsy, and past TRUS biopsies (Table 1). The results of rectal swabs and infectious complications within 30 days of the biopsy were also recorded. The definition of post-TRUSBx infection was distinct clinical presentations, including fever > 38.5°C, UTI, pyelonephritis, bacteremia, prostatitis, systemic inflammatory response syndrome, and sepsis. The indications for TRUS biopsies were an elevated prostate-specific antigen level (PSA) and/or abnormal digital rectal exam. All TRUSBx were performed at our institution in an office-based setting.\n\n2.1 TRUSBx technique\nAll patients provided informed consent before the biopsy after they had been instructed by the physician regarding all possible complications. Patients were strictly advised not to take nonsteroidal anti-inflammatories and anticoagulant medications for a week before the application.\n\nA standard prebiopsy preparation was applied for all patients. No enema was used. Patients only fasted the night before. The biopsy procedure was carried out under local periprostatic anesthesia. TRUS-guided biopsies were achieved through transrectal ultrasonography using a 7-MHz probe attached. Biopsies were carried out with the patient in the left decubital position using an automated biopsy gun with a disposable 18-G biopsy needle.\n\nAll biopsies were carried out through a systematic approach (a standard 12-core biopsy taken from the base, mid gland, and the apex of the right and left sides of the lateral and far-lateral peripheral zone). Two transitional zone biopsies were added in cases of a previous history of negative biopsies.\n\nPatients were advised to present to the emergency department if they developed symptoms of sepsis within 30 days of the biopsy.\n\nAll patients with sepsis, as defined as fever > 38°C in the presence of constitutional symptoms, were admitted for inpatient management. Empiric treatment with meropenem 1 g [intravenous (i.v.)] twice daily was commenced after collecting blood and urine for culture.\n\nThe main outcome criterion was the incidence of bacteriuria (defined as ≥ 103colony-forming units/mL) within 30 days of biopsy. Secondary endpoints included the incidence of clinical symptoms of fever, flushing, chills, or any weakness on physical examination and UTI, defined as the association of leukocyturia (>5 cells/high-power field) and bacteriuria, or any significant change in the biological results suggesting an infection including a blood cell count and C-reactive protein.\n\n2.2 Statistical analysis\nDifferences in risk factors between quinolone-resistant and nonresistant patients were compared using a Fisher exact test with statistical significance ascribed at P < 0.05. Univariate and multivariate analyses were performed to identify independent potential risk factors associated with FQ-resistant rectal flora. Statistical analyses were performed with SPSS version 21.0 (SPSS Inc., Chicago, IL, USA) statistical software package.\n\n3 Results\nThe mean age of patients was 63.6 years and 65.2 years in Group 1 and Group 2, respectively (P = 0.4).There was no difference in mean PSA value (P = 0.62) or age-adjusted Charlson comorbidity score (P = 0.25) between the two groups.\n\nSixteen men out of 279 men developed infectious complications after TRUSBx in the group receiving standard empirical prophylaxis (5.7%) in the form of fever and pyelonephritis including two cases of sepsis. None of the two men admitted for sepsis required intensive care treatment and all were successfully managed with i.v. fluids and i.v. meropenem (1 g twice daily). No men in the group who received targeted prophylactic antibiotic guided by rectal swab developed infectious complications. This result was statistically significant (P = 0.003). Culture and susceptibility results for the two men with sepsis demonstrated FQ resistant extended-spectrum β-lactamase-producing Escherichia coli.\n\nAmong the 262 patients who underwent prebiopsy rectal swab cultures, 76 men (29%) displayed FQ-resistant rectal flora (29%). Of the 76 bacterial isolates, 84.2% were E. coli and 10.5% were Klebsiella pneumonia. Antimicrobial susceptibility testing to FQ-resistant strains obtained by rectal swab showed the highest resistance notably to cotrimoxazole (85%), followed by cefotaxime (63%), and the highest sensitivity shown to carbapenems (92.1%), fosomycin (85.5%), amikacin (79%), followed by nitrofurantoin (63%), and sulbactam/cefoperazone (42.1%; Fig. 2).\n\nAge, diabetic status, presence of a urinary catheter, and a history of prior prostate biopsy were not associated with FQ resistance. Prior UTI and antibiotic exposure before prostate biopsy was associated with quinolone resistance (P = 0.041 and 0.001, respectively; Table 2).\n\nIn the univariate analysis, prior UTI and history of exposure to antibiotics increased the risk of FQ resistance [odds ratio (OR), 4.45; 95% confidence interval (CI), 1.36–10.52; P = 0.02, and OR, 34.2 CI, 3.16–178.52; P = 0.001, respectively] (Table 3).\n\nIn the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with increased risk of FQ resistance (OR, 41.2; 95% CI, 3.16–328.46; P = 0.008; Table 4).\n\n4 Discussion\nThe use of prophylactic antibiotics prior to TRUSBx reaches a consensus; however, data to guide the optimal choice of prophylactic antibiotic are currently lacking. No standard regimen for antibiotic prophylaxis has been formulated despite the need to optimize prophylaxis against infectious complications post-TRUSBx being recognized a long time ago.16\n\nMultiple strategies aimed at improving the safety and acceptability of prostate biopsies are the subject of ongoing research studies. Different prophylactic regimens depending on local microbiological profiles, and alternate approaches to prostate biopsies, such as the transperineal approach, are considered depending on availability.17 Rectal disinfection and washing the biopsy needle with povidone–iodine are other approaches used with the aim of reducing infection complications post-TRUSBx in some centers.18, 19\n\nThe European Association of Urology guideline recommends the use of a FQ as a first-line agent for the prevention of infection from transrectal prostate biopsy, with ciprofloxacin being superior to ofloxacin.20 Our current clinical practice usually includes an empirical oral FQ antibiotic usage of 3 days starting the day before the procedure owing to their excellent prostatic penetration;7 these agents also provide good coverage against the key pathogens implicated in post-TRUSBx infectious complications.21 However, FQ resistance has emerged as a growing problem resulting in a significant increase in infectious complications in men undergoing TRUS biopsies.\n\nMany reports have shown that the prevalence of FQ-resistant E. coli in Western countries is on the rise.9, 11 In the USA, FQ-resistant bacteria were identified in 22% of samples from rectal swab cultures before TRUSBx.22 Furthermore, in American men who developed acute prostatitis after TRUSBx, the FQ-resistant rate was reported to be 57.1%.23 Batura et al24 obtained rectal swabs from 445 men undergoing TRUSBx and found a 13.3% incidence of FQ-resistant coliforms. The present study looks at the local susceptibility for FQ in our patient population, with an incidence of FQ resistance as high as 29% which is relatively high and may be due to an increase in antibiotic prescriptions in the past few years. In light of the worldwide emergence of FQ resistance and its increasing implication in post-TRUSBx infectious complications including sepsis, the current recommendations for antimicrobial prophylaxis need to be reevaluated.\n\nOur results showed that targeted antibiotic prophylaxis guided by a pre-TRUSBx rectal swab was dramatically effective in lowering postbiopsy infectious complications. No men in the group who received targeted prophylactic antibiotics guided by a rectal swab developed an infectious complication. In contrast, men treated with empirical prophylactic antibiotic regimen had a 5.7% rate of infectious complications despite receiving ciprofloxacin and metronidazole for 3 days. This rate matches the worldwide reported incidence for infectious complication post-TRUSBx of around 2–6%.17 Two cases of sepsis had cultures of ciprofloxacin-resistant E. coli, suggesting that ciprofloxacin resistance is a significant contributor to the failure of standard prophylaxis. This may be attributed to the frequent unsupervised use of these antibiotics or inadequate dosing with subsequent development of resistance in the rectal flora, creating potentially worse problems in cases of post-TRUS biopsy sepsis, where these drugs would have reduced efficacy as empirical treatment.\n\nSeveral reports in literature have suggested that rectal swab cultures before a biopsy may allow for an individualized and targeted approach to providing prophylactic antibiotics and decreased overall cost of care. Duplessis et al22 showed that rectal cultures obtained before TRUSBx with the use of selective media to identify FQ-resistant Enterobacteriaceae facilitate targeted antibiotic prophylaxis and appear to be highly efficacious in reducing postprostatic biopsy infection rates. Taylor et al23 reported no infectious complications in 112 men who received targeted antimicrobial prophylaxis and this was associated with a reduced cost of care. Our data show similar results, with no cases of infectious complications in the group that received targeted antibiotic prophylaxis guided by rectal swab culture, whereas 16 cases among 279 patients receiving empirical FQ prophylaxis developed infectious complications including two cases of sepsis (P = 0.003).\n\nConcerns regarding the practical implementation of rectal swab collection need considering. Optimal timing of swab collection, duration of targeted antibiotic regimen, target population, and cost effectiveness has to be clearly established. The feasibility, and cost effectiveness of routine rectal swabs for every patient undergoing TRUSBx must be considered, as it represents a significant burden for clinical microbiology laboratories, and would incur several additional costs (culture media, targeted antibiotics, etc.).\n\nIn a previous study comparing cost-effectiveness of targeted versus empirical prophylaxis per 100 men undergoing TRUSBx, Taylor et al23 showed that the total cost of managing infectious complications in patients in the empirical group was US $13,219 including hospital admission, outpatient and emergency room visits, prolonged antibiotic treatment, diagnostic imaging procedures, laboratory tests, and professional fees. Cost-effectiveness analysis revealed that targeted prophylaxis yielded a cost savings of US $4,499 per post-TRUSBx infectious complication averted. Currently, there is no conclusive evidence of the overall benefit of routine adoption of targeted prophylaxis and the burden of the additional costs limits the widespread replacement of such an approach.\n\nA more practical and feasible approach to optimize the use of antimicrobial prophylaxis for TRUSBx is to consider the selective application of rectal swabs before prostate biopsy in patients with high risk factors and to use the standard protocol for low-risk patients. However, men at high risk for developing post-TRUSBx infections are not yet well defined. A number of recent studies tried to look at these risk factors for infection post-TRUSBx.\n\nLiss et al11 obtained rectal swabs from 136 men before TRUSBx over a 3-month period. In 22% of patients, rectal cultures showed quinolone-resistant E. coli, and patients with diabetes, Asian ethnicity, and a prior history of TRUSBx were determined to be at a higher risk for colonization with resistant organisms, although these differences did not reach statistical significance. In this series, five patients (3.6%) developed post-TRUSBx fever, among which only one had a positive rectal culture. Kanafani et al25 and Lautenbach et al26 pointed out in their studies that previous use of FQ was an independent risk factor for acquiring infections with extended-spectrum β-lactamase-producing E. coli-producing organisms. Similar to those observations, prior UTI and history of exposure to antibiotics increased the risk of FQ resistance by univariate analysis in the present study. In the multivariate analysis, a history of antibiotic exposure before prostate biopsy was the only independent factor associated with increased risk of FQ resistance (P = 0.008).\n\nAs an alternative to FQ standard prophylaxis, changing to broad-spectrum antimicrobials with extremely low resistance rates in rectal flora, eliminating the need for rectal culture has also been suggested.12, 14 However, the high cost and frequent use of these antibiotics again may lead to the subsequent development of resistance in rectal microbiota, potentially limiting its use in prophylaxis prior to TRUSBx. Our patients' antimicrobial susceptibility testing showed the highest sensitivity to cabapenems, fosomycin, and amikacin.\n\nThe present study raises awareness of local susceptibility for FQ in our patient population and highlights the utility of a rectal swab as an approach to optimize antibiotic prophylaxis prior to TRUSBx in high-risk patients. Thus a benefit of screening prior to TRUSBx and targeted prophylaxis should be considered as a thoughtful, predictable alternative to routine empirical prophylaxis. Using a risk stratification approach seems to be effective at identifying those men at higher risk of infectious complications. Future studies will need to evaluate the cost effectiveness and clinical utility of a prebiopsy rectal culture in targeting antibiotic prophylaxis.\n\nWe acknowledge several limitations of the present study. Firstly, there might be a recall bias, relying on patient recall for past histories of UTI and antibiotic use. Similarly, the frequency of exposure to FQ and the duration preceding TRUSBx could not be ascertained, therefore it is possible that some patients might have forgotten these past events which may have led to an underestimation of the total number of patients with a history of antibiotic use. Secondly, a true cost-benefit analysis between routine empirical antibiotic prophylaxis and targeted antibiotic prophylaxis has not been formally undertaken in our study. Finally, lack of culture standardization in microbiological laboratories may represent a limiting factor.\n\nIn conclusion, determining the prevalence of FQ resistance in rectal flora has important implications in the selection of targeted prophylactic antibiotic regimens. Antimicrobial profiles guided by rectal swabs may prove useful to optimize prophylaxis prior to TRUSBx; this strategy is effective at reducing the rates of infectious complications, including sepsis, especially in men at higher risk for infectious complications.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n\nFig. 1 Study cases. FQ, fluroquinolones; TRUSBx, transrectal ultrasound-guided prostate biopsies.\n\nFig. 2 Antimicrobial susceptibility testing to fluoroquinolone-resistant strains.\n\nTable 1 Patients' demographics.\n\nVariables\tGroup 1 (n = 279)\tGroup 2 (n = 262)\tP\t\nMean age (y)\t63.6\t65.2\t0.461\t\nMean PSA (ng/mL)\t18\t22\t0.624\t\nMean prostate volume (mL)\t64\t59\t0.187\t\nNo. of diabetes patients\t73 (26.2)\t80 (30.5)\t0.422\t\nAAC (mean)\t\t\t0.252\t\n• 0–1\n\n\t175\t156\t\n• 2–3\n\n\t65\t57\t\n• 2–5\n\n\t32\t38\t\n• ≥ 6\n\n\t7\t11\t\nPrior UTI\t136 (48.7)\t116 (44.3)\t0.582\t\nPresence of urinary catheter\t35 (12.5)\t26 (9.9)\t0.182\t\nPrior antibiotic exposure within 6 mo\t90 (32.2)\t87 (33.2)\t0.922\t\nPrior prostate biopsy\t52 (18.6)\t54 (20.6)\t0.863\t\nData are presented as n (%).\n\nACC, age-adjusted Charlson comorbidity score; PSA, prostate-specific antigen; UTI, urinary tract infection.\n\nTable 2 Risk factors and quinolone resistance status.\n\nVariables\tFQ resistant (n = 76)\tFQ sensitive (n = 186)\tP\t\nAge ≥ 65 (y)\t12 (15.7)\t30 (16.1)\t0.18\t\nDiabetes\t28 (36.8)\t52 (27.9)\t0.62\t\nPrior UTI\t39 (51.3)\t77 (41.33)\t0.041a)\t\nPresence of urinary catheter\t9 (11.8)\t17 (9.1)\t0.52\t\nPrior antibiotic exposure within 6 mo\t45 (59.2)\t42 (22.5)\t0.001a)\t\nPrior prostate biopsy\t18 (23.6)\t36 (19.3)\t0.24\t\nData are presented as n (%).\n\nFQ, fluoroquinolone; UTI, urinary tract infection.\n\na) Statistically significant.\n\nTable 3 Univariate logistic regression analysis of factors influencing quinolone resistance.\n\nFQ resistance\tOR (95% CI)\tP\t\nAge ≥ 65 y\t1.28 (0.42–4.35)\t0.453\t\nDiabetes\t3.47 (0.1–6.32)\t0.520\t\nPrior UTI\t4.45 (1.36–10.52)\t0.02a)\t\nPresence of urinary catheter\t1.08 (0.22–6.43)\t0.38\t\nPrior antibiotic exposure within 6 mo\t34.2 (3.16–178.52)\t0.001a)\t\nPrior prostate biopsy\t3.02 (0.82–6.88)\t0.24\t\nCI, confidence interval; FQ, fluoroquinolone; OR, odds ratio; URI, urinary tract infection.\n\na) Statistically significant.\n\nTable 4 Multivariate logistic regression analysis of factors influencing quinolone resistance.\n\nFQ resistance\tOR (95% CI)\tP\t\nPrior UTI\t1.62 (0.85–11.08)\t0.659\t\nPrior antibiotic exposure within 6 mo\t41.2 (3.16–328.46)\t0.008a)\t\nCI, confidence interval; FQ, fluoroquinolone; OR, odds ratio; URI, urinary tract infection.\n\na) Statistically significant.\n==== Refs\nReferences\n1 Challacombe B. 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Does washing the biopsy needle with povidone-iodine have an effect on infection rates after transrectal prostate needle biopsy? Urol Int 85 2010 147 151 20453481 \n20 Heidenreich A. Bastian P.J. Bellmunt J. Bolla M. Joniau S. Mason M.D. Guidelines on prostate cancer [Internet] 2013 European Association of Urology Arnhem (NL) [cited 2013 May 10]. Available from: http://www.uroweb.org/gls/pdf/09_Prostate_Cancer_LR.pdf \n21 Campeggi A. Ouzaid I. Xylinas E. Lesprit P. Hoznek A. Vordos D. Acute bacterial prostatitis after transrectal ultrasound-guided prostate biopsy: Epidemiological, bacteria and treatment patterns from a 4-year prospective study Int J Urol 21 2014 152 155 23906113 \n22 Duplessis C.A. Bavaro M. Simons M.P. Marguet C. Santomauro M. Auge B. Rectal cultures before transrectal ultrasound-guided prostate biopsy reduce post-prostatic biopsy infection rates Urology 79 2012 556 561 22386395 \n23 Taylor A.K. Zembower T.R. Nadler R.B. Scheetz M.H. Cashy J.P. Bowen D. Targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care J Urol 187 2012 1275 1279 22341272 \n24 Batura D. Rao G.G. Nielsen P.B. Prevalence of antimicrobial resistance in intestinal flora of patients undergoing prostatic biopsy: implications for prophylaxis and treatment of infections after biopsy BJU Int 106 2010 1017 1020 20346055 \n25 Kanafani Z.A. Mehio-Sibai A. Araj G.F. Kanaan M. Kanj S.S. Epidemiology and risk factors for extended-spectrum beta-lactamase-producing organisms: a case control study at a tertiary care center in Lebanon Am J Infect Control 33 2005 326 332 16061138 \n26 Lautenbach E. Patel J.B. Bilker W.B. Edelstein P.H. Fishman N.O. Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae : Risk factors for infection and impact of resistance on outcomes Clin Infect Dis 32 2001 1162 1171 11283805\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2287-8882", "issue": "4(3)", "journal": "Prostate international", "keywords": "Biopsy; Prophylactic antibiotic; Prostate biopsy; Transrectal", "medline_ta": "Prostate Int", "mesh_terms": null, "nlm_unique_id": "101605566", "other_id": null, "pages": "113-7", "pmc": null, "pmid": "27689069", "pubdate": "2016-09", "publication_types": "D016428:Journal Article", "references": "21334021;16391904;9763070;20224265;21771239;21958223;20346055;21705048;22341272;23906113;23009873;16061138;8705220;20453481;21420152;22244150;10759665;21029317;22982426;20089283;21944136;23532481;23041343;11283805;22386395", "title": "Optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound-guided prostate biopsies: A prospective randomized study.", "title_normalized": "optimizing prophylactic antibiotic regimen in patients admitted for transrectal ultrasound guided prostate biopsies a prospective randomized study" }

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{ "abstract": "Roux-en-y-gastric bypass (RYGB) is the most commonly performed bariatric procedure worldwide which is taking the lead in resolving of comorbid conditions. Short- and long-term complications of RYGB procedure have been recognized, including osteopenia, osteomalacia and more rarely neurological disorders. Oxalate nephropathy is a complication of RYGB that has been described earlier in the literature and may end with renal failure and dialysis if not recognized and treated early. The etiology of this phenomenon is still unclear, but the length of common limb remains the theory that mostly contributed to its development. We believe that this limb should be more than 100 cm to prevent severe malabsorption. Here, we report a reversible case of oxalate nephropathy 3 months after RYGB in a 51-year-old patient.", "affiliations": "Gastroenterology Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.;General Surgery Division, Central Military Hospital, Beirut, Lebanon.;General Surgery Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.;Gastroenterology Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.;General Surgery Division, Saint Georges Hospital University Medical Center, University of Balamand, Beirut, Lebanon.", "authors": "Farhat|Said|S|;Houssam|Abtar|A|;Ghassaoui|Ali|A|;Khaled|El Ajami|EA|;El Khoury|Mansour|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/omcr/omw054", "fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcromcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omw054omw054Case ReportA case of reversible hyperoxaluria nephropathy early after roux-en-y-gastric\nbypass induced by vitamin C intake Farhat Said 1*Houssam Abtar 2Ghassaoui Ali 3Khaled El Ajami 1El Khoury Mansour 3\n1 Gastroenterology Division, Saint Georges\nHospital University Medical Center, University of Balamand,\nBeirut, Lebanon\n2 \nGeneral Surgery Division, Central Military Hospital, Beirut, Lebanon\n\n3 \nGeneral Surgery Division, Saint Georges Hospital University Medical Center,\nUniversity of Balamand, Beirut, Lebanon\n* Corresponding address. Saint Georges Hospital\nUniversity Medical Center, University of Balamand, P.O. Box 166 378, Achrafieh, Beirut 11\n00 2807, Lebanon. Tel: +961-1-441-000 or +961-1-575-700; Fax:\n+961-1-582-560; E-mail:\[email protected] 2016 29 8 2016 29 8 2016 2016 8 omw05425 11 2015 24 5 2016 31 5 2016 © The Author 2016. Published by Oxford University\nPress.2016This is an Open Access article distributed under the terms of the Creative Commons\nAttribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits\nnon-commercial re-use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited. For commercial re-use, please contact\[email protected] bypass (RYGB) is the most commonly performed bariatric procedure\nworldwide which is taking the lead in resolving of comorbid conditions. Short- and\nlong-term complications of RYGB procedure have been recognized, including osteopenia,\nosteomalacia and more rarely neurological disorders. Oxalate nephropathy is a complication\nof RYGB that has been described earlier in the literature and may end with renal failure\nand dialysis if not recognized and treated early. The etiology of this phenomenon is still\nunclear, but the length of common limb remains the theory that mostly contributed to its\ndevelopment. We believe that this limb should be more than 100 cm to prevent severe\nmalabsorption. Here, we report a reversible case of oxalate nephropathy 3 months after\nRYGB in a 51-year-old patient.\n==== Body\nINTRODUCTION\nNearly 35% of adults aged 20 years and over were overweight in 2008, and 11%\nwere obese according to the World Health Organization (WHO); this percentage will continue\nto increase with time. Roux-en-y-gastric bypass (RYGB) is the most common procedure done and\nleads to improvements in weight, sugar levels, insulin resistance, cardiovascular risk\nfactors and sleep apnea. Although both short- and long-term complications of RYGB procedure\nhave been recognized, including osteopenia, osteomalacia, and more rarely neurological\ndisorders, the procedure has been deemed relatively safe and effective [1].\n\nRecent data suggest that modern bariatric procedures, such as RYGB, may also impart a\n2-fold increased risk of nephrolithiasis, whereas 20–75% of patients may have\nhyperoxaluria, including 20% with very high urine oxalate levels, also putting them\nat considerable risk of oxalate nephropathy [2].\n\nCASE REPORT\nWe report a case of RYGB that leads to oxalate nephropathy 3 months after the procedure: a\n51-year-old male patient with type 2 diabetes mellitus and a body mass index (BMI) of 42\nkg/m2 (Table 1). A\nstandard RYGB procedure was performed, and a 30–50 ml gastric pouch was created; the\nlength of the Roux segment was 150 cm, and the length of the jejunum from the ligament of\nTreitz to the jejuno-jejunal anastomosis was 40 cm. Table 1. Patient's demographics and biochemical results\n\nCharacteristics\t\nSex\tMale\t\nAge (year)\t51\t\nBMI (kg/m2)\t42\t\nRenal function\tNormal\t\nDiabetes mellitus\tYes\t\nHypertension\tNo\t\nHyperlipidemia\tNo\t\nChronic obstructive pulmonary disease\tNo\t\nSmoker\tYes\t\nBiochemical results on admission\t\nSerum creatinine (mg/dl)\t8.42\t\n24 h Urine oxalate level (mg)\t80\t\n\n\nThree months after the procedure, the patient started complaining of productive cough,\nchills and bilateral flank pain over a period of 2 days associated with decreased fluid\nintake and low urine output. He was found to have elevated creatinine on laboratory workup\n(8.42 mg/dl). He was admitted for further investigation and was started on the appropriate\nantibiotics for the diagnosis of pneumonia. During history taking, the patient was found to\nbe on non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen) and high-dose vitamin C, 1\ng/day which is much higher than the normal dose (75 mg for women and 90 mg for men) on his\nown. His creatinine continued to increase during his stay at the hospital reaching 9.5 mg/dl\nand was oliguric. Twenty-four-hour urine oxalate level was 80 mg (normal range =\n4–31 mg/24 h), and CT scan was done to rule out obstructive nephropathy. Kidney\nbiopsy specimen was obtained, and it showed deposition of calcium oxalate crystals in the\nlumen of few tubules compatible with oxalate nephropathy (Fig. 1). He was started on intravenous (IV) hydration, high oral calcium\nsupplementation (1500 mg/day), low oxalate diet and steroid therapy (20 mg/day) as treatment\nfor acute interstitial nephritis (AIN). After this regimen, the urine volume increased and\nhis creatinine level decreased. Progressively creatinine decreased to reach 1.9 mg/dl 10\ndays after (Fig. 2). During a period of 3\nmonths, the patient got readmitted twice: once for gastroenteritis and once for bilateral\nlower limbs edema, and investigations revealed low total protein, albumin levels and\ngeneralized fatigue. For this reason, decision was taken to reverse the RYGB. Figure 1. Histopathology showed deposition of calcium oxalate crystals in the lumen of\nfew tubules (black arrow). (A) Polarized light 50×. (B) Hematoxylin and eosin\n50×.\n\n\nFigure 2. Serum creatinine level changes during hospital stay.\n\n\n\nDISCUSSION\nOxalate nephropathy is a complication of RYGB that has been described earlier in the\nliterature and will be encountered more frequently clinically, in our opinion, as the number\nof bariatric operations is increasing, especially RYGB. In the study done by Nasr et\nal. [3], 11 patients presented with\nacute kidney injury (AKI) 6 months after RYGB and were diagnosed with oxalate nephropathy.\nIn another study done by Sinha et al. [1], 31 patients had oxalate nephropathy 2.2 years post RYGB. Oxalate nephropathy\nwas seen also in kidney transplant recipient patients 27 and 7 years, respectively, after\nRYGB as described by Troxell et al. [2]. Matlaga et al. [4] showed that nephrolithiasis incidence after RYGB is 7.65% (in a study with\n4639 RYGB patients) when compared with 4.63% in the same number of patients that did\nnot undergo bariatric operation. Our patient presented with AKI (creatinine = 8.42\nmg/dl) 3 months after the operation, which has never been reported before.\n\nWe think that the etiology of this early formation of oxalate deposits was multifactorial\nincluding: RYGB by itself as a malabsorptive factor, high dose of vitamin C intake, NSAIDs\nthat the patient was taking to relieve the flank pain, high oxalate diet (coffee,\nchocolates, cocoa) and low fluid intake by the patient over 24 h that led to low urinary\nvolumes.\n\nAccording to several studies, the use of traditional NSAIDs is well established to be\nassociated with AKI with relative risks compared with non-user ranging from 1.6 to 2.2.\nIndomethacin users account for the highest risk ratio of developing AKI. NSAIDs can cause\nAKI by two different mechanisms: hemodynamically mediated [decrease in prostaglandin (PG)\nsynthesis due to inhibition of cyclooxygenase (COX-1) enzymes in combination with renal\nvasoconstriction] and AIN [5].\n\nVitamin C is believed to result in a hyperoxaluric state. The recommended daily intake of\nvitamin C is between 75 and 90 mg/day. Several cases of oxalate nephropathy have been\nreported with vitamin C intake <2 g/day [6]. The mechanism of oxalate deposit formation is contributed by the increased fat\nmalabsorption which leads to increased colonic fat that binds to free calcium, increasing\nunbound oxalate that is able to cross the colonic mucosa. In malabsorptive states (like\nafter RYGB), the percentage of oxalate absorbed from the gut and excreted in urine can be\nmarkedly increased and hyperoxaluria often correlates with steatorrhea [7].\n\nThe pathogenesis of hyperoxaluria after RYGB is not completely understood, but the length\nof the common channel is one of the most important factors leading to significant fat\nmalabsorption in some, causing enteric hyperoxaluria. Although RYGB operation with a Roux\nlimb of <150 cm in length is generally believed not to cause fat malabsorption, data\nsuggest that hyperoxaluria may indeed occur, and represent a risk for calcium oxalate\nnephrolithiasis [1].\n\nSome earlier studies of patients with inflammatory bowel disease correlate the degree of\nhyperoxaluria with the degree of steatorrhea; this pathogenesis might explain why patients\nwho have had distal RYGB (through creation of a longer Roux limb and subsequently shorter\ncommon channel for nutrient absorption) can be at higher risk for developing calcium oxalate\nkidney stones compared with standard RYGB patients [8].\n\nThe goal of management is to reach normal creatinine levels and normal diuresis. Many\ntreatments can be applied starting with oxalate-free diet, limit fat intake, appropriate\nhydration to maintain urine output of at least 2 l, oral calcium supplementation and\nreversal of the surgery [9]. This strategy, if\napplied early, can reverse the nephropathy and can prevent irreversible tubular damage\nleading to dialysis. More recent treatments like supplementation of Oxalobacter\nformigenes bacteria, a normal commensurate part of the human gut\nmicroflora which metabolizes oxalate as an energy source have been applied and showed\npromising results by reducing the urinary oxalate levels [1].\n\nIn conclusion, surgeons should be aware of this complication and be aggressive in their\ntreatment strategies in order not to reach dialysis. We suggest counting accurately the\nlength of the common channel during each gastric bypass as well as maintaining oxalate-free\nand fat-free diet with oral calcium supplementation postoperatively.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n\nFUNDING\nThere were no sources of funding.\n\nETHICAL APPROVAL\nNo ethical approval is required.\n\nCONSENT\nWritten informed consent was obtained from the patient for the publication of this case\nreport.\n\nGUARANTORS\nF.S. and H.A. are guarantors of this study.\n==== Refs\nREFERENCES\n1 Sinha MK Collazo-Clavell ML Rule A Milliner DS Nelson W Sarr MG \nHyperoxaluric nephrolithiasis is a complication of roux-en-y gastric bypass\nsurgery . Kidney Int \n2007 ;72 :100 –7 .17377509 \n2 Troxell ML Houghton DC Hawkey M Batiuk TD Bennett WM \nEnteric oxalate nephropathy in the renal allograft: an underrecognized\ncomplication of bariatric surgery . Am J Transplant \n2013 ;13 :501 –9 .23311979 \n3 Nasr SH D'Agati VD Said SM Stokes MB Largoza MV Radhakrishnan J \nOxalate nephropathy complicating roux-en-y gastric bypass: an\nunderrecognized cause of irreversible cause of irreversible renal\nfailure . Clin J Am Soc Nephrol \n2008 ;3 :1676 –83 .18701613 \n4 Matlaga BR Shore AD Magnuson T Clark JM Johns R Makary MA \nEffect of gastric bypass surgery on kidney stone disease .\nJ Urol \n2009 ;181 :2573 –7 .19375090 \n5 Ungprasert P Cheungpasitporn W Crowson CS Matteson EL \nIndividual non-steroidal anti-inflammatory drugs and risk of acute kidney\ninjury: a systematic review and meta-analysis of observational studies .\nEur J Intern Med \n2015 ;26 :285 –91 .25862494 \n6 Sunkara V Pelkowski TD Dreyfus D Satoskar A \nAcute kidney disease due to excessive vitamin C ingestion and remote\nroux-en-y gastric bypass surgery superimposed on CKD . Am J\nKidney Dis \n2015 ;66 :721 –4 .26271145 \n7 Kumar R Lieske JC Collazo-Clavell ML Sarr MG Olson ER Vrtiska TJ \net al. Fat malabsorption and increased intestinal absorption are common\nafter roux-en-y gastric bypass surgery . Surgery \n2011 ;149 :654 –61 .21295813 \n8 Duffey BG Pedro RN Makhlouf A Kriedberg C Stessman M Hinck B \nRoux-en-y gastric bypass is associated with early increased risk factors\nfor development of calcium oxalate nephrolithiasis . J Am Coll\nSurg \n2008 ;206 :1145 –53 .18501812 \n9 Whitson J Stackhouse G Stoller M \nHyperoxaluria after modern bariatric surgery: case series and literature\nreview . Int Urol Nephrol. \n2010 ;42 :369 –74 .19572208\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2053-8855", "issue": "2016(8)", "journal": "Oxford medical case reports", "keywords": null, "medline_ta": "Oxf Med Case Reports", "mesh_terms": null, "nlm_unique_id": "101642070", "other_id": null, "pages": "omw054", "pmc": null, "pmid": "29497551", "pubdate": "2016-08", "publication_types": "D002363:Case Reports", "references": "25862494;26271145;23311979;19375090;18701613;18501812;17377509;19572208;21295813", "title": "A case of reversible hyperoxaluria nephropathy early after roux-en-y-gastric bypass induced by vitamin C intake.", "title_normalized": "a case of reversible hyperoxaluria nephropathy early after roux en y gastric bypass induced by vitamin c intake" }

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A CASE OF REVERSIBLE HYPEROXALURIA NEPHROPATHY EARLY AFTER ROUX?EN?Y?GASTRIC BYPASS INDUCED BY VITAMIN C INTAKE. OXFORD MEDICAL CASE REPORTS. 2017?2016 (8):205?207", "literaturereference_normalized": "a case of reversible hyperoxaluria nephropathy early after roux en y gastric bypass induced by vitamin c intake", "qualification": "1", "reportercountry": "LB" }, "primarysourcecountry": "LB", "receiptdate": "20180925", "receivedate": "20171222", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14319329, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20181010" }, { "companynumb": "LB-MYLANLABS-2017M1080610", "fulfillexpeditecriteria": "1", "occurcountry": "LB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASCORBIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH DOSE ASCORBIC-ACID AT 1 G/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASCORBIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "FLANK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oliguria", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Crystal nephropathy", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tubulointerstitial nephritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FARHAT S, HOUSSAM A, GHASSAOUI A, KHALED EA, EL KHOURY M. A CASE OF REVERSIBLE HYPEROXALURIA NEPHROPATHY EARLY AFTER ROUX-EN-Y-GASTRIC BYPASS INDUCED BY VITAMIN C INTAKE. OXF-MED-CASE-REPORTS 2017?2016(8):205-207.", "literaturereference_normalized": "a case of reversible hyperoxaluria nephropathy early after roux en y gastric bypass induced by vitamin c intake", "qualification": "3", "reportercountry": "LB" }, "primarysourcecountry": "LB", "receiptdate": "20180103", "receivedate": "20180103", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14347995, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.", "affiliations": "Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.;Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden.;Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.", "authors": "Ringdén|Olle|O|;Gustafsson|Britt|B|;Sadeghi|Behnam|B|", "chemical_list": "D015415:Biomarkers", "country": "Switzerland", "delete": false, "doi": "10.3389/fimmu.2020.567210", "fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.567210\nImmunology\nPerspective\nMesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease\nRingdén Olle 1* Gustafsson Britt 2 Sadeghi Behnam 1 1Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden\n2Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden\nEdited by: Robert James Hayashi, Washington University School of Medicine in St. Louis, United States\n\nReviewed by: Astrid Gertrude Suzanne Van Halteren, Leiden University Medical Center, Netherlands; Frederic Baron, University of Liège, Belgium\n\n*Correspondence: Olle Ringdén [email protected] article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology\n\n\n19 10 2020 \n2020 \n11 56721029 5 2020 02 9 2020 Copyright © 2020 Ringdén, Gustafsson and Sadeghi.2020Ringdén, Gustafsson and SadeghiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.\n\ngraft-versus-host disease (GVHD)mesenchymal stromal cell (MSC)pediatric haematopoietic stem cell transplantationcell theraphydecidua stromal cells (DSCs)\n==== Body\nIntroduction\nHematopoietic cell transplantation (HCT) is an established treatment for children with both malignant and non-malignant hematopoietic diseases and inborn errors of metabolism (1–4). The main obstacles to success are relapse of the disease, infections, graft failure, toxicity of various organs, hemorrhagic cystitis, and graft-versus-host disease (GVHD). To prevent GVHD, patients are treated with immunosuppressive drugs, most commonly, calcineurin inhibitor combined with Methotrexate (5). Despite this, a majority of the patients developed acute GVHD, with a considerable mortality, even if this was significantly lower in children compared to adults (6). To confirm the gastrointestinal GVHD histopathological biopsies is recommended, since e.g., viruses could cause gastrointestinal symptoms (7–9). Cortisone is first-line therapy for acute GVHD (10) and almost all immunosuppressive therapies are used as a secondary treatment with varying degrees of success (11). Friedenstein et al. were the first to describe MSCs (12). We introduced mesenchymal stromal cells (MSCs) as a new therapy for acute GVHD (13, 14). MSCs are rare in all tissues in the body and can differentiate into several cells of mesenchymal cell lineages, such as bone, cartilage, tendon, cardiomyocytes, muscles, and fat (15, 16). There is no specific CD marker for MSCs. However, they stain positive for CD29, CD73, CD90, CD105, and CD166. They are negative for hematopoietic markers, CD34, CD45, and CD14. They are not true stem cells because they cannot regenerate and maintain a whole tissue compartment. MSCs express HLA class I molecules and contain intracellular HLA class II that is expressed on the cell surface after interferon-γ stimulation (17). After injection, MSCs do not appear to be long lived and have been demonstrated in the circulation only shortly after infusion into patients who underwent autologous HCT for breast cancer (18).\n\nImmunosuppression\nMSCs have potent immunomodulatory effects and inhibit phytohemagglutinin induced T cell proliferation and alloreactivity in mixed lymphocyte cultures (MLC) (17, 19, 20). MSCs' inhibition of alloreactivity in vitro is independent of the major histocompatibility system (21). Furthermore, after differentiation into osteocytes, chondrocytes and adipocytes, immunosuppression was still induced (17). MSCs also prolonged skin allograft survival in baboons (19). Several factors and mechanisms are involved in MSC-mediated immune modulation.\n\nBone marrow MSCs (BM-MSCs) are susceptible to complement activation after contact with human blood (22). This results in cell dysfunction or cell death (23). When in contact with blood, BM-MSCs also elicit activation of clotting factors (24).\n\nMSC immunosuppression has been studied extensively (25–28). Stromal cells from various organs such as BM, Wharton's jelly, placenta tissues and cord blood have varying immunosuppressive effects in the MLC (17, 19–21, 29, 30). The MLC is also inhibited by skin fibroblasts (31). Immunosuppressive factors produced by MSCs include prostaglandin E2 (32), HLA-G5 (33), and galectins (34). MSCs also produce indoleamine-2,3, dioxygenase (IDO), which inhibits T cells by converting of tryptophan to kynurenine [(35), Figure 1]. IDO is involved in the induction of regulatory T cells and the inhibition of Th17 differentiation (36). IDO produced by MSCs also promotes differentiation of macrophages toward M2 phenotypes (37). MSCs also induce contact-dependent immunosuppression. Among these are activation of the PD-1 pathway (38), by activation of VCAM-1 and ICAM-1 (39), purification of CD39 and increased adenosine production (40), and Fas-mediated T-cell apoptosis (41). There are differences in various species and, in mice, several models failed to reduce alloreactivity and GVHD (42). To inhibit GVHD in mice, MSCs need to be licensed by IFN-γ, nitric oxide, or transduced with IL10 to prevent GVHD. In a colitis model in mice, it was shown that prevention of colitis by MSCs requires CD11b+ macrophages (43). In a murine model of GVHD, it was demonstrated that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic T-cells, and that this process is essential to initiate MSC-induced immunosuppression (44). After IV infusion, recipient phagocytes engulf apoptotic MSCs and produce IDO, which is necessary for immune suppression. MSCs produce exosomes and microparticles, some of which are small complexed entities that contain both immunomodulatory proteins, micro RNA and mediators for homing abilities (45). Exosomes were also used to reverse acute GVHD (46).\n\nFigure 1 The multiple effects of MSCs on immune cells. (A) MSCs increase the proportion of CD4+CD25+ cells and IL-10 production. (B) MSCs decrease markers for activated T cells, CD25, CD69, and CD38. MSCs delayed maturation of APC and decreased expression of HLA-DR. (C) Dendritic cell type 1 when stimulated had decreased TNF-α and IL-12, when co-cultured with MSCs. (D) MSCs increased IL-10 secretion by LPS-stimulated dendritic cells type 2, CD4+ cell had decreased IL5-secretion. (E) T-helper cell type 1 IFN-γ production was significantly decreased by MSCs. (F) T-helper cell type 2 increased IL-4 secretion in the presence of MSCs. (G) MSCs inhibit mixed lymphocyte cultures and subsequent development of cytotoxic T cells by a soluble factor. (H) Several soluble factors are produced by MSCs, amongst them are IL-6, IL-8, stem-cell derived factor 1 (SDF1), vascular endothelial growth factor (VEGF). Soluble factors that have been suggested to inhibit T-cell activation are prostaglandin E2, which induces regulatory T-cells, indoleamine 2,3-dioxygenase (IDO), which is induced by IFN-γ which catalyzes the conversion from tryptophan to kynurenine and inhibits T-cell responses. Other soluble factors that have been suggested to inhibit T-cell responses are TGFβ1, hepatocyte growth factor and IL-2. (I) MSC induce macrophage differentiation from M1 to M2. (References are mentioned in the text).\n\nMesenchymal Stromal Cells For Treatment of Acute GVHD\nWe introduced MSCs, as a therapy for acute GVHD, by treating a 9-year-old boy with life-threatening grade IV acute GVHD, as well as a phase-I study in GVHD patients whom were resistant to several immunosuppressive therapies (13, 14). We also performed a multi-center phase II study, including 55 patients with severe steroid resistant GVHD (47). Complete responders had lower transplantation-related mortality 1 year after infusion than patients with partial or no response (11 [37%] of 30 vs. 18 [72%] of 25; p = 0.002). Patients with complete response to MSCs had a 2-year survival of 53% as opposed to 16% in partial and non-responders. Children had a trend for better response (64%) as opposed to adults (47%). Subsequently, several single-center studies were performed with varying results using various sources of stromal cells, for instance, adipose tissue (48). Lucchini et al. gave platelet lysate expanded MSCs to children with severe steroid refractory acute or chronic GVHD with varying responses (49). Commercial MSCs (prochymal) were given to 12 children with therapy-resistant grade III and IV acute GVHD (50). A complete response was seen in seven children (58%), a partial response in two (17%), and mixed responses were recorded in three (25%) of the children. The 100-day survival was 58%. Osiris performed a double-blind placebo controlled phase 2/3 study using prochymal for severe acute GVHD (51). The children were given 8 × 106 MSCs/kg twice a week or placebo. Among 260 patients, including children and adults, who were randomized in this trial, a complete response at 28 days was 74% in the MSCs group and 30% in the placebo group (52). However, the 180-day durable response of liver GVHD was 29% in the MSC group compared to 5% in the placebo group (p = 0.047%). Among patients with acute GVHD grades III–IV, Remestemcell-L demonstrated significantly higher overall response, 65%, as opposed to 23% in the placebo arm (p = 0.05). Children had a better outcome of treatment with MSCs for acute GVHD as compared to adults. These pediatric patients were also reported separately (53). Ball and coworkers reported on 37 children treated with MSCs for steroid-refractory grade III–IV acute GVHD (54). A response was observed in 65% of the children. The 3-year survival was 37%. Kurtzberg et al. reported on 241 children with steroid refractory acute GVHD who were treated for 4 weeks with infusion of 2 × 106 MSCs/kg (Remestemcel-L) twice weekly (55). The overall response rate at day +28 was 65%. Survival at 100 days was 82% among the responders and 39% among the non-responders (p ≤ 0.001). In a Brazilian multicenter study, involving 16 children and 30 adults with steroid refractory GVHD, half of the patients responded and 1-year survival was 20% (56). A study using platelet-lysate-expanded MSC for steroid refractory acute GVHD included eight children and 22 adults. The overall response rate at day +28 was 50% in the adults and 88% in the children (p = 0.099). The survival was 88% in the children as opposed to 25% in the adults (p = 0.003) (57).\n\nA study used BM-MSCs pooled from multiple third-party donors (58). The study included 92 adult and pediatric patients with steroid refractory acute GVHD. The patients received a median of three doses of pooled MSCs without toxicity. The overall response was 82% and 6-month survival was 64%. In a previous separate analysis of children, the overall response at day 28 was 77% and the 2-year survival was 77% (59). At our unit, long-term follow up of patients treated with BM-MSCs with steroid refractory GVHD included nine children and 22 adults (60). Two-year survival was only 26%. Patients receiving MSCs from passage 1–2 had significantly better survival than those receiving MSCs from passage 3–4 (p < 0.01). A meta-analysis reported that children had a better response to MSCs therapy for steroid refractory acute GVHD, with an overall response rate of 82%, as opposed to 70% in adults (p = 0.04) (61). A more recent meta-analysis included children and adults given MSCs for prophylaxis (n = 651) and for treatment of acute GVHD (n = 149) and chronic GVHD (n = 76) (62).\n\nMesenchymal Stromal Cells For Treatment of Chronic Graft-Versus-Host Disease\nChronic GVHD is a great burden for many patients after HCT (63, 64). It seems logical to use MSCs to treat chronic GVHD, which resembles auto-immune disorders. MSCs were reported to be successful in many models of autoimmune diseases (65, 66). There are only a few reports on MSCs for chronic GVHD and most are about adults (14, 67, 68). Lucchini et al. used platelets-lysate expanded MSCs in four children with chronic GVHD (49). Transient benefits were noted. One child had a complete response that subsequently re-flared.\n\nDSCs appear to have a stronger immunosuppressive effect than MSCs from bone marrow (30, 69). Thus, we used DSCs to treat chronic GVHD in three pediatric patients with severe grade 3 chronic GVHD (Based on National Institute of Health, NIH) (70). The three pediatric patients were affected in several organs such as the skin, mouth, eyes, gastrointestinal tract, liver, lungs and joints, fascia. Two patients received two doses of DSC and one patient received one dose. Two patients had a partial response in the liver, normalization of elevated liver enzymes and, in one patient, esophageal varices disappeared. However, the overall grading of chronic GVHD remained very severe (3) according to NIH grading (71). A meta-analysis of 76 children and adults with chronic GVHD suggested improved survival using MSCs (62).\n\nPrevention of GVHD and Graft Failure\nIn mice, MSCs were shown to prevent the development of lethal GVHD (72). Lazarus et al. performed co-transplantation of HLA-identical sibling bone marrow and donor MSCs in 46 patients (73). No patient had graft failure and grades III–IV acute GVHD were seen in 15% of the patients. We performed co-transplantation of HCT and MSCs to enhance engraftment (74). All patients had engraftment and full donor chimerism. A prospective randomized study of HCT and with co-infusion of MSCs or placebo reported decreased risk of acute GVHD and increased likelihood of relapse (75). Engraftment of neutrophils and platelets was similar in the two groups. Most studies of co-transplantation of HCT and MSCs are performed in adult patients or in a combination of pediatric and adult patients (76, 77). In a pediatric study, parental haplo-identical MSCs were used to promote engraftment in unrelated donor umbilical cord blood transplantation (78). In another pediatric study, MSCs were given to recipients of haplo-identical grafts (79). No patient had graft failure as opposed to 10% of the retrospective controls. A meta-analysis, which included 651 children and adults, showed improved survival in patients treated with MSCs as prophylaxis (62). MSCs may also be used to treat graft failure (80, 81).\n\nMSCs For Metabolic Disorders\nHurler's disease is deficiency of the enzyme alfa-L-iduronidase. HCT may partially prevent disease progression if performed before the patient is 2 years of age (82, 83). HCT patients with Hurler's disease and metachromatic leukodystrophy were given MSCs to enhance enzyme production after HCT (84). The rationale for using MSCs was because these cells express high levels of alpha-L-iduromidase and arylsulphatase-A. Four out of five patients with metachromatic leukodystrophy had improved nerve conduction velocity. Five patients with osteogenesis imperfecta who underwent HCT had donor osteoblast engraftment, new dense bone, increased total bone mineral content and improved growth velocity (85). The frequency of bone fractures decreased. Gene-marked MSCs were given to six HCT patients with MSC engraftment in bone and accelerated growth velocity. In a fetus with bilateral femur fractures due to severe osteogenesis imperfecta, in utero transplantation of MSCs showed 7% engraftment and the patient had fewer fractures than expected after birth (86).\n\nMSCs For Hemorrhages and Side-Effects\nWe used MSCs for hemorrhagic cystitis, colon perforation, and pneumomediastinum after HCT (87). Adult patients are more vulnerable and had more toxicity after HCT as opposed to pediatric patients. However, toxicity also occurs in children with advanced hematological malignancies treated with multiple rounds of chemotherapy prior to transplantation. Stromal cells induce clotting and may stop or prevent bleeding. This effect appears to be stronger for DSCs than BM-MSCs (88). Yim et al. reported on two patients with pneumomediastinum/pneumothorax with resolution after MSCs treatment (89).\n\nMaterials and Methods\nPatients\nSix children diagnosed with grade II–IV acute gastrointestinal GVHD, with or without skin involvement, were treated with DSCs (Table 1). The patients comprised five boys and one girl aged from 10 months to l6 years. Informed consent was obtained from the legal guardians of the patients. Diagnoses were pre-B-ALL in two children, Langerhans cell histiocytosis (LCH), sickle cell anemia, osteopetrosis, and severe combined immunodeficiency (SCID). The conditioning therapy was total body irradiation and etoposide in the two patients with leukemia. The four children with other disorders were given fludarabine together with treosulfan in three patients and with the addition of thiotepa in one patient with sickle cell anemia. A boy with osteopetrosis was given a low dose of busulfan, in addition to fludarabine. Donors were matched unrelated in three patients, cord blood in two children, and bone marrow from an HLA-identical sibling donor in one patient. Post-transplant immunosuppression consisted of tacrolimus together with sirolimus in four patients (Table 1). Three patients were given antithymocyte globulin (90).\n\nTable 1 Characteristics of pediatric patients treated with DSCs for acute GVHD.\n\nNo\tUPN\tSex/age\tDiagnosis\tConditioning\tDonor\tGraft\tImmuno-suppression\tAcute GVHD grade\tOrgans involved\tDay of acute GVHD\tDay of DSC\t\n1\t1555\tM/1\tLangerhans cell, histiocytosis\tFlu treo\tUD\tCB\tPrograf rapamune\tIII SR\tGI skin\t+ 20\t+23, +43\t\n2\t1625\tF/16\tHigh risk pre B-ALL\tTBI+VP16\tMUD\tBM\tPrograf rapamune ATG\tII SR\tGI skin\t+ 18\t+30\t\n3\t1687\tM/9\tIntermediate risk pre B-ALL\tTBI+VP16\tHLA id sister\tBM\tPrograf rapamune\tIII SR\tGI skin\t+ 9\t+31, +38, +45, +55, +284, +298\t\n4\t1692\tM/14\tSickle cell anemia\tFlu treo TT\tMUD\tBM\tPrograf rapamune ATG\tII SR\tGI\t+ 182\t+200\t\n5\t1707\tM/1\tOsteopetrosis\tFlu Bu2\tMUD\tPB\tPrograf methotrexate ATG\tII SR\tGI\t+ 17\t+ 21, +70, +78, + 86, +93\t\n6\tUAH\tM/1\tSCID\tFlu treo\tUD\tCB\tCyclosporine MMF\tIV SR\tGI skin\t+ 33\t+ 57, +64, +71, +78, +92, +113\t\nM, male; F, female; Flu, Fludarabine; Treo, Treosulphan; UD, unrelated donor; CB, cord blood; GI, gastro-intestinal tract; TBI, total body irradiation; VP16, vepesid; BM, bone marrow; ATG, anti-thymocyte globulin; TT, Thiotepa; Bu, short course busulphan; SR, steroid refractory; MUD, matched unrelated donor; HLA id, human leukocyte antigen identical; UAH, Uppsala Academic Hospital; SCID, severe combined immunodeficiency; MMF, murophenolate mofetil.\n\nAcute GVHD was graded according to Seattle criteria (91). The diagnosis of gastrointestinal GVHD was based on biopsies from endoscopies (7–9). Skin biopsies were not performed. Donor recipient chimerism was followed by PCR and patients with acute GVHD were full-donor chimeras (9, 92). Cytomegalovirus (CMV) was followed weekly by PCR and reactivation was treated with ganciclovir (93). Epstein-Barr virus (EBV) PCR was only regularly followed in patients with an EBV-mismatched donor (94). Adenovirus was not monitored routinely (95), and only when an infection was suspected.\n\nEthics\nWe received ethical approval from the regional ethic committee to harvest DSCs from Caesarian section placentas and use them for treatment of GVHD and toxicity after HCT (2009/418-31-34 and 2010/2061-32, 2010/452-31/4, and 2014-2132-32). The procedure for using DSCs was also later approved by the Central Ethical Review Board in Sweden (Dnr 011-2016). The method for clinical culture of DSCs was also approved by the Swedish Product Agency (Dnr 6.1.3-42994/2013).\n\nDecidua Stromal Cell Culture\nThe method to culture and expand DSCs was previously published in detail (96). DSCs express CD166, CD105, CD73, CD44, and CD29. They did not express hematopoietic markers CD34, CD14, and CD45. DSCs were negative for bacteria, mycoplasma, and fungi before infusion. The DSCs were cultured and expanded in a good manufacturing process laboratory. DSCs were stored in liquid nitrogen, thawed, and resuspended in CliniMACS PBS/EDTA buffer, supplemented with 10% AB plasma or 5% albumin (69). The cells were washed three times and resuspended in NaCl and 10% AB serum or 5% albumin. The infusion solution was filtered through a 70 μM cell strainer (BD Bioscience, Franklin Lakes, NI) before being transferred to a heparinized syringe (Leo Pharma, Ballerup, Denmark) at 2 × 106 cells/ml. The DSC was infused intravenously using a central venous line. The central venous line was flushed with 2–5 mL of NaCl with 25 IE heparin/ml in children weighing over 15 kg and 12.5 IE heparin/ml in children weighing under 15 kg.\n\nResults\nPatient 1 (UPN, unique patient number, 1555). A male baby boy was presented with disseminated LCH disease including bone marrow involvement and was pretreated with steroids and chemotherapy, followed by a HCT. The boy received an unrelated cord blood transplant. We previously reported that LCH can be cured by HCT (97, 98). Due to poor engraftment he was treated with granulocytes colony-stimulating factor (G-CSF) from day +20 after HCT. He reached absolute neutrophil counts (ANC) >0.5 × 109/L on day +27. On day +20 after HCT, he started vomiting and had watery diarrhea 10 times/day. His diarrhea deteriorated and he developed a skin rash on the back of his body. He was given high- dose prednisolone (2 mg/kg). Due to unresponsiveness he was treated with DSCs 3 days later and one additional dose was administered 3 weeks after the steroids had been introduced (Table 1). DSC doses were above 2 × 106/kg and viability was 78 and 95% in the two infusions, respectively (Table 2). At day 28 after DSC infusion, he had a partial response (PR). At day 56 and at the 6-month follow-up he showed no signs of acute GVHD (Table 2). He was diagnosed with a CMV reactivation on day +61 treated with ganciclovir. He is currently alive and well more than 8 years after HCT and from last follow up he showed Lansky score of 100%.\n\nTable 2 Decidua stromal cells (DSCs) for therapy of acute GVHD characteristics, cell dose and outcome.\n\nPatient\tUPN\tDSC dose no\tDSC viability %\tCell dose × 106/kg\tPassage\tDay 28 response\tDay 56 response\t6 months response\tChronic GVHD grade\tOutcome\t\n1\t1555\t1\t78\t2.7\t2\tPR\tCR\tCR\t0\tAlive and well, Lansky score 100%\t\n\t\t2\t95\t2.4\t2\t\t\t\t\t\t\n2\t1625\t1\t91\t1.7\t3\tCR\tCR\tCR\t0\tDied from leukemic relapse 2 years post HCT\t\n3\t1687\t1\t97\t1.2\t4\tCR\tPR\tPR\t2\tModerate chronic GVHD obstructive bronchiolitis. Presently Lansky score 100%\t\n\t\t2\t69\t1.1\t3\t\t\t\t\t\t\n\t\t3\t96\t1.1\t4\t\t\t\t\t\t\n\t\t4\t96\t1.1\t4\t\t\t\t\t\t\n\t\t5\t96\t1.2\t4\t\t\t\t\t\t\n\t\t6\t94\t1.5\t3\t\t\t\t\t\t\n4\t1692\t1\t96\t0.9\t4\tPR\tPR\tPR\t2\tDied from cerebral hemorrhage\t\n5\t1707\t1\t89\t1.9\t4\tCR\tPR\tCR\t0\tAlive and well. Lansky score 100%\t\n\t\t2\t100\t1.7\t4\t\t\t\t\t\t\n\t\t3\t91\t1.5\t4\t\t\t\t\t\t\n\t\t4\t95\t1.6\t4\t\t\t\t\t\t\n\t\t5\t82\t1.5\t3\t\t\t\t\t\t\n6\tUAH\t1–6\t69–100\t1.0\t3–4\tPR\tCR\tCR\t0\tAlive and well, Lansky score 100%\t\nPR, partial response; CR, complete response; UAH, Uppsala Akademic Hospital.\n\nPatient 2 (UPN 1625). A 16-year-old female with high risk B-ALL in 2nd complete remission (CR) received bone marrow from an unrelated donor. The patient was treated pre-HCT according to the NOPHO (Nordic Pediatric Hematology Oncology) ALL protocol 2008 and was in complete remission pre HCT, including MRD <0.01% (99). She experienced CMV reactivation on day +19, treated with ganciclovir. ANC reached >0.5 × 109/L on day +23. Eighteen days post-transplant, she developed steroid refractory grade II acute GVHD of the gastro-intestinal tract and a skin rash. She was treated with a high dose of steroids from day +20, but did not respond. Due to steroid resistance, she was treated with one dose of DSCs 30 days after HCT (Table 1). The DSC dose was 1.7 × 106/kg with 91% viability (Table 2). Her symptoms of acute GVHD disappeared and she was considered to be in a complete response at day 28 and remained so. However, the patient died from leukemic relapse 2 years after HCT.\n\nPatient 3 (UPN 1687). A 9-year-old boy with an intermediate risk of B-ALL in CR2 received a bone marrow graft from his HLA-identical sister. He was previously treated according to the NOPHO ALL protocol 2008 (99). Both donor and recipient were CMV seropositive. He had no CMV reactivation. On day +10 he had hemorrhagic cystitis grade II that resolved. Already on day 9 after HCT he developed acute GVHD of the gastrointestinal tract and erythema of the skin. He did not respond to high doses of steroids and was considered steroid refractory. On day +30 he also developed a varicella-zoster reactivation. One month after HCT he was given 1.2 × 106 DSC/ × 106/kg with a viability of 97% (Table 2). At day 28 after DSC treatment was initiated, he had complete resolution of all signs of acute GVHD but received another three additional weekly doses (Tables 1, 2). However, at 6 months, it was evident that he had developed signs of chronic GVHD as sicca and lichenoid changes of the skin, treated with extracorporeal psoralene and ultraviolet light (PUVA). After another 2 months he developed signs of a more generalized GVHD, with symptoms from both the skin, the liver, and the gastrointestinal tract. The biopsy from the GI-tract revealed GVHD, grade II (8) and he was given two more doses of DSC (Tables 1, 2). The symptoms of acute GI-GVHD disappeared but one and a half year after transplant he was still having symptoms of moderate chronic GVHD, mainly symptoms of bronchiolitis obliterans. 6.5 years after HCT he is suffering from NIH grade 2 chronic GVHD and is now treated with a JAK2 inhibitor, but from his last follow up he scored Lansky 100%.\n\nPatient 4 (UPN 1692). A 14-year-old boy arrived in Sweden, from an African country with an untreated severe sickle cell disease. He had a history of multiple sickle cell crises, as severe pain, osteonecrosis, cerebral infarctions, and bleedings and was therefore planned for a HCT. Before HCT he was treated with Hydrea capsules, but the treatment showed very moderate effect. He was finally transplanted and received bone marrow (0.25 × 106 CD34+ cells/kg) from an unrelated donor (12/12 match). He reached ANC >0.5 × 109/kg on day +19. On day +28 he was treated with acyclovir for a herpes simplex virus infection. Immunosuppression was tacrolimus combined with sirolimus. During discontinuation of immunosuppression on day 182 after HCT he developed diarrhea diagnosed as gastrointestinal GVHD. Steroids were administered, but the diarrhea continued. One week later he was given 0.9 × 106 DSC/ × 106/kg (Table 2). He had a partial response at 28 days and at follow-up at 6 months. Seven months after HCT he had CMV reactivation treated with ganciclovir. One year after the transplant he developed chronic GVHD, NIH overall score 2 (Table 2). However, the patient died from severe cerebral hemorrhage 1 year and 9 months after HCT, where previous cerebral damage pre HCT probably contributed to cerebral hemorrhage post HCT.\n\nPatient 5 (UPN 1707). A 1-year-old boy with osteopetrosis rejected the first graft and was re-transplanted 2 months later. He received a peripheral blood graft from an unrelated donor (Table 1). HLA-match was 10/12 with one antigen-HLA-C and –DP-mismatches. CD34+ cell dose was 34 × 106/kg. He had CMV reactivation on day +11, treated with ganciclovir. On day 17 after HCT he developed diarrhea grade II that did not respond to steroids. He was subsequently given five doses of DSC in doses ranging from 1.5 to 1.9 × 106/kg per kg (Table 2). The viability of the cells ranged from 82 to 100%. At day 28 after initiation of DSC therapy, he had a complete response. At day 56 he had some abdominal pain and a loose stool. At the 6-month follow-up the stool was normal. He did not develop any chronic GVHD and is currently alive and well 6 years after transplantation, with a Lanskys score of 100%.\n\nPatient 6 The boy, born at term, non-consanguineous parents, was admitted to the hospital at the age of 9 months, with symptoms of severe respiratory infections, failure to thrive, and low lymphocytes. He was investigated for suspected severe combined immunodeficiency (SCID). Genetic analysis revealed a JAK-3 gene mutation (two heterozygous variants, leading to a frame shift and premature stop codon; p.Ser 449LysfsX71). At 12 months of age the boy was transplanted, with cord blood as a stem cell source. Pre-HCT the boy was colonized with rhinovirus, which also was observed after transplantation. On day 29, PCR-chimerism analysis revealed 60% donor cells. Subsequently, during immunosuppressive tapering, he developed a skin rash and, a few days later, also massive diarrhea due to gastrointestinal GVHD. This was diagnosed on a colon biopsy showing crypt destruction with several apoptotic bodies and regenerated features of grade IV gastrointestinal GVHD (8). He did not respond to steroids or mycophenolate mofetil therapy (Tables 1, 2). From day 57 after HCT, he was treated with weekly doses of DSCs. He had a partial response at day 28 and continued to need albumin transfusions. He received a total of six doses of DSCs before the resolution of gastrointestinal GVHD. At day 56 and 6 months after transplant he had a complete response and was doing well. Apart from rhinovirus, no viral, or fungal infections were diagnosed post-HCT. He is currently alive and well, 5 years after transplantation. He doesn't need any medications goes to school and shows Lanskys score of 100%.\n\nOverall Follow Up\nThe outcome among these six children treated for severe gastrointestinal and sometimes also acute skin GVHD at the 28-day follow-up was a complete response in three patients and a partial response in three patients (Table 2). At 6 months, a complete response was seen in four patients and a partial response in two patients. Two patients developed moderate chronic GVHD. One patient with high risk pre-B-ALL died of leukemic relapse 2 years after transplantation. A boy with sickle cell anemia died of cerebral hemorrhage 1 year and 1 month after HCT, although he had a history of multiple severe sickle cell crises before HCT. Three patients are alive and well and one patient is suffering from moderate chronic GVHD with obstructive bronchiolitis but responded to Jak-2 inhibition. Now he scores Lansky 100%. Overall, there is a 5-year survival of 67%.\n\nDiscussion\nAlthough this is only a small series of pediatric patients treated for acute GVHD, it still holds some promise. None of the children died from GVHD and 6-year survival was four out of six (67%). This is similar to what was achieved with DCSs with 21 patients, most of them older adults with a 4-year survival of 57% (100). The two deaths were due to relapse in the patient with high-risk ALL and cerebral hemorrhage in the patient with sickle cell disease. These are unfortunate yet expected complications after HCT. Patients who survived acute GVHD have an reduced risk of leukemic relapse (101). The graft-versus-leukemia (GVL) effect did not prevent relapse in this girl with high risk B-ALL. She did not develop chronic GVHD. The study from the International Registry suggested that acute GVHD had a profound GVL effect in ALL patients (102). A European study in ALL patients found that chronic GVHD was more important to decrease relapse probability (103). There were only two patients who developed moderate chronic GVHD. Children have a relatively low risk of chronic GVHD (104, 105). However, there is an increased risk of chronic GVHD in patients who survive acute GVHD (101). Children have a better outcome than adults after HCT and this is striking in patients with severe acute GVHD (6). In a prospective randomized study performed by Osiris, it was reported that children treated for severe acute GVHD, as opposed to adults, had a better outcome (51). The first multicenter study using MSCs for acute GVHD also showed a better outcome in children than adults (47). However, this was not supported by a meta-analysis, which showed that survival following MSC therapy for acute GVHD did not differ in children and adults (106).\n\nAn advantage of using MSCs as opposed to other drugs to treat acute GVHD is safety, with few, if any side-effects (107, 108). There were no side-effects caused by the stromal cells in any of the six children treated with DSCs.\n\nThe ideal source of stromal cell for treatment of acute GVHD, MSC from bone marrow, adipose tissue, Wharton's jelly, umbilical cord, placenta tissue or DSCs, may be discussed. In a humanized mouse model, it was shown that MSCs from BM, umbilical cord, and adipose tissue had different properties (109). In Table 3 is listed the different properties of MSCs from bone marrow compared to DSCs. Bone marrow aspiration is quite a painful procedure. Thus, alternative sources such as adipose tissue, cord, placenta tissue, or fetal membrane, stromal cells are more easily accessible. We found that DSCs had a stronger immunosuppression of alloreactivity in vitro in mixed lymphocyte cultures compared to MSCs from other sources. We therefore selected DSCs for further investigation (30). DSCs also appeared to be more effective for treating acute GVHD compared to BM-MSCs (69). However, it is unlikely that different sources of stromal cells will be compared in prospective randomized studies for the treatment of acute GVHD. Currently, there are several promising drugs for treating acute GVHD, such as Ruxolitinib, Vedolizumab and Etanercept (110–112). However, it seems that an advantage of using MSCs is the toxicity profile.\n\nTable 3 Differences between bone marrow-derived mesenchymal stromal cells and placenta-derived decidual stromal cells.\n\nCharacteristic\tMSC\tDSC\t\nExpansion potential\t++\t++++\t\nDifferentiation to fat and cartilage\t+++\t+/–\t\nSize, volume\t4600 fl\t2400 fl\t\nExpress PDL-1, PDL-2\t+\t++\t\nExpress CD49d, homing to inflammatory tissue (integrin)\t+\t++\t\nVascular cell adhesion molecule 1 (VCAM-1) expression\t+\t–\t\nExpress HLA class II after IFNγ stimulation\t+\t–\t\nPro-coagulant tissue factor\t6%\t39%\t\nCD55 complement regulatory activity\t62%\t98%\t\nReduction in clotting time\t55%\t70%\t\nPrevent alloreactivity in vitro (MLC)\t++\t+++\t\nNeeds direct contact for immunosuppression\t–\t+\t\nOverall response in steroid refractory acute GVHD\t75%\t100%\t\nMLC, mixed lymphocyte culture.\n\nThe first child (UPN1555) was treated with G-CSF for poor engraftment. G-CSF was reported to be associated with severe acute GVHD because it can trigger alloreactive T-cells (113, 114). G-CSF may have potentiated acute GVHD in this child.\n\nSeveral large studies have been using MSCs, as shown from a single report on children from Kurtzberg et al. who recently reported on 241 children with grade II–IV steroid refractory acute GVHD (115). The 28-day overall response rate was 65% with a 14% complete response. The 100-day survival was 67%. These results were achieved with the commercially available MSCs Remestemcel-L. The randomized study by Osiris, which did not show an overall improvement in the placebo-controlled trial, showed that pediatric patients had a significantly better outcome using MSCs compared to the placebo group (53). Bonig et al. used MSCs pooled from multiple donors to treat acute GVHD (58). They reported an overall response rate of 82% following a median of three doses of pooled MSCs. Overall, 6-month survival was 64%.\n\nMSCs have mainly been used for treatment of acute GVHD in pediatric patients. They have not been used much for chronic GVHD. This is because stromal cells have a strong anti-inflammatory effect, which may be more effective for acute inflammatory processes such as acute GVHD and less effective in chronic fibrotic processes (116). Another indication for MSCs, mainly used in adults, is hemorrhagic cystitis (117, 118). MSCs have also been used for the treatment of acute respiratory distress syndrome (ARDS). There is a wealth of experimental data suggesting the potential of MSCs for sepsis and ARDS (119–121). We treated a young boy who developed ARDS after HCT with MSCs (122). He died from massive Aspergillus infection. DSCs were shown to dramatically reverse ARDS in a male patient early after HCT (123). There is limited clinical experience (124). The lack of data on pediatric patients for these more novel indications could be because they are under development. If effective in the adult studies, MSCs will also be used for hemorrhagic cystitis, ARDS, and other indications that are more experimental today.\n\nIn addition to acute GVHD, MSCs have also been used to prevent and reverse graft failure, enhance engraftment, or as prophylaxis to reduce GVHD (74, 79–81). These studies include pediatric patients and adults.\n\nAs discussed above, the immunosuppressive effects of MSCs are induced by direct contact, as well as via several soluble factors. Exosomes and microvesicles derived from MSCs were shown to protect from acute kidney injury (125), myocardial ischemia (126), and pulmonary hypotension (127) in animal models. Exosomes for MSCs were also demonstrated to reverse severe acute GVHD (46). Since exosomes will only transfer soluble effect by MSCs and not a direct immunosuppressive effect, it is less likely that exosomes will replace MSCs in the near future.\n\nTo conclude, MSCs from various sources are mainly used in pediatric patients to treat severe acute GVHD and have shown encouraging response rates and survival efficacy. Thus, commercially available MSCs are registered as a drug in Canada, Japan and New Zeeland (128). Furthermore, MSCs also have the potential to cure other acute inflammatory and toxic disorders seen in pediatric patients, such as hemorrhages, ARDS, poor engraftment, and possibly also neuroinflammatory disorders (129).\n\nData Availability Statement\nThe datasets presented in this article are not readily available because There is no restriction for the authors of this article to use this datasets. However it is not publicly available. The reviewers are of course welcome to request any data they feel are of importance for evaluating the study properly. Requests to access the datasets should be directed to [email protected]; [email protected].\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Ethical committee of Karolinska Institutet, Stockholm, Sweden. Approval to collect placentas and isolate decidual stromal cells (DSC), Dnr 20019/413-31/4 and 2010/2061-32. To use DSCs for treatment of acute GVHD and toxicity after hematopoietic cell transplantation (Dnr 2010/452-31/4 and 2014/2132-32). Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.\n\nAuthor Contributions\nOR, BG, and BS: concept and design, collection and assembly of data, manuscript writing, and final approval of manuscript. OR and BG: financial support. OR and BS: administrative support. 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(2014 ) 4 :1 –5\n. 10.4172/2157-7633.1000244 \n124. Matthay MA Calfee CS Zhuo H Thompson BT Wilson JG Levitt JE . Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial\n. Lancet Respir Med. (2019 ) 7 :154 –62\n. 10.1016/S2213-2600(18)30418-1 30455077 \n125. Bruno S Grange C Collino F Deregibus MC Cantaluppi V Biancone L . Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury\n. PLoS ONE. (2012 ) 7 :e33115 . 10.1371/journal.pone.0033115 22431999 \n126. Lai RC Arslan F Lee MM Sze NS Choo A Chen TS . Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury\n. Stem Cell Res. (2010 ) 4 :214 –22\n. 10.1016/j.scr.2009.12.003 20138817 \n127. Lee C Mitsialis SA Aslam M Vitali SH Vergadi E Konstantinou G . Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension\n. Circulation. (2012 ) 126 :2601 –11\n. 10.1161/CIRCULATIONAHA.112.114173 23114789 \n128. Allison M . NCATS launches drug repurposing program\n. Nat Biotechnol. (2012 ) 30 :571 –2\n. 10.1038/nbt0712-571a 22781662 \n129. Sadeghi B Ersmark B Moretti G Mattsson J Ringdén O . Treatment of radiculomyelopathy in two patients with placenta-derived decidua stromal cells\n. Int J Hematol. (2020 ) 111 :591 –4\n. 10.1007/s12185-019-02804-w 31853810\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-3224", "issue": "11()", "journal": "Frontiers in immunology", "keywords": "cell theraphy; decidua stromal cells (DSCs); graft-versus-host disease (GVHD); mesenchymal stromal cell (MSC); pediatric haematopoietic stem cell transplantation", "medline_ta": "Front Immunol", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003656:Decidua; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D010865:Pilot Projects; D011379:Prognosis; D012720:Severity of Illness Index; D017154:Stromal Cells; D016896:Treatment Outcome", "nlm_unique_id": "101560960", "other_id": null, "pages": "567210", "pmc": null, "pmid": "33193339", "pubdate": "2020", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "21934657;32044400;31817480;5654088;30471340;22966167;26228813;11233907;21042238;26765648;15615264;3547128;17541394;25162829;17709496;31989101;20130212;21396594;23114789;19309241;38500;17664353;16338616;1316137;20644118;10637244;18185520;24904175;27941780;20138817;8932846;7004534;22288598;29395680;24452962;15846293;31505228;11986244;32070420;24445866;22542159;15846285;17611560;6116868;6340576;22510383;19308773;21393326;9846518;22704511;18955980;15121408;2653461;31231381;6437023;29027756;17638847;32018062;18468541;25529339;27777142;20955701;3892795;22277374;28819280;23992039;15827960;20818445;19330008;11823036;10102814;21843360;20350611;7760610;20109568;21076475;21820393;29533533;22431999;31853810;16732175;15494428;19489103;26192403;28287644;28306336;16885046;21307841;30455077;9040587;10560915;19905962;19498381;3910558;23307526;19424010;32248590;18420833;21546330;31173898;12589164;14550804;10086387;27175026;33085820;2996920;22781662;15940052;29141887;2297567;15257050;15001472;17910665;14691124;14751;14972;23133515;31001253;29045348;21747949;20457269;25478942;12542793", "title": "Mesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease.", "title_normalized": "mesenchymal stromal cells in pediatric hematopoietic cell transplantation a review and a pilot study in children treated with decidua stromal cells for acute graft versus host disease" }

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MESENCHYMAL STROMAL CELLS IN PEDIATRIC HEMATOPOIETIC CELL TRANSPLANTATION A REVIEW AND A PILOT STUDY IN CHILDREN TREATED WITH DECIDUA STROMAL CELLS FOR ACUTE GRAFT?VERSUS?HOST DISEASE. 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MESENCHYMAL STROMAL CELLS IN PEDIATRIC HEMATOPOIETIC CELL TRANSPLANTATION A REVIEW AND A PILOT STUDY IN CHILDREN TREATED WITH DECIDUA STROMAL CELLS FOR ACUTE GRAFT?VERSUS?HOST DISEASE. FRONT?IMMUNOL 2020?11:567210.", "literaturereference_normalized": "mesenchymal stromal cells in pediatric hematopoietic cell transplantation a review and a pilot study in children treated with decidua stromal cells for acute graft versus host disease", "qualification": "3", "reportercountry": "SE" }, "primarysourcecountry": "SE", "receiptdate": "20210721", "receivedate": "20210721", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19591372, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" } ]

{ "abstract": "Pediatric patients with non-Hodgkin lymphoma (NHL) in developing countries (DCs) present with greater tumor load even at lower stages and with comorbidities that impact therapy delivery. This causes toxic mortality with \"standard\" intensive protocols or recurrences with \"gentler\" treatment.\n\n\n\nWe developed and evaluated a risk stratification schema that guides intensity of therapy.\n\n\n\nSixty-nine patients were prospectively assigned to five risk groups (A-E; n = 6, 15, 16, 15, and 17) following staging and treated with protocols of risk-stratified intensity. Risk stratification utilized St. Jude stage, disease bulk, and sites involved.\n\n\n\nBetween 2006 and 2011, 69 patients with B-cell NHL were enrolled. Among these, 72.5% were boys with mean age of 6.9 years (±3.33 [SD]; range 2.4-14.2 years). Eighty-seven percent had Burkitt lymphoma, 82.6% had advanced stage (25 [36.2%] stage III; 32 [46.4%] stage IV), and 24.6% were central nervous system positive. Mean lactate dehydrogenase increased progressively across the risk strata. Among these, 0/6, 1/15, 3/16, 2/15, and 7/17 patients relapsed/progressed within each risk stratum. Fifteen patients died; three from treatment-related toxicity. At a median follow-up of 6.2 years, the overall and event-free survival (EFS) for all patients was 78.1 and 75.4%, respectively; EFS was related to risk assignment. The frequency of documented infectious and noninfectious toxicities increased with higher risk group assignment causing prolongation of admissions and potential treatment delays.\n\n\n\nReduction in treatment intensity for an identified subset of patients with NHL is feasible, while high-intensity therapy is required for high-risk groups. This risk stratification system may be a first step toward improving the outcomes in some DCs.", "affiliations": "Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Division of Nursing, King Fahd National Center for Children's Cancer, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.;Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.", "authors": "Belgaumi|Asim F|AF|;Anas|Mohammed|M|;Siddiqui|Khawar S|KS|;Akhter|Mohammed F|MF|;Al-Kofide|Amani|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.26335", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(6)", "journal": "Pediatric blood & cancer", "keywords": "developing countries; lymphoma; pediatrics; risk stratification; toxicity", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000359:Aftercare; D002051:Burkitt Lymphoma; D002648:Child; D002675:Child, Preschool; D019049:Developed Countries; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D011446:Prospective Studies; D018570:Risk Assessment; D015996:Survival Rate", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "27878966", "pubdate": "2017-06", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Risk-adapted stratification for optimally intensive treatment assignment of pediatric patients with non-Hodgkin lymphoma is an effective strategy in developing countries.", "title_normalized": "risk adapted stratification for optimally intensive treatment assignment of pediatric patients with non hodgkin lymphoma is an effective strategy in developing countries" }

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DOSE/ ONCE 12 H FOR 6 DOSES (PROTOCOL C AND D)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DOSE-2MG/ KG/ DAY (PROTOCOL A, B, C, D)??DOSE-60MG/ M2/ DAY (PROTOCOL E)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DOSE-2000 MG/ M2/ DOSE (PROTOCOL C)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DOSE-100 MG/ M2 / DOSE (PROTOCOL C)", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, 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{ "abstract": "BACKGROUND\nBing-Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy.\nA 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye.\nBrain imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration. Flow cytometry of the cerebrospinal fluid (CSF) revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for immunoglobulin M and kappa light chain. Thus, the diagnosis of BNS was established.\n\n\nMETHODS\nThe patient was initially treated with intrathecal methotrexate and systemic chemotherapy. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start maintenance treatment with IV rituximab and per os ibrutinib.\n\n\nRESULTS\nFollowing 1 year posttreatment initiation, visual problems have resolved completely and the patient remains on hematologic and imaging complete response.\n\n\nCONCLUSIONS\nWe propose a novel sequential chemoimmunotherapy approach for BNS treatment aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity.", "affiliations": "Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;First Department of Radiology, National and Kapodistrian University of Athens, School of Medicine, Areteion Hospital.;\"Athens Vision\" Ophthalmology Clinic, Athens, Greece.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;First Department of Radiology, National and Kapodistrian University of Athens, School of Medicine, Areteion Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.;Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital.", "authors": "Gavriatopoulou|Maria|M|;Ntanasis-Stathopoulos|Ioannis|I|;Moulopoulos|Lia-Angela|LA|;Manaios|Alexandros|A|;Fotiou|Despina|D|;Eleutherakis-Papaiakovou|Evangelos|E|;Migkou|Magdalini|M|;Bourgioti|Charis|C|;Terpos|Evangelos|E|;Kastritis|Efstathios|E|;Dimopoulos|Meletios-Athanasios|MA|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000017794", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31689856MD-D-19-0139210.1097/MD.0000000000017794177944800Research ArticleClinical Case ReportTreatment of Bing–Neel syndrome with first line sequential chemoimmunotherapy A case reportGavriatopoulou Maria MD, PhDa∗Ntanasis-Stathopoulos Ioannis MDaMoulopoulos Lia-Angela MD, PhDbManaios Alexandros MDcFotiou Despina MDaEleutherakis-Papaiakovou Evangelos MD, PhDaMigkou Magdalini MD, PhDaBourgioti Charis MDbTerpos Evangelos MD, PhDaKastritis Efstathios MD, PhDaDimopoulos Meletios-Athanasios MD, PhDaNA. a Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospitalb First Department of Radiology, National and Kapodistrian University of Athens, School of Medicine, Areteion Hospitalc “Athens Vision” Ophthalmology Clinic, Athens, Greece.∗ Correspondence: Maria Gavriatopoulou, Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece (e-mails: [email protected], [email protected]).11 2019 01 11 2019 98 44 e1779421 2 2019 04 9 2019 03 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nBing–Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy.\n\nPatient concerns:\nA 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye.\n\nDiagnoses:\nBrain imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration. Flow cytometry of the cerebrospinal fluid (CSF) revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for immunoglobulin M and kappa light chain. Thus, the diagnosis of BNS was established.\n\nInterventions:\nThe patient was initially treated with intrathecal methotrexate and systemic chemotherapy. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start maintenance treatment with IV rituximab and per os ibrutinib.\n\nOutcomes:\nFollowing 1 year posttreatment initiation, visual problems have resolved completely and the patient remains on hematologic and imaging complete response.\n\nLessons:\nWe propose a novel sequential chemoimmunotherapy approach for BNS treatment aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity.\n\nKeywords\nBing–NeelibrutinibmethotrexaterituximabWaldenström macroglobulinemiaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nBing–Neel syndrome (BNS) is a rare manifestation of Waldenström macroglobulinemia (WM) with <200 cases reported in the literature. Although the recent years there has been a significant effort in formulating clinical practice guidelines, still diagnosis and management remains challenging.[1] BNS is characterized by the malignant invasion of lymphoplasmacytic cells in the central nervous system (CNS), including brain parenchyma, spinal cord, meninges, and cerebrospinal fluid (CSF). It may present as a disease relapse among previously treated patients with WM or as the initial manifestation of symptomatic disease even in the absence of other criteria for symptomatic WM, as in our case.[1,2] From its initial description by Bing and von Neel in 1936,[3] the literature reports of the disease are scarce, whereas the 4 largest multicenter case-series encompass 24 to 44 patients.[2,4–6] Although the incidence of BNS is difficult to be determined precisely, a retrospective cohort including more than 1500 patients with WM suggested a prevalence of <1%.[7] Clinical presentation varies significantly among BNS cases ranging from locomotor and sensory deficits to neuropsychiatric disorders, and it depends on the affected CNS compartment.[1,6] Hyperviscosity syndrome, immunoglobulin M (IgM)-related neuropathies, WM transformation to high-grade lymphoma or de novo lymphomas evading CNS may have overlapping clinical signs and symptoms with BNS and, thus, they should be ruled out during the diagnostic workup.[1] Magnetic resonance imaging (MRI) is recommended and may be highly suggestive of CNS invasion; interestingly, optic nerve involvement has been rarely reported.[5] Although biopsy is considered the gold standard for definitive diagnosis, CSF analysis supporting the presence of lymphoplasmacytic lymphoma is also acceptable.[1] Herein, we describe a case of newly diagnosed BNS treated with a novel therapeutic strategy. In our case, CSF flow cytometry and immunofixation showing monoclonal B-cells and IgM paraprotein with the same kappa-light chain restriction as in the serum and the bone marrow established BNS diagnosis. In compliance with the CARE guidelines, patient informed consent has been obtained and all reported clinical and imaging data have been de-identified.\n\n2 Case description\nA 67-year-old woman diagnosed with asymptomatic WM 3 years ago presented with gradual vision deterioration the past 3 months. Ophthalmologic examination revealed bilateral reduction in visual acuity (7/10) and bilateral optic disc swelling which was more prominent in the left eye. Clinical examination was otherwise unremarkable. The patient reported no weight loss or B-symptoms. At the time of initial WM diagnosis, the bone marrow biopsy showed 15% infiltration of M(κ)-clonal lymphoplasmacytic cells and the serum immunofixation was positive for monocloncal IgM, while serum IgM levels were 147 mg/dL. Laboratory examinations were within normal ranges with no signs of anemia or thrombocytopenia, whereas clinical and imaging assessment did not reveal any sites of lymphadenopathy or hepatosplenomegaly. Therefore, the patient was defined as asymptomatic and had been under follow-up every 4 months. Two years postinitial diagnosis a new diagnostic bone marrow biopsy revealed an increase in clonal infiltration up to 40% and genetic tests performed both in the bone marrow and in the serum cell-free DNA did not detect any MYD88 or CXCR4 mutations. The presence of mutations in the aforementioned genes was evaluated by allele-specific polymerase chain reaction and direct sequencing, as previously described.[8] Serum IgM levels had been gradually increasing as well with no other concurrent symptomatology and reached at 723 mg/dL at the time of presentation with visual loss (serum M-peak = 0.61 g/dL) (Fig. 1A). Her medical history was also remarkable of right eye cataract surgery, thyroidectomy, and T4 hormone replacement therapy, but she had no history of migraine. She was also current smoker with mild hypercholesterolemia. Due to the presence of risk factors for cardiovascular disease, we performed initially an extensive workup including electrocardiogram, cardiac ultrasound, sonography of the carotid, and vertebral arteries that revealed no clinically significant abnormalities. Coagulation studies were within normal limits. No serum autoantibodies were detected. Apart from an erythrocyte sedimentation rate of 140 mm at 1st hour, there were no other clinical signs of giant cell arteritis. Although the IgM was relatively low, we evaluated serum viscosity, which was 2.0 cp and, thus, we ruled out hyperviscosity syndrome. MRI of brain revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. Patchy enhancement of optic nerves was also shown upon intravenous contrast administration (Fig. 2A). MRI of the spine indicated no abnormalities. Subsequently, we performed a lumbar puncture; flow cytometry of the CSF revealed the presence of κ-light chain restricted, monoclonal B-lymphocytes accounting for the 86% of CD45 positive cells along with CD3(+)CD4(+) and CD3(+)CD8(+) T-lymphocytes. CSF protein electrophoresis showed a monoclonal band in the gamma region and immunofixation was positive for IgM and kappa light chain (Fig. 1B). MYD88 status was indeterminate. Thus, the diagnosis of BNS was established. Patient was initially treated with intrathecal methotrexate 15 mg twice weekly and systemic chemotherapy with HyperCVAD. However, after the course 1 of the 1st cycle she experienced grade 3 neutropenic fever that eventually resolved with granulocyte colony-stimulating factor and intravenous antibiotics. Following 2 intrathecal methotrexate infusions, CSF flow cytometry did not detect any cells, whereas the patient reported improvement in visual acuity. Therefore, we opted to start treatment with IV rituximab 375 mg/m2 every 4 weeks and per os ibrutinib 420 mg daily. Six months posttreatment initiation the patient has great visual improvement with resolution of papilledema and bilateral optic nerve swelling (Fig. 2B), whereas IgM levels have been reduced to 25.6 mg/dL, the serum protein electrophoresis (Fig. 1C) and immunofixation are negative for monoclonal component and bone marrow biopsy shows no evidence of disease infiltration. Therefore, the patient has achieved clinical, hematologic, and radiologic complete response. No adverse events have been reported except for transient diarrhea grade 1 probably related to ibrutinib. After completing 1 year treatment with rituximab, the patient discontinued rituximab and remains on ibrutinib monotherapy in complete response and with no major adverse events.\n\nFigure 1 (A) Serum electrophoresis before treatment initiation demonstrating a monoclonal M-paraprotein of 0.61 g/dL. (B) Cerebrospinal fluid (CSF) electrophoresis showing a monoclonal component in the gamma region; immunofixation revealed immunoglobulin M and kappa light-chain monoclonal bands. (C) Serum electrophoresis after 6 months of treatment initiation showing disappearance of the monoclonal band, whereas serum immunofixation was negative.\n\nFigure 2 (A) At presentation brain magnetic resonance imaging revealed bilateral swelling of optic nerves extending from the retina to the optic chiasm and swelling of the left optic tract. T1-weighted image in the axial plane shows diffuse enlargement of both optic nerves (arrows). (B) Corresponding T1-weighted image in the axial plane of the same patient 3 months after treatment demonstrates decrease in the size of both nerves.\n\n3 Discussion\nThe principal aim of BNS therapeutics is patients’ clinical improvement and progression-free survival (PFS) prolongation irrespectively of the possible persistence of the lymphoplasmacytic clone or MRI findings.[1] Due to the rarity of the disease, no universal treatment guidelines have been formulated yet; thus, the therapeutic strategy is personalized and depends on patient characteristics and comorbidities, prior lines of therapy, the involved CNS compartment and the availability of treatment regimens. It may include systemic and/or intrathecal chemotherapy, radiotherapy, and targeted therapies.[1] The reported response rates among patients receiving traditional chemotherapy regimens with or without rituximab reach at 70%, whereas a response rate of 85% has been recently reported with ibrutinib monotherapy.[2,4,6] Interestingly, exposure to rituximab was associated with improved overall survival in 1 retrospective study.[4] Ibrutinib has been shown to penetrate the blood–brain barrier[9] and has shown significant clinical efficacy as monotherapy among 28 BNS cases in a multicenter case series study[6] and 9 case reports.[9–15] In our case, we initially chose to administrate high-dose intrathecal methotrexate along with systemic chemotherapy that resulted in rapid improvement in symptoms and disappearance of malignant clonal cells in the CSF. Subsequently, based on the reported efficacy results of both rituximab and ibrutinib we decided to switch therapy to a less toxic chemofree regimen. Taking into consideration the benefit mentioned earlier from rituximab and ibrutinib administration for patients with BNS, along with the improved PFS of patients with WM receiving ibrutinib-rituximab in the phase 3 iNNOVATE trial,[16] we opted for administrating ibrutinib and rituximab combination and our patient has achieved complete remission according to the Task Force criteria from the 8th International Workshop for WM.[1]\n\nIn conclusion, we report an infrequent presentation of the extremely rare BNS and we propose a novel sequential chemoimmunotherapy approach aiming both at rapid disease control and deep and durable remission with minimization of induced toxicity. In the absence of randomized clinical trials, multidisciplinary and inter-institutional collaboration is considered essential to improve diagnosis and treatment outcomes for patients with BNS.\n\nAuthor contributions\nConceptualization: Maria Gavriatopoulou, Meletios-Athanasios Dimopoulos.\n\nInvestigation: Maria Gavriatopoulou.\n\nMethodology: Maria Gavriatopoulou.\n\nWriting – original draft: Maria Gavriatopoulou.\n\nWriting – review & editing: Maria Gavriatopoulou, Ioannis Ntanasis-Stathopoulos, Lia-Angela Moulopoulos, Alexandros Manaios, Despoina Fotiou, Evangelos Eleutherakis-Papaiakovou, Charis Bourgioti, Evangelos Terpos, Efstathios Kastritis, Meletios-Athanasios Dimopoulos.\n\nAbbreviations: BNS = Bing–Neel syndrome, CSF = cerebrospinal fluid, MRI = magnetic resonance imaging, PFS = progression-free survival, WM = Waldenström macroglobulinemia.\n\nHow to cite this article: Gavriatopoulou M, Ntanasis-Stathopoulos I, Moulopoulos LA, Manaios A, Fotiou D, Eleutherakis-Papaiakovou E, Migkou M, Bourgioti C, Terpos E, Kastritis E, Dimopoulos MA. Treatment of Bing–Neel syndrome with first line sequential chemoimmunotherapy. Medicine. 2019;98:44(e17794).\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Minnema MC Kimby E D'Sa S \nGuideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome . Haematologica \n2017 ;102 :43 –51 .27758817 \n[2] Simon L Fitsiori A Lemal R \nBing-Neel syndrome, a rare complication of Waldenstrom macroglobulinemia: analysis of 44 cases and review of the literature. A study on behalf of the French Innovative Leukemia Organization (FILO) . Haematologica \n2015 ;100 :1587 –94 .26385211 \n[3] Bing J Neel A \nTwo cases of hyperglobulinemia with affection of the central nervous system on a toxi-infectious basis . Acta Med Scand \n1936 ;88 :492 –506 .\n[4] Castillo JJ D'Sa S Lunn MP \nCentral nervous system involvement by Waldenstrom macroglobulinaemia (Bing-Neel syndrome): a multi-institutional retrospective study . Br J Haematol \n2016 ;172 :709 –15 .26686858 \n[5] Fitsiori A Fornecker LM Simon L \nImaging spectrum of Bing-Neel syndrome: how can a radiologist recognise this rare neurological complication of Waldenstrom's macroglobulinemia? \nEur Radiol \n2019 ;29 :102 –14 .29922935 \n[6] Castillo JJ Itchaki G Paludo J \nIbrutinib for the treatment of Bing-Neel syndrome: a multicenter study . Blood \n2019 ;133 :299 –305 .30523119 \n[7] Kulkarni T Treon SP Manning R \nClinical characteristics and treatment outcome of CNS involvement (Bing-Neel syndrome) in Waldenstrom's macroglobulinemia . Blood \n2013 ;122 :5090 .\n[8] Bagratuni T Ntanasis-Stathopoulos I Gavriatopoulou M \nDetection of MYD88 and CXCR4 mutations in cell-free DNA of patients with IgM monoclonal gammopathies . Leukemia \n2018 ;32 :2617 –25 .30026568 \n[9] Mason C Savona S Rini JN \nIbrutinib penetrates the blood brain barrier and shows efficacy in the therapy of Bing Neel syndrome . Br J Haematol \n2017 ;179 :339 –41 .27409073 \n[10] Cabannes-Hamy A Lemal R Goldwirt L \nEfficacy of ibrutinib in the treatment of Bing-Neel syndrome . Am J Hematol \n2016 ;91 :E17 –9 .26689870 \n[11] Varettoni M Defrancesco I Diamanti L \nBing-Neel syndrome: illustrative cases and comprehensive review of the literature . Mediterr J Hematol Infect Dis \n2017 ;9 :e2017061 .29181138 \n[12] Boudin L Patient M Romeo E \nEfficacy of ibrutinib as first-line treatment of tumoral Bing-Neel syndrome . Leuk Lymphoma \n2018 ;59 :2746 –8 .29569974 \n[13] O’Neil DS Francescone MA Khan K \nA case of Bing-Neel syndrome successfully treated with ibrutinib . Case Rep Hematol \n2018 ;2018 :8573105 .30228918 \n[14] Plander M Szendrei T Vadvari A \nStandard dose of ibrutinib is effective in the treatment of Bing-Neel syndrome . Pathol Oncol Res \n2018 .\n[15] Tallant A Selig D Wanko SO \nFirst-line ibrutinib for Bing-Neel syndrome . BMJ Case Rep \n2018 ;2018 .\n[16] Dimopoulos MA Tedeschi A Trotman J \nPhase 3 trial of ibrutinib plus rituximab in Waldenstrom's macroglobulinemia . N Engl J Med \n2018 ;378 :2399 –410 .29856685\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "98(44)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000368:Aged; D001927:Brain Diseases; D005260:Female; D006801:Humans; D007167:Immunotherapy; D060828:Induction Chemotherapy; D009902:Optic Neuritis; D013577:Syndrome; D008258:Waldenstrom Macroglobulinemia", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e17794", "pmc": null, "pmid": "31689856", "pubdate": "2019-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of Bing-Neel syndrome with first line sequential chemoimmunotherapy: A case report.", "title_normalized": "treatment of bing neel syndrome with first line sequential chemoimmunotherapy a case report" }

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"reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GAVRIATOPOULOU M. TREATMENT OF BING-NEEL SYNDROME WITH FIRST LINE SEQUENTIAL CHEMOIMMUNOTHERAPY: A CASE REPORT. 2019?98(44):E17794.", "literaturereference_normalized": "treatment of bing neel syndrome with first line sequential chemoimmunotherapy a case report", "qualification": "3", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17207819, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GR-TEVA-2019-GR-1156732", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { 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"1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "375 MG/M2 EVERY 4 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "375", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75493", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRIAMYCIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "1", "drugadministrationroute": "037", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BING-NEEL SYNDROME", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "15", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GAVRIATOPOULOU M, NTANASIS-STATHOPOULOS I, MOULOPOULOS LA, MANAIOS A, FOTIOU D, ELEUTHERAKIS-PAPAIAKOVOU E, ET AL. TREATMENT OF BING-NEEL SYNDROME WITH FIRST LINE SEQUENTIAL CHEMOIMMUNOTHERAPY: A CASE REPORT. MEDICINE 2019?98(44):E17794.", "literaturereference_normalized": "treatment of bing neel syndrome with first line sequential chemoimmunotherapy a case report", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200104", "receivedate": "20191224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17194442, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "To review the experience of a dedicated paediatric multidisciplinary lipid clinic in the management of familial hypercholesterolaemia (FH) by studying the demographics, clinical presentations as well as statin therapy and outcomes.\n\n\n\nRetrospective database review of all patients under 18 years old seen in the lipid clinic at an Australian tertiary paediatric hospital between April 1999 and August 2017. Outcome measures collected included patient demographics, family history, lipid profile, age at treatment commencement, treatment outcomes and complications.\n\n\n\nOne hundred and eight patients (53 males) were seen in the lipid clinic. Eighty-five had low-density lipoprotein cholesterol (LDL-C) levels at or above the 75th percentile for sex prior to treatment. Of these, 75 had a first-degree relative with hypercholesterolaemia and/or early cardiac death. Four patients had clinical manifestations. Thirty-two patients (14 males) were started on statin therapy for likely FH. LDL-C levels reduced by 2.4 mmol/L (1.4 to 2.7) in boys and 1.9 mmol/L (0.8 to 2.8) in girls at 12 month follow-up. Five patients reported side effects requiring adjustment in therapy. Main reasons for not starting statin therapy in eligible patients were parental refusal and/or lost to follow up (77%).\n\n\n\nA dedicated multidisciplinary lipid clinic is helpful for streamlining and monitoring management of paediatric FH. Clinical manifestations of FH are rare in children and may represent more severe form of FH or other lipid disorder. Statin therapy is efficacious and well tolerated but current recommended targets of treatment are difficult to attain. Greater awareness and coordinated services are required to overcome poor family engagement.", "affiliations": "Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.;Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.;Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.;Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.", "authors": "Yeung|Jeffrey|J|0000-0002-6385-667X;Chisholm|Kerryn|K|;Spinks|Catherine|C|;Srinivasan|Shubha|S|", "chemical_list": "D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors", "country": "Australia", "delete": false, "doi": "10.1111/jpc.15426", "fulltext": null, "fulltext_license": null, "issn_linking": "1034-4810", "issue": "57(8)", "journal": "Journal of paediatrics and child health", "keywords": "dedicated lipid clinic; paediatric familial hypercholesterolaemia; statin; treatment refusal", "medline_ta": "J Paediatr Child Health", "mesh_terms": "D000293:Adolescent; D001315:Australia; D002648:Child; D008078:Cholesterol, LDL; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006938:Hyperlipoproteinemia Type II; D008297:Male; D012189:Retrospective Studies", "nlm_unique_id": "9005421", "other_id": null, "pages": "1201-1207", "pmc": null, "pmid": "33830584", "pubdate": "2021-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic.", "title_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic" }

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Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. 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Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. 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Familial hypercholesterolaemia: Experience of a tertiary paediatric lipid clinic. Journal of Paediatrics and Child Health. 2021;57(8):1201-1207", "literaturereference_normalized": "familial hypercholesterolaemia experience of a tertiary paediatric lipid clinic", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20211217", "receivedate": "20211217", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20200975, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220303" } ]

{ "abstract": "OBJECTIVE\nThere is a paucity of the studies of adolescents with acute lymphoblastic leukemia (ALL). This is more noticeable in low- and middle-income countries. The international 5-year event-free survival (EFS) and overall survival (OS) for this age group is around 80%, with pediatric-inspired protocols offering better results.\n\n\nMETHODS\nA retrospective analysis of adolescents aged 16-20 diagnosed with ALL during the period 2004-2015 treated with a high-risk pediatric protocol at an academic center from a middle-income country was performed. Five-year OS and EFS were estimated by the Kaplan-Meier analysis. Hazard ratios of relapse and death were estimated by the Cox regression model.\n\n\nRESULTS\nFive-year EFS and OS for 57 adolescents were 23.3% and 48.9%, respectively. From the 41 patients who achieved complete remission, 24 (58.5%) relapsed. Bone marrow and central nervous system were the most frequent sites of relapse. Hazard ratio of treatment failure and death for patients with organomegaly at diagnosis was 2.026 and 2.970, respectively. Treatment-related toxicity developed in 31 (54.4%) patients and febrile neutropenia was the most frequent in 14 (24.6%) cases. Twelve patients (21.1%) had poor adherence to treatment.\n\n\nCONCLUSIONS\nHigh relapse rate and low 5-year EFS compared with international standards, was documented. Use of intensified pediatric regimens, adherence to proven effective medications, improved supportive care, and prevention of abandonment are necessary to improve survival rates in these patients.", "affiliations": "Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.;Internal Medicine Division, Department of Hematology, \"Dr. José E. González\" University Hospital of the School of Medicine of the Universidad Autónoma de Nuevo León, Monterrey, México.", "authors": "Jaime-Pérez|José C|JC|;Jiménez-Castillo|Raúl A|RA|;Pinzón-Uresti|Mónica A|MA|;Cantú-Rodríguez|Olga G|OG|;Herrera-Garza|José L|JL|;Marfil-Rivera|Luis J|LJ|;Gómez-Almaguer|David|D|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.26396", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(7)", "journal": "Pediatric blood & cancer", "keywords": "acute lymphoblastic leukemia; adherence; adolescence; compliance; survival rates", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D003906:Developing Countries; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007843:Latin America; D008137:Longitudinal Studies; D008297:Male; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016016:Proportional Hazards Models; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "27957789", "pubdate": "2017-07", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Real-world outcomes of treatment for acute lymphoblastic leukemia during adolescence in a financially restricted environment: Results at a single center in Latin America.", "title_normalized": "real world outcomes of treatment for acute lymphoblastic leukemia during adolescence in a financially restricted environment results at a single center in latin america" }

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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL?WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA. 2017; 64 (7) :E26396. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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REAL-WORLD OUTCOMES OF TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA DURING ADOLESCENCE IN A FINANCIALLY RESTRICTED ENVIRONMENT: RESULTS AT A SINGLE CENTER IN LATIN AMERICA.. 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{ "abstract": "Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors.\n\n\n\nPatients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value.\n\n\n\nAmong 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality.\n\n\n\nIn this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.", "affiliations": "Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.;Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.", "authors": "Koks|Marije S|MS|0000-0002-0559-6881;Ocak|Gurbey|G|;Suelmann|Britt B M|BBM|;Hulsbergen-Veelken|Cornelia A R|CAR|;Haitjema|Saskia|S|;Vianen|Marieke E|ME|;Verhaar|Marianne C|MC|;Kaasjager|Karin A H|KAH|;Khairoun|Meriem|M|", "chemical_list": "D000082082:Immune Checkpoint Inhibitors", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0252978", "fulltext": "\n==== Front\nPLoS One\nPLoS One\nplos\nPLoS ONE\n1932-6203\nPublic Library of Science San Francisco, CA USA\n\n10.1371/journal.pone.0252978\nPONE-D-21-05652\nResearch Article\nMedicine and Health Sciences\nEpidemiology\nMedical Risk Factors\nCancer Risk Factors\nMedicine and Health Sciences\nOncology\nCancer Risk Factors\nBiology and Life Sciences\nBiochemistry\nBiomarkers\nCreatinine\nBiology and Life Sciences\nPopulation Biology\nPopulation Metrics\nDeath Rates\nBiology and Life Sciences\nAnatomy\nRenal System\nKidneys\nMedicine and Health Sciences\nAnatomy\nRenal System\nKidneys\nMedicine and Health Sciences\nPharmacology\nDrugs\nDiuretics\nMedicine and health sciences\nPharmacology\nDrugs\nAnalgesics\nNSAIDs\nMedicine and health sciences\nPain management\nAnalgesics\nNSAIDs\nMedicine and Health Sciences\nWomen's Health\nObstetrics and Gynecology\nGynecologic Cancers\nMedicine and Health Sciences\nOncology\nCancers and Neoplasms\nLung and Intrathoracic Tumors\nNon-Small Cell Lung Cancer\nImmune checkpoint inhibitor-associated acute kidney injury and mortality: An observational study\nImmune checkpoint inhibitor-associated acute kidney injury and mortality\nhttps://orcid.org/0000-0002-0559-6881\nKoks Marije S. Data curation Formal analysis Investigation Methodology Validation Writing – original draft Writing – review & editing 1*\nOcak Gurbey Conceptualization Data curation Formal analysis Investigation Methodology Supervision Validation Writing – original draft Writing – review & editing 123\nSuelmann Britt B. M. Methodology Supervision Writing – review & editing 4\nHulsbergen-Veelken Cornelia A. R. Data curation Investigation Writing – review & editing 5\nHaitjema Saskia Data curation Investigation Writing – review & editing 5\nVianen Marieke E. Data curation Investigation Writing – review & editing 6\nVerhaar Marianne C. Methodology Supervision Writing – review & editing 1\nKaasjager Karin A. H. Conceptualization Methodology Supervision Writing – review & editing 6\nKhairoun Meriem Conceptualization Data curation Formal analysis Investigation Methodology Supervision Validation Writing – original draft Writing – review & editing 1\n1 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\n2 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands\n3 Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands\n4 Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\n5 Central Diagnostic Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\n6 Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands\nStepkowski Stanislaw Editor\nUniversity of Toledo, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\n* E-mail: [email protected]\n8 6 2021\n2021\n16 6 e025297819 2 2021\n26 5 2021\n© 2021 Koks et al\n2021\nKoks et al\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\nBackground\n\nImmune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors.\n\nMethods\n\nPatients receiving checkpoint inhibitors between January 2013 and May 2020 at the University Medical Center Utrecht, the Netherlands, were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes criteria. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent renal dysfunction was diagnosed in AKI patients with a final serum creatinine measurement of >1.3 times the baseline value.\n\nResults\n\nAmong 676 patients receiving checkpoint inhibitors, the overall incidence of AKI was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, or proton pump inhibitor at baseline. AKI was checkpoint inhibitor-associated in one third of all patients with AKI. Checkpoint inhibitor-associated AKI was mostly low-grade, occurred a median of 15 weeks after checkpoint inhibitor initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Patients with all-cause AKI had a twofold increased mortality risk, but checkpoint inhibitor-associated AKI was not associated with increased mortality.\n\nConclusions\n\nIn this study, patients receiving checkpoint inhibitors frequently developed AKI due to various etiologies. AKI directly related to the effect of checkpoint inhibitor toxicity did not increase mortality. However, AKI not related to the effect of checkpoint inhibitor toxicity was associated with increased mortality.\n\nThe author(s) received no specific funding for this work. Data AvailabilityAll relevant data are within the manuscript.\nData Availability\n\nAll relevant data are within the manuscript.\n==== Body\nIntroduction\n\nIn the last decade, immune checkpoint inhibition has become an important treatment for patients with a broad range of malignancies, including melanoma, non-small-cell lung carcinoma, urinary tract cancer, and Hodgkin lymphoma [1–5]. Immune checkpoint inhibitors (ICPi) are humanized monoclonal antibodies that increase antitumor immune responses by blocking inhibitory pathways in T lymphocytes [6,7]. The first ICPi, targeting cytotoxic T lymphocyte–associated antigen 4, earned FDA approval in 2011 [8]. ICPi blocking programmed cell death protein 1 and programmed death ligand 1 have followed since, and novel agents are currently entering clinical trials [9].\n\nAlongside their beneficial effects in patients with cancer, ICPi are known to cause a unique spectrum of autoimmune-related side effects through unrestrained T cell activation. These immune-related adverse events (irAE) may affect multiple organ systems, typically involving the skin, gastrointestinal tract, liver, and endocrine system [10,11]. Renal dysfunction, presenting as acute kidney injury (AKI), is increasingly recognized as an irAE of ICPi [12]. Diagnosing ICPi-associated AKI (ICPi-AKI) can be challenging as patients with advanced malignancies may have various other reasons for developing AKI, including fluid depletion, infection, exposure to nephrotoxic agents, cardiac failure, hypercalcemia, or urinary tract obstruction due to tumor progression [13]. The majority of kidney biopsies in patients with suspected ICPi-AKI show acute tubulointerstitial nephritis as the dominant histopathological lesion, although glomerular diseases are also reported [14–17].\n\nRecently, two observational studies showed that AKI is common in patients receiving ICPi, both reporting an incidence of 17% [18,19]. These studies also aimed to identify risk factors for development of AKI in ICPi users. The first and largest cohort study reported proton pump inhibitor use at baseline to be associated with increased risk of AKI, while the most recent cohort study found previous diagnosis of hypertension and development of non-kidney irAE to increase AKI risk. As the reported risk factors for AKI are inconsistent, further research on this topic is necessary. Other issues that require further investigation is whether development of ICPi-AKI is associated with long-term renal dysfunction and increased mortality. Insights regarding long-term renal function and mortality might affect decision-making on continuation of ICPi treatment in patients who develop ICPi-AKI and hence affect cancer outcomes.\n\nThe aim of this study was to describe the incidence, risk factors, and mortality of AKI in patients receiving ICPi. Furthermore, we sought to investigate renal outcomes after development of AKI in ICPi users.\n\nMaterials and methods\n\nStudy population\n\nWe performed a retrospective observational cohort study of patients aged ≥18 years who received ICPi between January 1, 2013, and May 31, 2020, at the University Medical Center Utrecht, an academic hospital in the Netherlands. Patients who received nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab, or tremelimumab were included. When patients were consecutively treated with more than one ICPi, i.e. 9.5% of all patients, only the first ICPi was recorded. We excluded patients on renal replacement therapy, without serum creatinine measurement in the 12 months prior to first ICPi administration, or without any serum creatinine measurement after first ICPi administration. This study was performed in accordance with the Declaration of Helsinki. The Medical Research Ethics Committee Utrecht decided that institutional review board approval was not required, as no patients were subjected to interventions nor were any rules of conduct imposed upon them. Patient IDs were visible to the researchers in order to access electronic patient files, required to determine presumptive AKI etiologies. All data were anonymized before analysis. Follow-up started at first ICPi administration and ended with either death or the end of follow-up (July 31, 2020), whichever occurred first.\n\nData collection\n\nPatients receiving ICPi were identified through the Utrecht Patient Oriented Database (UPOD). In brief, UPOD is an infrastructure of relational databases based on the hospital-wide electronic patient record systems, comprising characteristics of all patients treated at the University Medical Center Utrecht since 2004. The structure and content of UPOD have been described in more detail elsewhere [20]. Through UPOD, data on patient age, sex, malignancy type, comorbid conditions, date of death, serum creatinine measurements, and baseline use of antihypertensive- and nephrotoxic medication were collected. Treatment with potentially nephrotoxic chemotherapy or targeted therapy during the six months prior to first ICPi administration was recorded (Table 1). Patients were defined as having hypertension if they were using antihypertensive medication at baseline. The Charlson Comorbidity Index was used to quantify the extent of comorbidities, including diabetes, chronic kidney disease, and cardiovascular diseases [21]. As ICPi-associated myositis has been reported and would be accompanied with serum creatinine elevation not due to kidney dysfunction, episodes of myositis were recorded [22]. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [23].\n\n10.1371/journal.pone.0252978.t001 Table 1 Baseline characteristics.\n\n\tAll patients N = 676\tNo AKI N = 580\tAKI N = 96\t\nAge, median (IQR)\t64\t(53–71)\t64\t(54–71)\t64\t(53–73)\t\nFemale (%)\t256\t(37.9)\t215\t(37.1)\t41\t(42.7)\t\neGFR (mL/min/1.73 m2), median (IQR)\t90\t(75–101)\t90\t(75–101)\t92\t(73–103)\t\neGFR group\t\t\t\t\t\t\t\n <60 mL/min/1.73 m2 (%)\t68\t(10.1)\t57\t(9.8)\t11\t(11.5)\t\n 60–90 mL/min/1.73 m2 (%)\t263\t(38.9)\t229\t(39.5)\t34\t(35.4)\t\n ≥90 mL/min/1.73 m2 (%)\t345\t(51.0)\t294\t(50.7)\t51\t(53.1)\t\nMalignancy type\t\t\t\t\t\t\t\n Melanoma (%)\t319\t(47.2)\t273\t(47.1)\t46\t(47.9)\t\n NSCLC (%)\t163\t(24.1)\t143\t(24.7)\t20\t(20.8)\t\n Gynecologic cancer (%)\t19\t(2.8)\t12\t(2.1)\t7\t(7.3)\t\n Urinary tract cancer (%)\t81\t(12.0)\t72\t(12.4)\t9\t(9.4)\t\n Other (%)\t94\t(13.9)\t80\t(13.8)\t14\t(14.6)\t\nCharlson Comorbidity Index, median (IQR)\t8\t(7–9)\t8\t(7–9)\t8\t(7–9)\t\nDiabetes (%)\t63\t(9.3)\t51\t(8.8)\t12\t(12.5)\t\nHypertension (%)\t234\t(34.6)\t196\t(33.8)\t38\t(39.6)\t\nMedication\t\t\t\t\t\t\t\n ACEi or ARB, diuretic, PPI, or NSAID (%)\t344\t(50.9)\t284\t(49.0)\t60\t(62.5)\t\n ACEi or ARB (%)\t147\t(21.7)\t119\t(20.5)\t28\t(29.2)\t\n Diuretic (%)\t96\t(14.2)\t76\t(13.1)\t20\t(20.8)\t\n PPI (%)\t243\t(35.9)\t200\t(34.5)\t43\t(44.8)\t\n NSAID (%)\t64\t(9.5)\t53\t(9.1)\t11\t(11.5)\t\nPrior chemotherapy or targeted therapya (%)\t193\t(28.6)\t162\t(27.9)\t31\t(32.3)\t\nCheckpoint inhibitor type\t\t\t\t\t\t\t\n Nivolumab (%)\t202\t(29.9)\t176\t(30.3)\t26\t(27.1)\t\n Ipilimumab (%)\t45\t(6.7)\t35\t(6.0)\t10\t(10.4)\t\n Pembrolizumab (%)\t236\t(34.9)\t200\t(34.5)\t36\t(37.5)\t\n Combined therapyb (%)\t132\t(19.5)\t113\t(19.5)\t19\t(19.8)\t\n Other (%)\t61\t(9.0)\t56\t(9.7)\t5\t(5.2)\t\nACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin-receptor blocker; eGFR, estimated glomerular filtration rate; NSAID, non-steroidal anti-inflammatory drug; NSCLC, non-small-cell lung carcinoma; PPI, proton pump inhibitor.\n\naChemotherapy or targeted therapy included carboplatin, cisplatin, oxaliplatin, gemcitabine, capecitabine, cyclophosphamide, methotrexate, pemetrexed, mitomycin, topotecan, ifosfamide, irinotecan, axitinib, imatinib, pazopanib, bortezomib, bevacizumab, sorafenib, sunitinib, bortezomib, carfilzomib, everolimus, temsirolimus, imatinib, dasatinib, vemurafenib, dabrafenib, cetuximab, panitumumab, venetoclax, lenalidomide, crizotinib, and ibrutinib.\n\nbCombined therapy consisted of nivolumab and ipilimumab.\n\nOutcomes\n\nThe primary outcome was development of AKI, defined as an increase in serum creatinine of ≥1.5 times the baseline value, based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria [24]. Baseline creatinine was defined as the most recent creatinine measurement before the date of first ICPi administration (median of 1 (IQR 0 to 4) day, maximum of 37 days). The highest creatinine value within three months of AKI onset was used to define AKI as KDIGO stage 1, stage 2, and stage 3, referring to an increase of 1.5 to 1.9, 2.0 to 2.9, and ≥3.0 times the baseline creatinine value, respectively. We analyzed predetermined baseline variables as potential risk factors for AKI. Furthermore, we evaluated renal outcome (persistent renal dysfunction) and mortality in patients who had developed AKI and ICPi-AKI. Persistent renal dysfunction was diagnosed in AKI patients with a final creatinine measurement (at the end of follow-up) of >1.3 times the baseline value. This definition was based on results of a study comparing different definitions of renal recovery after cardiac surgery-associated AKI [25].\n\nICPi-AKI versus non-ICPi-AKI\n\nAKI etiology was determined by retrospective chart review performed by three researchers. A novel definition and classification system for ICPi-AKI, proposed by Gupta et al., was applied to distinguish ICPi-AKI from other AKI etiologies (non-ICPi-AKI) [26]. This classification acknowledges several gradations of diagnostic uncertainty in the absence of kidney biopsy by identifying definite, probable, and possible ICPi-AKI. Definite ICPi-AKI was confirmed when kidney biopsy showed a histopathological lesion compatible with nephrotoxicity caused by ICPi. Probable ICPi-AKI was allocated to patients meeting three criteria: 1) creatinine elevation of ≥1.5 times the baseline value on at least two consecutive values or need for renal replacement therapy; 2) absence of an alternative plausible cause; 3) at least one of three additional criteria: sterile pyuria, eosinophilia, or recent or concomitant non-kidney irAE. An AKI episode was labeled as possible ICPi-AKI when an alternative etiology was not readily attributable, i.e. there was no prior or simultaneous episode of dehydration, hypotension, sepsis, hypercalcemia, acute cardiac event, excessive bleeding, myeloma cast nephropathy, hydronephrosis, or bladder outlet obstruction. AKI was considered non-ICPi-related in patients with hemodynamic or pre-renal causes (including acute tubular necrosis), post-renal obstruction, or other causes.\n\nStatistical analysis\n\nWe present continuous variables with medians and interquartile ranges (IQRs) and categorical variables with counts and percentages. The association between baseline characteristics and AKI was evaluated using Cox proportional hazard regression analysis. Persistent renal dysfunction rates in patients with ICPi-AKI versus non-ICPi-AKI were compared using a Pearson’s chi-squared test. To evaluate the association between AKI and subsequent mortality, a time-dependent Cox proportional hazard regression model was used [27]. Crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. HRs were adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to a diuretic, angiotensin-converting enzyme inhibitor (ACE-inhibitor) or angiotensin-receptor blocker (ARB), proton pump inhibitor, or non-steroidal anti-inflammatory drug (NSAID), chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index. All analyses were performed using IBM SPSS Statistics version 25.0.\n\nResults\n\nOf the 678 patients who received ICPi between January 1, 2013, and May 31, 2020, one patient had previously objected to use of personal data for research, and one patient had no baseline creatinine measurement, resulting in inclusion of 676 patients in the cohort. Baseline characteristics of the 676 patients are shown in Table 1. The median age was 64 (IQR 53 to 71) years, 256 (37.9%) patients were female, and the median baseline eGFR was 90 (IQR 75 to 101) mL/min/1.73 m2. Melanoma (47.2%) was the most frequent malignancy type, followed by non-small-cell lung carcinoma (24.1%). Nivolumab was the most commonly prescribed ICPi when considering both monotherapy and combined therapy, used by 334 (49.4%) patients.\n\nIncidence and causes of AKI\n\nA total of 96 (14.2%) patients developed AKI following ICPi therapy, during a total follow-up time of 856 person-years (Table 2). Stage 1 AKI occurred in 73 (76.0%), stage 2 in 16 (16.7%), and stage 3 in seven (7.3%) patients. None of the patients required renal replacement therapy. The rate of AKI was 112 per 1000 person-years. Median time from first ICPi administration to AKI was 15 (IQR 5 to 37) weeks. A nephrologist was consulted in 12 (12.5%) patients with AKI, and urinalysis was performed in 54 (56.3%) patients with AKI. Urinalysis showed leucocyturia in 20 patients (37.0% of all AKI patients with urinalysis) and microscopic hematuria in 18 patients (33.3% of all AKI patients with urinalysis). Among all patients meeting AKI criteria based on serum creatinine elevation (N = 96), one patient was diagnosed with myositis, however, this diagnosis was established more than six months after the initial serum creatinine elevation.\n\n10.1371/journal.pone.0252978.t002 Table 2 Stage, etiology, and renal outcome of patients with AKI and ICPi-AKI.\n\nPatients with AKI\t96\t(14.2% of all patients)\t\nAKI stage\t\t\t\n Stage 1 (%)\t73\t(76.0)\t\n Stage 2 (%)\t16\t(16.7)\t\n Stage 3 (%)\t7\t(7.3)\t\nRenal outcome after AKI\t\t\t\n Persisting renal dysfunction (%)\t34\t(35.4)\t\n Renal recovery (%)\t62\t(64.6)\t\nEtiology among patients with AKI\t\t\t\n Definite ICPi-AKI (%)\t1\t(1.0)\t\n Probable ICPi-AKI (%)\t8\t(8.3)\t\n Possible ICPi-AKI (%)\t23\t(24.0)\t\n Hemodynamic or pre-renal cause (%)\t53\t(55.2)\t\n Post-renal cause (%)\t7\t(7.3)\t\n Other cause (%)\t4\t(4.2)\t\nPatients with ICPi-AKI\t32\t(4.7% of all patients)\t\nICPi-AKI stage\t\t\t\n Stage 1 (%)\t26\t(81.3)\t\n Stage 2 (%)\t6\t(18.8)\t\n Stage 3 (%)\t0\t\t\nRenal outcome after ICPi-AKI\t\t\t\n Persisting renal dysfunction (%)\t13\t(40.6)\t\n Renal recovery (%)\t19\t(59.4)\t\nAKI, acute kidney injury; ICPi-AKI, immune checkpoint inhibitor-associated acute kidney injury.\n\nChart review regarding causes of AKI in all 96 patients revealed that 32 patients (33.3% of all AKI patients) had ICPi-AKI, which was subdivided into three levels of diagnostic certainty. One (1.0%) patient was diagnosed with definite ICPi-AKI as confirmed by kidney biopsy, which showed acute tubulointerstitial nephritis. Eight (8.3%) patients met the criteria of probable ICPi-AKI, and 23 (24.0%) patients had possible ICPi-AKI. In 53 (55.2%) patients, AKI was likely related to a hemodynamic or pre-renal cause, and in seven (7.3%) patients, AKI was attributed to post-renal obstruction. Four (4.2%) patients had AKI due to other causes, including urinary tract infection and myeloma cast nephropathy.\n\nRegarding the 32 patients with definite, probable, and possible ICPi-AKI, 81.3% had stage 1 AKI and 18.8% had stage 2 AKI. There were no cases of stage 3 AKI among patients with ICPi-AKI. Median time from first ICPi administration to ICPi-AKI was 15 (IQR 5 to 31) weeks. A nephrologist was consulted in six (18.8%) ICPi-AKI patients, and urinalysis was performed in 14 (43.8%) ICPi-AKI patients. Urinalysis showed leucocyturia in six patients (42.9% of all ICPi-AKI patients with urinalysis) and microscopic hematuria in three patients (21.4% of all ICPi-AKI patients with urinalysis). Corticosteroid treatment was started in 11 (34.4%) patients with ICPi-AKI and ICPi treatment was interrupted in 14 (43.8%) patients with ICPi-AKI. Three patients with ICPi-AKI were re-challenged with ICPi, whereupon one patient once more developed AKI. This AKI episode was attributed to a combination of ICPi nephrotoxicity and a hemodynamic cause.\n\nRisk factors for AKI\n\nAnalysis of the relationship between baseline variables and development of AKI showed that, after adjustment for potential confounders, a gynecologic malignancy was associated with a 3.91-fold (95% CI 1.55 to 9.85) increased risk of AKI, and monotherapy with ipilimumab was associated with a 2.31-fold (95% CI 1.03 to 5.20) increased risk of AKI. The risk of developing AKI was increased 2.61-fold (95% CI 1.21 to 5.60) with the use of a diuretic, 2.49-fold (95% CI 1.10 to 5.60) with the use of an ACE-inhibitor or ARB, and 1.69-fold (95% CI 1.04 to 2.75) with the use of a proton pump inhibitor (Table 3). Diabetes was not associated with AKI (crude HR 1.44, 95% CI 0.79 to 2.64; adjusted HR 1.06, 95% CI 0.55 to 2.05).\n\n10.1371/journal.pone.0252978.t003 Table 3 Risk factors for AKI.\n\n\tHazard ratio (95% CI)\t\nCrude\tAdjusted\t\nAge (years)*\t<65\t1\t(reference)\t1\t(reference)\t\n≥65\t0.97\t(0.65–1.45)\t0.86\t(0.51–1.45)\t\nSex†\tMale\t1\t(reference)\t1\t(reference)\t\nFemale\t1.21\t(0.80–1.81)\t1.24\t(0.82–1.88)\t\nBaseline eGFR group‡ (mL/min/1.73 m2)\t≥90\t1\t(reference)\t1\t(reference)\t\n60–90\t0.85\t(0.55–1.31)\t0.78\t(0.48–1.27)\t\n<60\t1.10\t(0.57–2.11)\t0.82\t(0.40–1.68)\t\nMalignancy type§\tMelanoma\t1\t(reference)\t1\t(reference)\t\nNSCLC\t0.91\t(0.54–1.54)\t0.67\t(0.38–1.19)\t\nGynecologic cancer\t3.38\t(1.52–7.51)\t3.91\t(1.55–9.85)\t\nUrinary tract cancer\t0.93\t(0.46–1.91)\t0.93\t(0.44–2.00)\t\nOther\t1.09\t(0.60–1.98)\t1.28\t(0.67–2.44)\t\nCharlson Comorbidity Index#\t0–3\t1\t(reference)\t1\t(reference)\t\n4–7\t1.17\t(0.36–3.83)\t1.27\t(0.36–4.56)\t\n8–11\t1.36\t(0.43–4.34)\t1.67\t(0.44–6.32)\t\n≥12\t2.98\t(0.67–13.33)\t3.17\t(0.56–17.97)\t\nHypertension¶\tNo\t1\t(reference)\t1\t(reference)\t\nYes\t1.30\t(0.86–1.96)\t0.66\t(0.31–1.40)\t\nMedication use at baselineπ\tNo ACEi or ARB, diuretic, PPI or NSAID\t1\t(reference)\t1\t(reference)\t\nACEi or ARB\t1.99\t(1.21–3.27)\t2.49\t(1.10–5.60)\t\nDiuretic\t2.15\t(1.25–3.72)\t2.61\t(1.21–5.60)\t\nPPI\t1.86\t(1.19–2.89)\t1.69\t(1.04–2.75)\t\nNSAID\t1.81\t(0.92–3.55)\t1.63\t(0.81–3.26)\t\nPrior chemotherapy or targeted therapyΔ\tNo\t1\t(reference)\t1\t(reference)\t\nYes\t1.41\t(0.92–2.16)\t1.41\t(0.90–2.21)\t\nCheckpoint inhibitor type■\tNivolumab\t1\t(reference)\t1\t(reference)\t\nIpilimumab\t1.72\t(0.83–3.57)\t2.31\t(1.03–5.20)\t\nPembrolizumab\t1.23\t(0.74–2.03)\t1.52\t(0.89–2.60)\t\nCombined therapya\t1.26\t(0.70–2.29)\t1.72\t(0.93–3.21)\t\nOther\t0.63\t(0.24–1.64)\t0.49\t(0.18–1.29)\t\nACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin-receptor blocker; eGFR, estimated glomerular filtration rate; NSAID, non-steroidal anti-inflammatory drug; NSCLC, non-small-cell lung carcinoma; PPI, proton pump inhibitor.\n\n*Adjusted for sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, and NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n†Adjusted for age, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n‡Adjusted for age, sex, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n§Adjusted for age, sex, baseline eGFR, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n#Adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, and checkpoint inhibitor type.\n\n¶Adjusted for age, sex, baseline eGFR, malignancy type, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\nπAdjusted for age, sex, baseline eGFR, malignancy type, hypertension, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\nΔAdjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\n■Adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, and Charlson Comorbidity Index.\n\naCombined therapy consisted of nivolumab and ipilimumab.\n\nRenal outcomes and mortality\n\nThe median time between baseline creatinine measurement and last creatinine measurement was 36 (IQR 14 to 77) weeks. Persistent renal dysfunction at the end of follow-up was seen in 34 (35.4%) patients and renal recovery in 62 (64.6%) patients of all patients who had developed AKI (Table 2). The incidences of persistent renal dysfunction in patients with ICPi-AKI (40.6%) and patients with non-ICPi-AKI (32.8%) were not different (p-value 0.45). Overall mortality was high in our cohort. After a median follow-up time of 44 (IQR 22 to 89) weeks, 314 (46.4%) patients had died (mortality rate 367 per 1000 person-years). After adjustment for potential confounders, all-cause AKI was associated with a 2.13-fold (95% CI 1.58 to 2.87) increased mortality risk. Further analysis differentiating between AKI etiologies showed that patients with non-ICPi-AKI had an increased risk of mortality (HR 2.87, 95% CI 2.04 to 4.04), but patients with ICPi-AKI (definite, probable, and possible) had no higher risk of mortality (HR 1.11, 95% CI 0.64 to 1.92) (Table 4).\n\n10.1371/journal.pone.0252978.t004 Table 4 AKI and mortality.\n\n\tHazard ratio (95% CI)\t\nCrude\tAdjusted*\t\nNo AKI\tN = 580\t1\t(reference)\t1\t(reference)\t\nAKI\tN = 96\t2.18\t(1.62–2.93)\t2.13\t(1.58–2.87)\t\n ICPi-AKI\tN = 32\t1.17\t(0.68–2.03)\t1.11\t(0.64–1.92)\t\n Non-ICPi-AKI\tN = 64\t2.83\t(2.03–3.93)\t2.87\t(2.04–4.04)\t\nAKI, acute kidney injury; ICPi-AKI, immune checkpoint inhibitor-associated AKI.\n\n*Adjusted for age, sex, baseline eGFR, malignancy type, hypertension, baseline exposure to ACEi or ARB, diuretic, PPI, or NSAID, prior chemotherapy, checkpoint inhibitor type, and Charlson Comorbidity Index.\n\nDiscussion\n\nIn this observational study, the overall incidence of AKI among 676 patients receiving ICPi was 14.2%. Baseline variables independently associated with AKI were a gynecologic malignancy, monotherapy with ipilimumab, and the use of a diuretic, ACE-inhibitor or ARB, or proton pump inhibitor at baseline. AKI was ICPi-associated in one third of all patients with AKI. ICPi-AKI was mostly low-grade, occurred a median of 15 weeks after ICPi initiation, and resulted in persistent renal dysfunction in approximately 40% of the patients. Although patients with all-cause AKI had a twofold increased mortality risk, ICPi-AKI was not associated with increased mortality.\n\nIncidence of AKI and ICPi-AKI\n\nThe incidence of AKI in our cohort was similar to the results of two other cohort studies on AKI in ICPi users by Meraz-Muñoz et al. and Seethapathy et al. [18,19]. These studies both reported an AKI incidence of 17%. With regard to ICPi-AKI, our observed incidence (4.7%) was higher than found in a meta-analysis by Cortazar et al. among a total of 3695 patients treated with ICPi in phase 2 and 3 clinical trials, where the estimated incidence of ICPi-AKI was 2.2% [15]. However, the true incidence of ICPi-AKI may have been underestimated in clinical trials, due to delay in AKI onset after ICPi initiation and inaccurate attribution of mild cases of ICPi-AKI to other etiologies. The ICPi-AKI incidence in our cohort differed from the incidences reported by Seethapathy et al. (3.0%) and Meraz-Muñoz et al. (9.7%) [18,19]. A possible explanation for the difference between the findings of Seethapathy et al. and our findings could be that Seethapathy et al. categorized AKI without a plausible etiology as “AKI of undetermined cause”, while in our study, this was recorded as possible ICPi-AKI. Both Seethapathy et al. and Meraz-Muñoz et al. only reviewed episodes of sustained AKI (i.e. AKI lasting ≥72 hours) for a potential relationship with ICPi, and episodes of transient AKI (i.e. AKI lasting <72 hours) were excluded. However, it is unlikely that this caused differences between our observed ICPi-AKI incidences, as in the study of Seethapathy et al., there were no cases of potential ICPi-AKI in patients with transient AKI, and only a minority (14%) of AKI patients in the study of Meraz-Muñoz had transient AKI. We did not differentiate sustained AKI from transient AKI, as a considerable number of patients in our cohort had intervals longer than 72 hours between creatinine measurements. These longer intervals between creatinine measurements might be explained by the low AKI stage in the majority of AKI patients.\n\nRisk factors for AKI\n\nAlthough a gynecologic malignancy was present in only a small number of patients, this baseline characteristic was the strongest predictor for AKI in ICPi recipients. While this result has not been reported by the other cohort studies, gynecologic cancers are known to increase risk of AKI and chronic kidney disease in the general oncology population by ureteral obstruction and retroperitoneal fibrosis caused by radiotherapy [28]. Indeed, in three out of seven (42.9%) patients with a gynecologic tumor and AKI, the cause of AKI was post-renal obstruction. Secondly, monotherapy with ipilimumab was associated with increased risk of AKI. Seethapathy et al. also reported ipilimumab use to increase AKI risk (HR 1.85, 95% CI 1.05 to 3.27), however, the calculated p-value (0.21) did not reach statistical significance [19]. The meta-analysis by Cortazar et al., comparing renal toxicity among ICPi, showed that the combination of ipilimumab plus nivolumab caused higher AKI rates (4.9%) than ipilimumab alone (2.0%) [14]. Additionally, a case-control study by Cortazar et al., with 138 biopsy-confirmed ICPi-AKI patients and 276 control patients without AKI, found combined ICPi treatment, and not ipilimumab monotherapy, to be a risk factor for ICPi-AKI [14]. Thirdly, the baseline use of specific medication, i.e. diuretics, ACE-inhibitors or ARBs, and proton pump inhibitors, was also associated with increased risk of AKI. Among these drugs, only proton pump inhibitor use has been previously described to be a risk factor for development of AKI and ICPi-AKI in patients using ICPi [14,19]. Although the causal pathway remains unknown, previous studies have hypothesized that ICPi do not only induce loss of host tolerance for self-antigens, but also for exogenous agents like proton pump inhibitors [29,30]. The association between AKI and diuretics, ACE-inhibitors, and ARBs has not been previously reported in ICPi users, however, the mechanism might be similar. Additionally, these drugs may induce pre-renal AKI. Finally, our study and previous observational studies on AKI in patients using ICPi found no significant effect of female sex on the risk of AKI nor ICPi-AKI [14,18,19]. These observations contrast with results of a large meta-analysis demonstrating that the risk of developing hospital-associated AKI is significantly greater in men than in women [31]. Furthermore, animal- and clinical studies have shown that premenopausal women are relatively protected from renal disease as compared with age-matched men. However, this effect seems to disappear with advancing age and menopause, suggesting a protective role of estrogen [32–34]. As female patients in our study had a median age of 61 (IQR 49 to 71) years, they would not benefit from such a potential renoprotective estrogen effect. In addition, risk factors for AKI in the general population could be different from those in our patients, who had advanced malignancies and received anticancer therapy.\n\nRenal outcomes and mortality\n\nThe association between AKI and renal recovery status is relevant, as the case-control study by Cortazar et al. showed that absence of renal recovery in patients with ICPi-AKI was independently associated with increased mortality [14]. The same study reported that complete and partial renal recovery occurred in 40 and 45% of patients with ICPi-AKI, respectively. Partial renal recovery was defined as a return of creatinine to less than twice the baseline value or discharge from renal replacement therapy regardless of the creatinine value. In our cohort, with the use of different criteria of renal recovery, patients with ICPi-AKI showed renal recovery in approximately 60% at the end of follow-up. This may indicate that ICPi-AKI more often progresses to long-term impairment of renal function than initially thought.\n\nThe only other cohort study exploring the association between AKI and mortality found that AKI was not associated with increased mortality among 309 patients receiving ICPi, using Kaplan-Meier survival analysis [18]. However, the risk of mortality was not adjusted for variables potentially confounding the association between AKI and mortality (such as medication use at baseline). Furthermore, the Kaplan-Meier model does not consider time-dependency in the relationship between AKI and subsequent mortality. In our cohort, AKI was associated with a twofold increased mortality risk using a time-dependent Cox proportional hazard regression model. Increased mortality risk was not seen in patients with ICPi-AKI, but only in patients with AKI with a non-ICPi-related etiology. The increased mortality risk in patients with non-ICPi-AKI might be a reflection of concurrent problems in these patients, such as infections and tumor progression. The fact that mortality did not increase with ICPi-AKI could be related to the low AKI stages in ICPi-AKI patients (>80% had stage 1 and no patients had stage 3). An alternative theory is that occurrence of irAE, including ICPi-AKI, represents effective antitumor response and hence might improve survival. This hypothesis is suggested by recent studies showing improved progression-free and overall survival in ICPi users who develop irAE [35,36].\n\nKidney biopsy\n\nSince the American Society of Clinical Oncology recommends to forego kidney biopsy and proceed directly with immunosuppressive therapy in case of suspected ICPi-related renal toxicity [37], patients with histopathological evidence of ICPi-AKI are scarce. In our study, as in the study of Seethapathy et al. [19], biopsy was performed in only one patient with suspected ICPi-AKI, showing acute tubulointerstitial nephritis. Unfortunately, no clinical characteristics accurately differentiate between ICPi-AKI and other causes of AKI. However, some characteristics are suggestive, e.g. sterile pyuria, non-kidney irAE, and eosinophilia [26]. Therefore, we chose to use the definition and classification system of ICPi-AKI proposed by Gupta et al., which incorporates these clinical characteristics and accordingly acknowledges several gradations of diagnostic uncertainty in the absence of a kidney biopsy [26]. In addition to the recommendation to forego kidney biopsy, the American Society of Clinical Oncology advises to empirically treat an increase in creatinine ≥2 times the baseline value by interrupting ICPi therapy and to start intravenous prednisone or equivalent after exclusion of other etiologies [37]. As the majority of patients with ICPi-AKI in our cohort had stage 1 AKI (i.e. creatinine elevation <2 times the baseline value), this could explain why treatment with corticosteroids and interruption of ICPi was only initiated in less than half of the patients.\n\nStrengths and limitations\n\nThis study has several strengths. We were able to demonstrate the incidence of AKI in a representative population of patients using a variety of ICPi classes. Patient data were collected using a comprehensive infrastructure of databases, and determination of AKI etiology was thoroughly performed by three researchers. A strength of the Cox regression was that we used time-dependent analyses to show the association between AKI and mortality. Furthermore, to the best of our knowledge, this is the first study to provide information on the association between ICPi-AKI and mortality. This study also has limitations that need to be addressed. First, as previously discussed, ICPi-AKI was confirmed by kidney biopsy in only one patient. It is possible that other episodes of ICPi-AKI were erroneously attributed to non-ICPi-related causes and vice versa. Furthermore, as data on serum creatinine levels of patients were retrospectively collected, it is possible that AKI events were unnoticed and the incidence of AKI was thus underestimated. However, the mean number of creatinine measurements after ICPi initiation was 18 per patient per year, indicating that our population was carefully monitored. Theoretically, AKI incidence might have been overestimated by ICPi-associated myositis leading to increase of serum creatinine. This was, however, not the case in our study, since among all patients meeting AKI criteria, only one patient was diagnosed with myositis and this diagnosis was established more than six months after the initial serum creatinine elevation. Additionally, our definition of AKI did not meet all KDIGO criteria, which demand that the increase of baseline creatinine should have occurred within seven days prior to AKI onset. However, as ICPi treatment was usually managed in an outpatient setting, the majority of patients experiencing AKI did not have a creatinine measurement shortly before presenting with AKI. Another limitation of our study was the limited power in the association between several baseline variables and AKI. There were specifically low numbers of patients with gynecologic cancer and patients receiving ipilimumab monotherapy. Another possible limitation was that adding potentially related confounders to the same multiple regression model could distort the risk estimates due to collinearity. However, excluding risk factors could lead to under-correction. Therefore, we presented full models with many potential confounders to decrease confounding. A final important limitation is the fact that, due to the observational methodology of this study, no conclusions can be drawn on causal relations between risk factors and AKI and between AKI and mortality, as unmeasured confounding is possible.\n\nIn conclusion, clinicians should be aware that AKI is frequently observed in patients using ICPi and that renal function should be monitored closely after initiation of treatment, especially in patients using specific medication. In this observational cohort study, ICPi-associated AKI was not associated with increased mortality.\n\nWe thank all the patients who contributed to this study.\n==== Refs\nReferences\n\n1 Hodi FS , O’Day SJ , McDermott DF , Weber RW , Sosman JA , Haanen JB , et al . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363 (8 ):711–23. doi: 10.1056/NEJMoa1003466 20525992\n2 Larkin J , Chiarion-Sileni V , Gonzalez R , Grob JJ , Cowey CL , Lao CD , et al . 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Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. J Clin Oncol. 2017;35 (7 ):785–92. doi: 10.1200/JCO.2015.66.1389 28068177\n12 Perazella MA , Sprangers B . AKI in Patients Receiving Immune Checkpoint Inhibitors. Clin J Am Soc Nephrol. 2019;14 (7 ):1077–9. doi: 10.2215/CJN.02340219 31048326\n13 Sise ME , Seethapathy H , Reynolds KL . Diagnosis and Management of Immune Checkpoint Inhibitor-Associated Renal Toxicity: Illustrative Case and Review. Oncologist. 2019;24 (6 ):735–42. doi: 10.1634/theoncologist.2018-0764 30902916\n14 Cortazar FB , Kibbelaar ZA , Glezerman IG , Abudayyeh A , Mamlouk O , Motwani SS , et al . Clinical Features and Outcomes of Immune Checkpoint Inhibitor-Associated AKI: A Multicenter Study. J Am Soc Nephrol. 2020;31 (2 ):435–46. doi: 10.1681/ASN.2019070676 31896554\n15 Cortazar FB , Marrone KA , Troxell ML , Ralto KM , Hoenig MP , Brahmer JR , et al . Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90 (3 ):638–47. doi: 10.1016/j.kint.2016.04.008 27282937\n16 Mamlouk O , Selamet U , Machado S , Abdelrahim M , Glass WF , Tchakarov A , et al . Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer. 2019;7 (1 ):2. doi: 10.1186/s40425-018-0478-8 30612580\n17 Okawa S , Fujiwara K , Shimonishi A , Matsuura H , Ozeki T , Nishimura J , et al . Rapidly Progressive Acute Kidney Injury Associated with Nivolumab Treatment. Case Rep Oncol. 2020;13 (1 ):85–90. doi: 10.1159/000505235 32110225\n18 Meraz-Munoz A , Amir E , Ng P , Avila-Casado C , Ragobar C , Chan C , et al . Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes. 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Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. Eur J Cancer. 2019;106 :12–23. doi: 10.1016/j.ejca.2018.09.033 30453170\n23 Levey AS , Stevens LA , Schmid CH , Zhang YL , Castro AF 3rd , Feldman HI , et al . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150 (9 ):604–12. doi: 10.7326/0003-4819-150-9-200905050-00006 19414839\n24 KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int. 2012;2 (1 ):1–141.\n25 Xu J , Xu X , Shen B , Zhuang Y , Liu L , Wang Y , et al . Evaluation of five different renal recovery definitions for estimation of long-term outcomes of cardiac surgery associated acute kidney injury. BMC Nephrol. 2019;20 (1 ):427. doi: 10.1186/s12882-019-1613-6 31752748\n26 Gupta S , Cortazar FB , Riella LV , Leaf DE . Immune Checkpoint Inhibitor Nephrotoxicity: Update 2020. Kidney 360 2020. p. 130–40.\n27 Dekker FW , de Mutsert R , van Dijk PC , Zoccali C , Jager KJ . Survival analysis: time-dependent effects and time-varying risk factors. Kidney Int. 2008;74 (8 ):994–7. doi: 10.1038/ki.2008.328 18633346\n28 Malyszko J , Tesarova P , Capasso G , Capasso A . The link between kidney disease and cancer: complications and treatment. Lancet. 2020;396 (10246 ):277–87. doi: 10.1016/S0140-6736(20)30540-7 32711803\n29 Perazella MA , Shirali AC . Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do? Kidney Int. 2020;97 (1 ):62–74. doi: 10.1016/j.kint.2019.07.022 31685311\n30 Rosner MH , Perazella MA . Acute Kidney Injury in Patients with Cancer. N Engl J Med. 2017;377 (5 ):500–1. doi: 10.1056/NEJMc1707248 28767352\n31 Neugarten J , Golestaneh L . Female sex reduces the risk of hospital-associated acute kidney injury: a meta-analysis. BMC Nephrol. 2018;19 (1 ):314. doi: 10.1186/s12882-018-1122-z 30409132\n32 Bairey Merz CN , Dember LM , Ingelfinger JR , Vinson A , Neugarten J , Sandberg KL , et al . Sex and the kidneys: current understanding and research opportunities. Nat Rev Nephrol. 2019;15 (12 ):776–83. doi: 10.1038/s41581-019-0208-6 31586165\n33 Boddu R , Fan C , Rangarajan S , Sunil B , Bolisetty S , Curtis LM . Unique sex- and age-dependent effects in protective pathways in acute kidney injury. Am J Physiol Renal Physiol. 2017;313 (3 ):F740–F55. doi: 10.1152/ajprenal.00049.2017 28679590\n34 Coggins CH , Breyer Lewis J , Caggiula AW , Castaldo LS , Klahr S , Wang SR . Differences between women and men with chronic renal disease. Nephrol Dial Transplant. 1998;13 (6 ):1430–7. doi: 10.1093/ndt/13.6.1430 9641172\n35 Riudavets M BA , Maroto P , Sullivan IG , Anguera G , Paez D , et al . Correlation between immune-related adverse events (irAEs) and efficacy in patients with solid tumors treated with immune-checkpoints inhibitors (ICIs). J Clin Oncol. 2018;36.\n36 Rogado J , Sanchez-Torres JM , Romero-Laorden N , Ballesteros AI , Pacheco-Barcia V , Ramos-Levi A , et al . Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients. Eur J Cancer. 2019;109 :21–7. doi: 10.1016/j.ejca.2018.10.014 30682533\n37 Brahmer JR , Lacchetti C , Thompson JA . Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract. 2018;14 (4 ):247–9. doi: 10.1200/JOP.18.00005 29517954\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "16(6)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009426:Netherlands; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0252978", "pmc": null, "pmid": "34101756", "pubdate": "2021", "publication_types": "D016428:Journal Article; D064888:Observational Study", "references": "29517954;32601079;28767352;30115704;32110225;31685311;31048326;19414839;26027431;26028407;30612580;27354476;26406148;17243908;30682533;33459118;32711803;20525992;30453170;28068177;31672794;31752748;3558716;31896554;18633346;9641172;28679590;27282937;30902916;30937112;30409132;22437870;21900389;31586165", "title": "Immune checkpoint inhibitor-associated acute kidney injury and mortality: An observational study.", "title_normalized": "immune checkpoint inhibitor associated acute kidney injury and mortality an observational study" }

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{ "abstract": "Kaposi's varicelliform eruption is a cutaneous eruption caused by the herpes simplex virus and a few other viruses that infect persons with pre-existing dermatosis such as atopic dermatitis. We report the case of a 56-year-old man who was treated with the mammalian target of rapamycin inhibitor, everolimus, for metastatic renal cell carcinoma. He presented with painful, umbilicated vesicles and pustules on his face, genital region, forearms, and legs suggestive of Kaposi's varicelliform eruption. He did not have a history of any visceral viral disease and pre-existing dermatosis. The diagnosis was based on the clinical features. He was treated with acyclovir for 7 days, with improvement of his skin lesions. We discuss the clinical manifestations of the Kaposi varicelliform-like eruption in an immunocompromised patient treated with everolimus.", "affiliations": "Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea ; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.;Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea ; Department of Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea ; Department of Brain Korea 21 Project for Medical Science, Seoul, Korea.", "authors": "Hong|Soojung|S|;Kim|Eun Hye|EH|;Cho|Sung Bin|SB|;Rha|Sun Young|SY|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000362925", "fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, [email protected] 10.1159/000362925cro-0007-0337Published online: May, 2014Kaposi's Varicelliform-Like Eruption in a Patient Treated with Everolimus for Metastatic Renal Cell Carcinoma: Report of a Rare Case Hong Soojung abKim Eun Hye bCho Sung Bin cRha Sun Young bde*aDepartment of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, KoreabDepartment of Internal Medicine, Yonsei University College of Medicine, Seoul, KoreacDepartment of Dermatology, Yonsei University College of Medicine, Seoul, KoreadDepartment of Institute for Cancer Research, Yonsei University College of Medicine, Seoul, KoreaeDepartment of Brain Korea 21 Project for Medical Science, Seoul, Korea*Sun Young Rha, MD, PhD, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea), E-Mail [email protected] 2014 27 5 2014 27 5 2014 7 2 337 342 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Kaposi's varicelliform eruption is a cutaneous eruption caused by the herpes simplex virus and a few other viruses that infect persons with pre-existing dermatosis such as atopic dermatitis. We report the case of a 56-year-old man who was treated with the mammalian target of rapamycin inhibitor, everolimus, for metastatic renal cell carcinoma. He presented with painful, umbilicated vesicles and pustules on his face, genital region, forearms, and legs suggestive of Kaposi's varicelliform eruption. He did not have a history of any visceral viral disease and pre-existing dermatosis. The diagnosis was based on the clinical features. He was treated with acyclovir for 7 days, with improvement of his skin lesions. We discuss the clinical manifestations of the Kaposi varicelliform-like eruption in an immunocompromised patient treated with everolimus.\n\nKey words\nKaposi's varicelliform eruptionRenal cell carcinomaMammalian target of rapamycin inhibitor\n==== Body\nIntroduction\nKaposi's varicelliform eruption is a disseminated cutaneous infection usually caused by the herpes simplex virus (HSV). It predominantly occurs in patients with pre-existing active dermatosis [1] and is characterized by disseminated vesiculopustules and erosions. It is common in patients with atopic dermatitis and rarely develops in an immunocompromised host. There have been several case reports of Kaposi's varicelliform eruption occurring in patients with cutaneous T-cell lymphoma and multiple myeloma [2, 3]. Herein, we report a nonfatal case of Kaposi's varicelliform-like eruption occurring in an immunocompromised patient taking the mammalian target of rapamycin (mTOR) inhibitor, everolimus, for metastatic renal cell carcinoma (RCC).\n\nCase Report\nA 56-year-old man presented with a 6-day history of fever, chills, and severe forehead pain and 5 days of vesicular eruptions involving the skin of the forehead, both eyelids, and nose. The skin lesions spread to his chest, back, and bilateral upper and lower extremities over the subsequent 4 days (fig. 1a, b). The patient had not had chickenpox during childhood or any recent exposure to it.\n\nHe had been diagnosed with left RCC in June 2007. He underwent radical nephrectomy and the pathologic type was clear cell carcinoma with T3N0M0, stage III, Fuhrman grade II. The patient was given sorafenib 400 mg twice daily for 7 months as adjuvant treatment. Follow-up computed tomography of the abdomen and pelvis performed 8 months after surgery revealed recurrence of the lesion in the left renal fossa invading the tail of the pancreas, transverse colon, and spleen. He underwent splenectomy, distal pancreatectomy, and segmental resection of the transverse colon. Two months later, computed tomography showed three metastatic nodules in the liver, and the patient underwent liver metastasectomy. After surgery, he was started on 37.5 mg of sunitinib, which he took for 7 months. Eleven months after the liver surgery, disease progression involving the liver and lungs was detected, and the patient was enrolled in a clinical trial of second-line treatment using RAD001 (everolimus), which he took for 19 months. Thereafter, disease progressed in his lungs and the patient took palliative sunitinib on a 4-week-on and 2-week-off schedule. Seven months later, a whole-body bone scan revealed multiple bone metastases involving the left ribs, left proximal femur, left ischium, and right iliac bone. The patient underwent palliative radiation therapy (45 Gy) for the pain-causing left ribs and weight bearing both pelvic bones. After finishing the radiation therapy, the patient began everolimus as palliative treatment. He took everolimus for 10 days before the appearance of the rash. The patient had stopped the drug 3 days before admission.\n\nAt admission, the patient's temperature was 38.1°C, his blood pressure was 151/102 mm Hg, and the pulse rate was 110 beats/min. He had vesicles and pustules, with crusting and swelling on the skin of his forehead, both eyelids and nose. Both eyelids were also tender and red. Vesicles, pustules and scabs were present on his trunk and extremities as well. He also had grade 2 oral mucositis. No lymphadenopathy was present.\n\nThe patient's complete blood count revealed a white blood count of 4,640/μl (neutrophils 2,210/μl, lymphocytes 1,370/μl), hemoglobin of 13.0 g/dl, and platelet count of 79,000/μl presenting mild lymphopenia and thrombocytopenia. The C-reactive protein (CRP) was elevated at 85.8 mg/l (normal range, 0–8). The results of other laboratory studies, including routine biochemistry and chest X-rays, were normal. The CD4 and CD8 lymphocyte counts were 0.28 × 109/l and 0.64 × 109/l, respectively (CD4:CD8 ratio = 0.44). Serology for human immunodeficiency virus was negative. His serum IgM and IgG antibodies were negative for varicella-zoster virus. HSV type 1 and type 2 were also undetectable by polymerase chain reaction assay.\n\nA dermatologic clinical diagnosis of Kaposi's varicelliform eruption was made based on the patient's typical skin manifestations, including viral infection-like blisters and eruptions. The patient was intravenously administered 250 mg of acyclovir every 8 h. Twenty-four hours after initiation of treatment, there were no new vesicles, and the patient's clinical status improved. However, his fever did not completely resolve. We reconsulted the dermatologist, and skin biopsy was performed after 6 days of acyclovir.\n\nThe biopsy showed interstitial granulomatous dermatitis with a few eosinophils, extravasated red blood cells and basal vacuolization (fig. 2). There was no evidence of herpetic viral infection in the biopsy specimen. The pathologic findings were suggestive of a granulomatous drug eruption. Therefore, we concluded that the patient had an everolimus-induced drug eruption manifesting as Kaposi's varicelliform eruption considering both clinical presentation and pathologic findings.\n\nAfter stopping everolimus, a follow-up bone scan of the patient revealed new spinal metastases involving the T3 and L1 vertebrae and a compression fracture of L3. He had palliative radiation therapy (42 Gy) of his thoracic and lumbar spine. Three months later, the patient died of disease progression of the metastatic RCC.\n\nDiscussion\nKaposi's varicelliform eruption is characterized by dissemination of cutaneous infection of HSV, and some other viruses in patients with pre-existing dermatoses [2, 4]. It is also called eczema herpeticum because it is most commonly seen in patients with atopic dermatitis [5, 6]. Kaposi's varicelliform eruption has also been described in association not only with dermatologic conditions, such as psoriasis, lupus vulgaris, contact dermatitis, and rosacea, but also malignant diseases such as cutaneous T-cell lymphoma and multiple myeloma [2, 3, 7]. There has been a single report of a patient with Kaposi's varicelliform eruption associated with a drug reaction (phenytoin) [1].\n\nThe severity of Kaposi's varicelliform eruption appears to be unrelated to the extent of the eczematous lesions, and active dermatitis is not necessary for the development of eruption. Systemic viremia involving multiple organs, including the liver, lungs, brain, gastrointestinal tract, adrenal glands, and eyes, is the major cause of morbidity and mortality [8]. Transmission can occur through contact with infected persons or by dissemination of primary or recurrent herpes. Recurrent episodes may also occur because the virus persists in the host and periodically reactivates in the mucosa and skin; however, the manifestations of recurrent episodes are milder and usually not systemic [8].\n\nThe diagnosis of Kaposi's varicelliform eruption is mainly clinical. There are several tests that can be useful. A Tzanck smear can provide rapid diagnosis when it shows the characteristic epithelial multinucleated giant cells. Polymerase chain reaction assays can be used to detect a virus. Both biopsy and serology are of little diagnostic value, and these are not recommended as routine tests [5, 9].\n\nOur patient did not have pre-existing dermatitis, but was taking everolimus for the treatment of the metastatic RCC. As an mTOR inhibitor, everolimus modulates T-lymphocyte homeostasis [10], and is therefore used for immunosuppression after organ transplantation and as an anticancer therapeutic. The patient first took everolimus for 19 months in a clinical trial and achieved stable disease. At that time, he only had grade 1 mucositis, insomnia, and hypertriglyceridemia but no skin manifestations of toxicity. However, when taking everolimus for a second time, he developed a drug rash and pruritus after 10 days on everolimus, which were followed by clusters of umbilicated vesiculopustules. These progressed to painful hemorrhagic, crusted, and punched-out erosions. Administration of everolimus was stopped, and the patient started with the antiviral therapy. His condition improved after administration of acyclovir.\n\nThe exact factors for Kaposi's varicelliform eruption are still unclear. However, many studies commonly explained two factors. A defective epidermal barrier and immunosuppression associated with either therapy or a debilitated state of the patient may lead to disseminated HSV infection [1]. In a retrospective review of 100 atopic dermatitis patients with Kaposi's varicelliform eruption, a high IgE serum level was found to be a risk factor [5]. Defective cytokine secretion and decreased cell-mediated immunity is important in the control of primary and recurrent HSV infections [6]. The suppressed immunity and the loss of the epidermal barrier function as a result of everolimus may have contributed to the development of Kaposi's varicelliform-like eruption in our patient, who had an increasing tumor burden and a worsening performance status.\n\nSome investigators have shown that markers of tumor inflammation or host immune status, such as CRP and neutrophil-to-lymphocyte ratio, may be predictive to survival outcome [10, 11]. At admission, the patient had a high CRP level, mild lymphopenia, and a relatively high neutrophil-to-lymphocyte ratio, which taken together, reflected the poor condition of the patient.\n\nWe ultimately diagnosed the patient with Kaposi's varicelliform-like eruption associated with a drug eruption based on the pathologic findings, clinical manifestations, and the clinical course of the patient after everolimus treatment. Unfortunately, we were unable to confirm a viral infection, perhaps because of delays in performing the skin biopsy and other laboratory tests. However, we believe that the most important tool for the diagnosis of Kaposi's varicelliform eruption is clinical judgment.\n\nThis is a rare case of Kaposi's varicelliform-like eruption occurring as an everolimus-induced rash. Physicians need to be aware that patients with increasing tumor activity and decreasing immunity may be at risk for this problem. Early diagnosis, stopping the suspected medication and appropriate treatment of patients at risk for viral complications are very important medical considerations.\n\nDisclosure Statement\nThe authors have no conflicts of interest to disclose.\n\nS. Hong and E.H. Kim contributed equally to this work.\n\nFig. 1 Clusters of erythematous papules and crusts are seen on the patient's face (a). Erythematous papules and crusts are scattered on the other areas of the trunk (b).\n\nFig. 2 Skin biopsy showing interstitial granulomatous dermatitis with a few eosinophils, extravasated red blood cells and basal vacuolization.\n==== Refs\nReferences\n1 Ajith C Dogra S Handa S Kaposi's varicelliform eruption in a patient with phenytoin-induced drug rash Int J Dermatol 2006 45 1452 1453 17184260 \n2 Fukuzawa M Oguchi S Saida T Kaposi's varicelliform eruption of an elderly patient with multiple myeloma J Am Acad Dermatol 2000 42 921 922 10767705 \n3 Masessa JM Grossman ME Knobler EH Bank DE Kaposi's varicelliform eruption in cutaneous T cell lymphoma J Am Acad Dermatol 1989 21 133 135 2787337 \n4 Smith BD Son CB Wilson LD Disseminated herpes simplex after total skin electron beam radiotherapy for mycosis fungoides J R Soc Med 2003 96 500 501 14519729 \n5 Olson J Robles DT Kirby P Colven R Kaposi varicelliform eruption (eczema herpeticum) Dermatol Online J 2008 14 18 18700121 \n6 Peng WM Jenneck C Bussmann C Risk factors of atopic dermatitis patients for eczema herpeticum J Invest Dermatol 2007 127 1261 1263 17170734 \n7 Paradisi A Capizzi R Guerriero G Rotoli M Bussoletti C Amerio PL Kaposi's varicelliform eruption complicating allergic contact dermatitis J Am Acad Dermatol 2006 54 732 733 16546605 \n8 Shenoy MM Suchitra U Kaposi's varicelliform eruption Indian J Dermatol Venereol Leprol 2007 73 65 17323459 \n9 Hayashi S Yamada Y Dekio S Jidoi J Kaposi's varicelliform eruption in a patient with mycosis fungoides Clin Exp Dermatol 1997 22 41 43 9330054 \n10 Thiery-Vuillemin A Laheurte C Mansi L Immunomodulatory effects of everolimus in a long responsive patient with metastatic renal cell carcinoma J Immunother 2014 37 51 54 24316556 \n11 Santoni M De Giorgi U Iacovelli R Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma Br J Cancer 2013 109 1755 1759 24008663\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "7(2)", "journal": "Case reports in oncology", "keywords": "Kaposi's varicelliform eruption; Mammalian target of rapamycin inhibitor; Renal cell carcinoma", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "337-42", "pmc": null, "pmid": "24987353", "pubdate": "2014-05", "publication_types": "D002363:Case Reports", "references": "2787337;17170734;24316556;9330054;14519729;24008663;17323459;18700121;10767705;16546605;17184260", "title": "Kaposi's Varicelliform-Like Eruption in a Patient Treated with Everolimus for Metastatic Renal Cell Carcinoma: Report of a Rare Case.", "title_normalized": "kaposi s varicelliform like eruption in a patient treated with everolimus for metastatic renal cell carcinoma report of a rare case" }

[ { "companynumb": "PHHY2015KR033819", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022334", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG, BID FOR 7 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CELL CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5 MG, FOR 7 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "37.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash pustular", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Spinal compression fracture", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Metastases to spine", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Skin swelling", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metastatic renal cell carcinoma", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Interstitial granulomatous dermatitis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Rash vesicular", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Metastases to lung", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Kaposi^s varicelliform eruption", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug eruption", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metastases to bone", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Blister", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "RHA SY, HONG S, KIM EH, CHO SB. KAPOSI^S VARICELLIFORM-LIKE ERUPTION IN A PATIENT TREATED WITH EVEROLIMUS FOR METASTATIC RENAL CELL CARCINOMA: REPORT OF A RARE CASE. CASE REPORTS IN ONCOLOGY. 2014;7:337-342", "literaturereference_normalized": "kaposi s varicelliform like eruption in a patient treated with everolimus for metastatic renal cell carcinoma report of a rare case", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20150326", "receivedate": "20150326", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10958343, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "A 37-year-old woman with a history of type II diabetes and Crohn's disease, status postcholecystectomy, presented with a >2-week history of cramping abdominal pain, nausea, non-bloody/non-bilious emesis and, later, diarrhoea. A flexible sigmoidoscopy was performed, revealing that 'a segmental pseudomembrane was found from rectum to sigmoid colon'. Clostridium difficile PCR on the stool was repeated twice and resulted negative both times. A food history prior to onset of symptoms was consistent with Staphylococcal food poisoning and a stool culture was positive for heavy growth of methicillin-resistant Staphylococcus aureus and the absence of enteric flora. The patient was successfully treated with oral vancomycin.", "affiliations": "Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, Florida, USA.;Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, Florida, USA.;Department of Medicine, Division of Infectious Diseases, University of Florida, Gainesville, Florida, USA.", "authors": "Pressly|Kalynn B|KB|;Hill|Emilie|E|;Shah|Kairav J|KJ|", "chemical_list": "D014640:Vancomycin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2016()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000284:Administration, Oral; D000328:Adult; D004761:Enterocolitis, Pseudomembranous; D005260:Female; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D013203:Staphylococcal Infections; D016896:Treatment Outcome; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "27165998", "pubdate": "2016-05-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "16208012;20567553;24405901;20567554;16086721;15356793;25769243;16891493;19727105", "title": "Pseudomembranous colitis secondary to methicillin-resistant Staphylococcus aureus (MRSA).", "title_normalized": "pseudomembranous colitis secondary to methicillin resistant staphylococcus aureus mrsa" }

[ { "companynumb": "US-BAYER-2016-115187", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "019537", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METRONIDAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METRONIDAZOLE." } ], "patientagegroup": "5", "patientonsetage": "37", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pseudomembranous colitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug intolerance", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KALYNN B PRESSLY, EMILIE HILL, KAIRAV J SHAH. PSEUDOMEMBRANOUS COLITIS SECONDARY TO METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA). BMJ CASE REPORTS,. 2016;(-)", "literaturereference_normalized": "pseudomembranous colitis secondary to methicillin resistant staphylococcus aureus mrsa", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20160622", "receivedate": "20160622", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12489404, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "Fentanyl induces pharmacological effects and abuse liability comparable to other prescription opioids and heroin. A surge in fentanyl-related fatalities has been periodically reported throughout the USA. The University of Florida Forensic Toxicology Laboratory observed a significant increase in fentanyl-related deaths starting in mid-2014. The present report evaluated toxicological findings, demographics of the decedents and circumstances of death in the postmortem cases that were submitted to the laboratory for toxicological analysis from July 2014 to January 2015 and that were tested for fentanyl in biological specimens. The cases originated from 6 of the 24 Florida Medical Examiner Districts, with the majority from District 12 (Desoto, Manatee and Sarasota counties). The specimens were analyzed for fentanyl by gas chromatography-mass spectrometry; the limit of detection (LOD) was 0.62 ng/mL and the limit of quantification (LOQ) was 2.5 ng/mL. During the 7-month period, the laboratory tested 143 postmortem cases for fentanyl and 50% had quantifiable fentanyl in postmortem blood. Fentanyl concentrations ranged from 2.5 to 68 ng/mL (n = 66; median: 9.8 ng/mL); six cases were positive for fentanyl >LOD but <LOQ. The majority of the cases (85%) had indications of possible drug abuse with heroin use being the most often suspected. Concurrent detection of 6-acetylmorphine, morphine and cocaine along with other opioids and benzodiazepines was common. Of the 59 deaths from District 12, the cause of death was accidental drug intoxication with fentanyl as a sole or contributing factor for 57 cases (two non-drug intoxication deaths). The median age of the 57 decedents was 35 (range: 19-63) years. Males represented 87% of the deaths and 96% were Whites. Most of the decedents (n = 53) had no prescription for fentanyl. Considering fentanyl's high potency and abuse liability, the recent rise in fentanyl-related deaths is a serious public health concern and signifies the urgent need to establish prevention and treatment efforts.", "affiliations": "Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA Houston Forensic Science Center, Houston, TX, USA.;Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;District Twelfth Medical Examiner's Office, Sarasota, FL, USA.;Forensic Toxicology Laboratory, Division of Forensic Medicine, Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA [email protected].", "authors": "Lee|Dayong|D|;Chronister|Chris W|CW|;Broussard|Wilson A|WA|;Utley-Bobak|Suzanne R|SR|;Schultz|Daniel L|DL|;Vega|Russell S|RS|;Goldberger|Bruce A|BA|", "chemical_list": "D000701:Analgesics, Opioid; D009022:Morphine Derivatives; D001569:Benzodiazepines; D003932:Heroin; D009020:Morphine; D003042:Cocaine; C026979:6-O-monoacetylmorphine; D005283:Fentanyl", "country": "England", "delete": false, "doi": "10.1093/jat/bkw087", "fulltext": null, "fulltext_license": null, "issn_linking": "0146-4760", "issue": "40(8)", "journal": "Journal of analytical toxicology", "keywords": null, "medline_ta": "J Anal Toxicol", "mesh_terms": "D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D001344:Autopsy; D001569:Benzodiazepines; D002423:Cause of Death; D003042:Cocaine; D062787:Drug Overdose; D005260:Female; D005283:Fentanyl; D005431:Florida; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D003932:Heroin; D006801:Humans; D057230:Limit of Detection; D008297:Male; D008875:Middle Aged; D009020:Morphine; D009022:Morphine Derivatives; D015995:Prevalence; D015813:Substance Abuse Detection; D055815:Young Adult", "nlm_unique_id": "7705085", "other_id": null, "pages": "588-594", "pmc": null, "pmid": "27702938", "pubdate": "2016-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Illicit Fentanyl-Related Fatalities in Florida: Toxicological Findings.", "title_normalized": "illicit fentanyl related fatalities in florida toxicological findings" }

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{ "abstract": "A 15-year-old boy with a posterior urethral valve received a deceased donor kidney transplant (KT) in March 2011. Basiliximab induction followed by tacrolimus-based triple medication was used as immunosuppression. Eleven months after KT, the graft function deteriorated and the biopsy demonstrated interstitial nephritis suggestive of acute rejection. BK polyomavirus (BKPyV) surveillance in urine and plasma was negative. The patient received methylprednisolone pulses and anti-thymocyte globulin. Immunohistochemistry was positive for simian virus 40 (SV40) large T-antigen (LTag) in the biopsies, and quantitative polymerase chain reaction for JC polyomavirus (JCPyV) indicated high viral loads in urine and borderline levels in plasma. Immunosuppression was reduced and follow-up biopsies showed tubular atrophy and interstitial fibrosis. Two years after KT, antibody-mediated rejection resulted in graft loss and return to hemodialysis. Retrospective serologic work-up indicated a primary JCPyV infection with seroconversion first for IgM, followed by IgG, but no indication of BKPyV infection. In the SV40 LTag positive biopsies, JCPyV deoxyribonucleic acid (DNA) with archetype noncoding control region was detected, while BKPyV DNA was undetectable. To the best of our knowledge, this is the first reported case of primary JCPyV infection as the cause of PyV-associated nephropathy in KT.", "affiliations": "Department of Virology, Helsinki University Hospital (HUSLAB) and University of Helsinki, Helsinki, Finland.", "authors": "Lautenschlager|I|I|;Jahnukainen|T|T|;Kardas|P|P|;Lohi|J|J|;Auvinen|E|E|;Mannonen|L|L|;Dumoulin|A|A|;Hirsch|H H|HH|;Jalanko|H|H|", "chemical_list": "D004279:DNA, Viral; D007166:Immunosuppressive Agents", "country": "United States", "delete": false, "doi": "10.1111/ajt.12945", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "14(12)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": "biopsy; clinical research/practice; infection and infectious agents; infectious disease; kidney transplantation/nephrology; rejection: acute; rejection: antibody-mediated (ABMR); viral: BK/JC/polyoma", "medline_ta": "Am J Transplant", "mesh_terms": "D000293:Adolescent; D004279:DNA, Viral; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007577:JC Virus; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D009395:Nephritis, Interstitial; D027601:Polyomavirus Infections; D011183:Postoperative Complications; D011379:Prognosis; D006435:Renal Dialysis; D014412:Tumor Virus Infections; D019562:Viral Load", "nlm_unique_id": "100968638", "other_id": null, "pages": "2887-92", "pmc": null, "pmid": "25359127", "pubdate": "2014-12", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A case of primary JC polyomavirus infection-associated nephropathy.", "title_normalized": "a case of primary jc polyomavirus infection associated nephropathy" }

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A CASE OF PRIMARY JC POLYOMAVIRUS INFECTION-ASSOCIATED NEPHROPATHY. AM J TRANSPLANT. 2014 OCT 30.", "literaturereference_normalized": "a case of primary jc polyomavirus infection associated nephropathy", "qualification": "3", "reportercountry": "FI" }, "primarysourcecountry": "FI", "receiptdate": "20141114", "receivedate": "20141114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10582889, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone.", "affiliations": "Department of Hematology, Nagaoka Red Cross Hospital, Japan.", "authors": "Hashimoto|Shigeo|S|;Kuroha|Takashi|T|;Yano|Toshio|T|;Sato|Naoko|N|;Furukawa|Tatsuo|T|", "chemical_list": "D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.55.6470", "fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.6470Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27746443Case ReportThe Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma Hashimoto Shigeo 1Kuroha Takashi 1Yano Toshio 1Sato Naoko 1Furukawa Tatsuo 11 Department of Hematology, Nagaoka Red Cross Hospital, JapanCorrespondence to Dr. Shigeo Hashimoto, [email protected]\n\n15 10 2016 55 20 3025 3028 27 8 2015 2 12 2015 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted. Peripheral neuropathy did not increase after thalidomide addition. Adding low-dose thalidomide may safely improve the responses for multiple myeloma refractory to bortezomib and dexamethasone. \n\nmultiple myelomabortezomibdexamethasonethalidomide\n==== Body\nIntroduction\nCombination therapy using bortezomib and dexamethasone (BD) is now widely considered to be the standard induction chemotherapy for newly-diagnosed or relapsed symptomatic multiple myeloma (1-5). Although the effect of this therapy is better than that of previous conventional therapies such as melphalan with prednisolone (MP), many patients may develop refractory disease or may only demonstrate a brief remission after BD therapy. We herein report five cases with multiple myeloma that were treated with BD therapy and subsequently experienced disease progression during BD therapy. In four of five cases, the addition of low-dose thalidomide (50 mg per day) to BD therapy [bortezomib, thalidomide, dexamethasone (VTD) 50] made refractory disease respond to therapy. One case was treated with the combination of four drugs (bortezomib, cyclophosphamide, dexamethasone and thalidomide) after the disease had become refractory to the three drug combination. After adding bortezomib to thalidomide, 50 mg/day, cyclophosphamide and dexamethasone, back pain was relieved quickly and the laboratory findings, including anemia and elevation of β2 microglobulin, showed continuous improvement since this four-drug combination was started. Several reports showed the effects of bortezomib, dexamethasone and thalidomide therapy for multiple myeloma as induction chemotherapy, consolidation chemotherapy after autologous stem cell transplantation and salvage chemotherapy (6,7). However, most of these reports used thalidomide at a dose of 100 mg to 200 mg per day. There are few reports of low-dose thalidomide in combination with BD therapy, and adding only 50 mg daily thalidomide (VTD 50) may be effective against multiple myeloma refractory to BD therapy. We herein report the results of VTD 50 therapy.\n\nCase Reports\nCase 1\nA 68-year-old man was referred to our hospital after the detection of an IgG λ elevation. The serum IgG level was 3,861 mg/mL, with all other globulins markedly suppressed. He had been diagnosed with stage I multiple myeloma according to the International Staging System (ISS) in January 2009. He had been treated with MP therapy first with a minimal response, and was subsequently treated with 100 mg of daily dose thalidomide with dexamethasone and MP plus thalidomide. The effect of that therapy with thalidomide was a minimal response. Computed tomography revealed the development of an interstitial shadow in both lung fields; therefore, BD therapy was not considered for primary therapy. In early 2011, weekly BD therapy (2.1 mg of bortezomib and 20 mg intravenous dexamethasone) was safely started, and IgG decreased markedly. The serum levels of IgG decreased from 3,806 mg/mL to 1,684 mg/mL within two months. He was considered to have attained a partial remission by February 2011. After weekly outpatient injections of bortezomib, the patient was later switched to two injections every three weeks, and he had neither any lung side effects nor severe sensory disturbances for over a half year. In October 2011, a rapid increase in the IgG levels was observed (3,066 mg/mL). He was given VTD 50 therapy, adding 50 mg of thalidomide daily, even though thalidomide previously had been ineffective when combined with dexamethasone or MP. We administered VTD 50 therapy with bortezomib due to concerns of potential sensory disturbance from the administration of both drugs. The combination of VTD 50 caused a decrease in the levels of IgG (down to 2,163 mg/mL in May 2013) and β2 microglobulin, which was considered to be a partial response, again with the disappearance of back pain and no sensory disturbance, and this partial response was maintained for eleven months. After a repeated deterioration of the laboratory findings, he refused further therapies using bortezomib or other combination chemotherapies. He has been treated with conventional therapy using melphalan, cyclophosphamide, and prednisolone and has since remained stable since that time.\n\nCase 2\nA 75-year-old woman was referred to our hospital in June 2010 after the detection of anemia and renal dysfunction. Her serum IgA level was 2,845 mg/mL. She was diagnosed with IgA λ myeloma, ISS stage III. She initially refused BD therapy, as she was concerned about potential side effects such as interstitial pneumonia. She had agreed to use weekly BD therapy (1.7 mg of bortezomib and 20 mg intravenous dexamethasone) when her IgA was elevated after several conventional therapies, including MP and dexamethasone monotherapy (serum level of IgA was up to 946 mg/mL in April 2011 from the normal range). Pancytopenia was observed after weekly bortezomib and dexamethasone injection with a marked decrease in the IgA levels (down to 73 mg/mL after one month), suggesting a very good partial response. Bortezomib therapy was changed to weekly, then monthly, and the patient was free of granulocytopenia and did not require transfusions. After continuing BD therapy for approximately one year, IgA and β2 microglobulin again became elevated. Biweekly injection of bortezomib became ineffective by early 2012. The patient's serum IgA level was 1,515 mg/mL in March 2012. She agreed to add thalidomide, 50 mg daily, to BD, according to our previous treatment experience (as in case 1). After VTD 50 was initiated, a rapid decrease in the IgA and β2 microglobulin levels was observed and the patient again attained a partial response (IgA level was reduced to 290 mg/mL in October 2012). These effects continued for eleven months without any sensory disturbance. After repeated deterioration of the laboratory data despite VTD 50 therapy, a rapid progressive disease status was observed, and other drugs such as lenalidomide had a minimal effect. She died from plasma cell leukemia in December 2013.\n\nCase 3\nA 62-year-old man was diagnosed with ISS stage III IgG κ myeloma in September 2007. He was treated with tandem autologous stem cell transplantation followed by several courses of vincristine, doxorubicin, and dexamethasone induction therapy from July through November 2008. No further treatment after transplantation was performed due to the development of a viral infection and pneumonia shortly after transplantation. After transplantation, he remained in a complete remission for several years. In February 2011, a routine examination revealed re-elevation of IgG (2,215 mg/mL), elevation of the atypical plasma cell ratio in the bone marrow, and positive monoclonal immunoelectrophoresis, leading to a diagnosis of relapsed myeloma. BD therapy (2.2 mg of bortezomib and 20 mg intravenous dexamethasone) was started in March 2011. Outpatient bortezomib was given on a weekly to biweekly basis. The IgG level increased again from the normal range to over 2,000 mg/mL in May 2012, suggesting a partial response after relapse. The patient began VTD 50 therapy in combination with BD therapy in July 2012. VTD 50 therapy decreased the IgG levels to 1,077 mg/mL by August 2011, again achieving a partial response with the disappearance of bone pain, and this response was maintained until June 2013, when the patient again developed progressive bone pain and IgG elevation. Lenalidomide plus dexamethasone or bortezomib, cyclophosphamide and dexamethasone combination therapy had no effect after progression. He eventually died from plasma cell leukemia in November 2013.\n\nCase 4\nA 58-year-old woman was transferred from another hospital with severe back pain in January 2012. She was diagnosed with ISS stage II IgG κ multiple myeloma. Her serum IgG level was 5,440 mg/mL at the initial visit. She initially refused up-front autologous stem cell transplantation at the diagnosis, and thus began biweekly BD therapy (2 mg of bortezomib and 20 mg intravenous dexamethasone) from April 2012 to January 2013, achieving a partial response. Progressive back pain and re-elevation of IgG were observed after ten months of BD therapy. The serum IgG level had increased to 2,364 mg/mL at that time. She agreed to take VTD 50 therapy with BD therapy. She had a rapid decrease of IgG and disappearance of back pain within two to three weeks after starting VTD 50 therapy. The IgG level was decreased to 1,208 mg/mL in May 2013, again achieving a partial response. This response was sustained for 10 months before progressive bone pain again developed in December 2013. The IgG level had increased to 1,825 mg/mL at that time. She was treated with 20 mg of lenalidomide for several months after VTD 50 therapy. Although lenalidomide controlled the IgG elevation, symptomatic bone pain had not disappeared completely. She then decided to undergo autologous stem cell transplantation after achieving a response after multiple salvage chemotherapies.\n\nCase 5\nA 63-year-old man was referred to our hospital following the detection of anemia in October 2011. He was diagnosed with ISS stage III Bence Jones λ multiple myeloma. Since all peripheral blood gamma-globulins were heavily suppressed, his disease status was followed according to symptoms of back pain, anemia, and elevation of β2 microglobulin (7.864 mg/L at the initial visit). He was not considered to be a candidate for up-front autologous stem cell transplantation due to a past history of cardiac bypass. Weekly to biweekly BD therapy (2 mg of bortezomib and 20 mg intravenous dexamethasone) was started in December 2011, which resulted in a rapid improvement in back pain, improvement in anemia, and a decrease in the β2 microglobulin levels within two weeks. In March 2013, his back pain returned, and in October 2013, β2 microglobulin increased rapidly (4.146 mg/L) accompanied by uncontrollable back pain. Increased cycles of BD with VTD 50 or treatment with lenalidomide plus dexamethasone had no effect. Morphine was required to reduce his severe pain, and within a short time, he could not walk. In December 2013, he developed worsening anemia and hypogammaglobulinemia, and further elevation of the β2 microglobulin levels (up to 5.685 mg/L) was observed, and he had to be admitted to our hospital. Treatment with cyclophosphamide (500 mg biweekly), thalidomide (50 mg daily), and dexamethasone (20 mg weekly) combination therapy briefly stabilized the β2 microglobulin levels, but his severe back pain persisted. Adding bortezomib (2 mg weekly) to the three-drug combination rapidly improved the back pain and decreased the β2 microglobulin levels. He has been treated with this four-drug combination (100 mg oral cyclophosphamide for four continuous days/every two weeks, 50 mg thalidomide daily, 20 mg oral dexamethasone weekly, and 2 mg bortezomib injected subcutaneously weekly) for over one and a half years maintaining stable disease without back pain, elevated β2 microglobulin levels (2 to 3 mg/mL by a biweekly routine examination), or further sensory disturbance beyond those present at the time of BD therapy.\n\nDiscussion\nBD therapy is considered a standard chemotherapy for multiple myeloma for autologous transplantation eligible patients (1-3), transplantation ineligible patients (4) and even patients with relapsed or refractory disease following previous therapy (5). In transplantation-eligible patients and refractory or relapsed patients, cyclophosphamide (VCD) or thalidomide (VTD) may be added to BD therapy to achieve optimal results (6). With VTD, peripheral neuropathy is one of the adverse effects, which is observed more often than with thalidomide and dexamethasone therapy (7). Both bortezomib and thalidomide have peripheral neurotoxicity. In particular, when these two drugs are used in combination, the thalidomide daily dose can range from 50 to 200 mg (6). A dose reduction of thalidomide (50 mg) may reduce this toxicity considerably (8,9). Among transplantation-ineligible patients, there are decision criteria according to the patients' clinical status or frailty (10). For induction, patients can be treated with monotherapy up to a three-drug combination. After induction, therapeutic options include bortezomib-based, lenalidomide-based or bortezomib and thalidomide-based combinations [such as bortezomib-melphalan-predinsone-thalidomide (VMPT)-bortezomib-thalidomide (VT) therapy (11)]. In frail patients, bortezomib, lenalidomide, dexamethasone and cyclophosphamide should be considered for dose reduction, however, dose reduction of thalidomide is excluded (6). Another report showed that the daily dose of thalidomide could be reduced 50 mg in two days to 100 mg per day for frail patients (12). According to the findings of our study, combination therapy with thalidomide and other drugs may be used for both transplantation-eligible and -ineligible patients with a wider range to reduce the daily dose of thalidomide than for other drugs while still achieving optimal effects. Our five cases were treated with a 50 mg daily dose of thalidomide together with BD therapy for refractory disease. Four of five cases showed improvement, including reduction of M protein and symptoms. One case showed improvement with combination therapy of bortezomib, thalidomide, cyclophosphamide, and dexamethasone. All five cases were treated with thalidomide, 50 mg daily, without excess peripheral neuropathy. Two of five cases were over 65 years of age. VTD 50 therapy safely induced a partial response of refractory disease and a rapid improvement of bone pain, together with simultaneous regression of M protein and β2 microglobulin. These findings were maintained for nearly one year in four of five cases. In two of five cases, the diseases eventually transformed into plasma cell leukemia after VTD 50 therapy. Further studies are required to find new strategies for further extending the response duration or maintaining stable disease using this drug combination.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Harousseau JL , Attal M , Avet-Loiseau H , et al \nBortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial . J Clin Oncol \n28 : 4621 -4629 , 2010 .20823406 \n2. Sonneveld P , Goldschmidt H , Rosiñol L , et al \nBortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials . J Clin Oncol \n31 : 279 -287 , 2013 .\n3. Nooka AK , Kaufman JL , Behera M , et al \nBortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials . Cancer \n119 : 4119 -4128 , 2013 .24005889 \n4. Palumbo A , Rajkumar SV , San Miguel JF , et al \nInternational Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation . J Clin Oncol \n32 : 587 -600 , 2014 .24419113 \n5. Kropff MH , Bisping G , Wenning D , et al \nBortezomib in combination with dexamethasone for relapsed multiple myeloma . Leuk Res \n29 : 587 -590 , 2005 .15755512 \n6. Ludwig H , Sonneveld P , Davies F , et al \nEuropean perspective on multiple myeloma treatment strategies in 2014 . Oncologist \n19 : 829 -844 , 2014 .25063227 \n7. Cavo M , Pantani L , Petrucci MT , et al \nBortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma . Blood \n120 : 9 -19 , 2012 .22498745 \n8. Pineda-Roman M , Zangari M , van Rhee F , et al \nVTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma . Leukemia \n22 : 1419 -1427 , 2008 .18432260 \n9. Glasmacher A , von Lilienfeld-Toal M \nThe current status of thalidomide in the management of multiple myeloma . Acta Haematol \n114 (Suppl 1 ): 3 -7 , 2005 .16166765 \n10. Palumbo A , Anderson K \nMultiple myeloma . N Engl J Med \n364 : 1046 -1060 , 2011 .21410373 \n11. Palumbo A , Bringhen S , Larocca A , et al \nBortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival . J Clin Oncol \n32 : 634 -640 , 2014 .24449241 \n12. Palumbo A , Bringhen S , Ludwig H , et al \nPersonalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN) . Blood \n118 : 4519 -4526 , 2011 .21841166\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "55(20)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": null, "medline_ta": "Intern Med", "mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000069286:Bortezomib; D003520:Cyclophosphamide; D003907:Dexamethasone; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D013792:Thalidomide; D016896:Treatment Outcome", "nlm_unique_id": "9204241", "other_id": null, "pages": "3025-3028", "pmc": null, "pmid": "27746443", "pubdate": "2016", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "21410373;22498745;23897961;24449241;16166765;15755512;24005889;25063227;24419113;21841166;20823406;18432260", "title": "The Addition of Low-dose Thalidomide to Bortezomib and Dexamethasone for Refractory Multiple Myeloma.", "title_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma" }

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THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA. 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"drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypogammaglobulinaemia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201312" } }, "primarysource": { "literaturereference": "HASHIMOTO S, HASHIMOTO S. THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA.. INTERNAL MEDICINE.. 2016;3025-3028.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161201", "receivedate": "20161201", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12991382, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "JP-CELGENEUS-JPN-2016106782", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "19.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug effect decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2012" } }, "primarysource": { "literaturereference": "HASHIMOTO S. THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA.. INTERNAL MEDICINE. 2016;3025-3028.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161129", "receivedate": "20161107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12921045, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170207" }, { "companynumb": "JP-BAUSCH-BL-2016-026868", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "40069", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "200811", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201207", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "THALIDOMIDE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": 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THE ADDITION OF LOW-DOSE THALIDOMIDE TO BORTEZOMIB AND DEXAMETHASONE FOR REFRACTORY MULTIPLE MYELOMA. INTERNATIONAL MEDICINE. 2016;55:3025-3028.", "literaturereference_normalized": "the addition of low dose thalidomide to bortezomib and dexamethasone for refractory multiple myeloma", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20161104", "receivedate": "20161104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12914001, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170207" } ]

{ "abstract": "BACKGROUND\nHepatic sinusoidal obstruction syndrome (SOS) during treatment of childhood acute lymphoblastic leukemia (ALL) has mainly been associated with 6-thioguanine. The occurrence of several SOS cases after the introduction of extended pegylated asparaginase (PEG-asparaginase) therapy in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol led us to hypothesize that PEG-asparaginase, combined with other drugs, may trigger SOS during 6-thioguanine-free maintenance therapy.\n\n\nMETHODS\nIn children with ALL treated in Denmark according to the NOPHO ALL2008 protocol, we investigated the risk of SOS during methotrexate (MTX)/6-mercaptopurine (6MP) maintenance therapy that included PEG-asparaginase until week 33 (randomized to two- vs. six-week intervals), as well as alternating high-dose MTX or vincristine/dexamethasone pulses every four weeks.\n\n\nRESULTS\nAmong 130 children receiving PEG-asparaginase biweekly, 29 developed SOS (≥2 criteria: hyperbilirubinemia, hepatomegaly, ascites, weight gain ≥2.5%, unexplained thrombocytopenia <75 × 109 l-1 ) at a median of 30 days (interquartile range [IQR]: 17-66) into maintenance (cumulative incidence: 27%). SOS cases fulfilling one, two, or three Ponte di Legno criteria were classified as possible (n = 2), probable (n = 8), or verified (n = 19) SOS, respectively. Twenty-six cases (90%) occurred during PEG-asparaginase treatment, including 21 (81%) within 14 days from the last chemotherapy pulse compared with the subsequent 14 days (P = 0.0025). Cytotoxic 6MP metabolites were significantly higher on PEG-asparaginase compared to after its discontinuation. Time-dependent Cox regression analysis showed increased SOS hazard ratio (HR) for erythrocyte levels of methylated 6MP metabolites (HR: 1.09 per 1,000 nmol/mmol hemoglobin increase, 95% confidence interval: 1.05-1.14). Six-week PEG-asparaginase intervals significantly reduced SOS-specific hazards (P < 0.01).\n\n\nCONCLUSIONS\nPEG-asparaginase increases cytotoxic 6MP metabolite levels and risk of SOS, potentially interacting with other chemotherapy pulses.", "affiliations": "Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.;Department of Pediatric Hematology and Oncology, H. C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.;Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark.;Department of Pediatric and Adolescent Medicine, Turku University Hospital, Turku, Finland.;Department of Pediatrics, Astrid Lindgrens Hospital, Stockholm, Sweden.;Department of Pediatrics, University Hospital North Norway, Tromsø, Norway.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.;Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.", "authors": "Toksvang|Linea Natalie|LN|;De Pietri|Silvia|S|;Nielsen|Stine N|SN|;Nersting|Jacob|J|;Albertsen|Birgitte K|BK|;Wehner|Peder S|PS|;Rosthøj|Steen|S|;Lähteenmäki|Päivi M|PM|;Nilsson|Daniel|D|;Nystad|Tove A|TA|;Grell|Kathrine|K|;Frandsen|Thomas L|TL|;Schmiegelow|Kjeld|K|", "chemical_list": "D011092:Polyethylene Glycols; C042705:pegaspargase; D015122:Mercaptopurine; D001215:Asparaginase; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1002/pbc.26519", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "64(9)", "journal": "Pediatric blood & cancer", "keywords": "acute lymphoblastic leukemia; asparaginase; liver toxicity; maintenance therapy; sinusoidal obstruction syndrome", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001215:Asparaginase; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D060046:Maintenance Chemotherapy; D008297:Male; D015122:Mercaptopurine; D008727:Methotrexate; D011092:Polyethylene Glycols; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016016:Proportional Hazards Models", "nlm_unique_id": "101186624", "other_id": null, "pages": null, "pmc": null, "pmid": "28423235", "pubdate": "2017-09", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites.", "title_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites" }

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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170613", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13600864, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003520", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563554, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057398", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170915", "receivedate": "20170915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13977944, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-051893", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595324, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057463", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "4", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563204, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ACCORD-051886", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": 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null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ORALLY, MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Blood albumin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19. DOI: 10.1002/PBC.26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13596987, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057489", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Splenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595297, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051889", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595307, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017DK074974", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13603617, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057465", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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"summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980267, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003519", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563317, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003524", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568327, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003538", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG/M2,DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASON" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609958, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051885", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595298, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017DK074990", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568318, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003511", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", 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"drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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"drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563556, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003534", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568376, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057487", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 20MG/M2 WEEKLY STARTED AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": null, 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"primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568336, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "PHHY2017DK075784", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, 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null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2, QW MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "60 MG/M2, UNK DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASON" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170614", "receivedate": "20170603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609969, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057402", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, 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"reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170915", "receivedate": "20170915", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13977979, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "PHHY2017DK075151", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CCONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980249, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-052002", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, 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"drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609822, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051891", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200750121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE AND INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", 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"drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ONCE WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neutrophil count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Hepatotoxicity", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Splenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595312, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051899", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ONCE WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULAR", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "200750121", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" } ], "patientagegroup": null, "patientonsetage": null, 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170611", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609820, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051895", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/M2 ONCE WEEKLY VIA ORALLY AS MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "040716", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595330, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057530", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980270, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003512", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568385, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003514", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170727", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563205, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-TEVA-771768ACC", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES..", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170614", "receivedate": "20170605", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13613365, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13607075, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003536", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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"ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, 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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170725", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13568495, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003529", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, 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"drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L,DE PIETRI S,NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES..", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13602325, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051882", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE AND DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { 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"reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Activated partial thromboplastin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "White blood cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null }, { "reactionmeddrapt": "Coagulation factor decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595295, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ACCORD-051897", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170608", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595331, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "PHHY2017DK074964", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "90029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": "3", "drugadministrationroute": "065", 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"drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "75 MG/M2, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170609", "receivedate": "20170609", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13637721, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003517", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170804", "receivedate": "20170519", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13563291, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" }, { "companynumb": "DK-MYLANLABS-2017M1057453", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "6", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170615", "receivedate": "20170603", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13609971, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057491", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "040594", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 75MG/M2 DAILY AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", 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"drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "STARTED AT WEEK 14, 60 MG/M2 PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, 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"drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE I 75MG/M2 DAILY AT WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEGASPARGASE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980271, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003522", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", 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"drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONSOLIDATION PHASE: 1,000 IU/M2 INTRAMUSCULARLY EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPARAGINASE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "THIOGUANINE ANHYDROUS" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION TREATMENT PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "60", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TIOGUANINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE 1 PHASE OF TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MERCAPTOPURINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DELAYED INTENSIFICATION PHASE", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIOTR BLOOD CANCER. 2017;26519:.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595311, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-MYLANLABS-2017M1057413", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980251, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-051995", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPARAGINASE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MAINTENANCE-I", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980283, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-051892", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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null, "drugtreatmentdurationunit": null, "medicinalproduct": "MERCAPTOPURINE/MERCAPTOPURINE ANHYDROUS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG L, DE PIETRI S, NIELSEN S,NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980253, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" }, { "companynumb": "DK-ACCORD-051881", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", 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"medicinalproduct": "CYTARABINE/CYTARABINE HYDROCHLORIDE/CYTARABINE OCFOSFATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR BLOOD CANCER. 2017 APR 19.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170612", "receivedate": "20170531", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13595293, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "DK-ASPEN PHARMA TRADING LIMITED US-AG-2017-003530", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { 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HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. 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[ { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Venoocclusive liver disease", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TOKSVANG LN, DE PIETRI S, NIELSEN SN, NERSTING J, ALBERTSEN BK, WEHNER PS, ET AL. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME DURING MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IS ASSOCIATED WITH CONTINUOUS ASPARAGINASE THERAPY AND MERCAPTOPURINE METABOLITES. PEDIATR-BLOOD-CANCER 2017;64(9):E26519.", "literaturereference_normalized": "hepatic sinusoidal obstruction syndrome during maintenance therapy of childhood acute lymphoblastic leukemia is associated with continuous asparaginase therapy and mercaptopurine metabolites", "qualification": "3", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170917", "receivedate": "20170917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13980263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171128" } ]

{ "abstract": "A 69-year-old male underwent elective percutaneous coronary intervention requiring placement of a drug-eluting stent to the first obtuse marginal artery. Four hours following the administration of a ticagrelor loading dose, he developed dyspnea and sinus pauses. Aminophylline was administered and resulted in immediate and sustained symptom resolution. Ticagrelor has been associated with dyspnea and bradyarrhythmias, both attributed to increased adenosine exposure. Ticagrelor inhibits reuptake of intracellular adenosine. Adenosine antagonists aminophylline and theophylline have been utilized to reverse the effects of adenosine and may relieve adenosine-mediated adverse effects induced by ticagrelor therapy. Aminophylline may be considered for reversal of dyspnea and bradyarrhythmia associated with ticagrelor therapy through alterations in adenosine exposure.", "affiliations": "1 Hospital Pharmacy Services, The University of Chicago Medicine, Chicago, IL, USA.;1 Hospital Pharmacy Services, The University of Chicago Medicine, Chicago, IL, USA.;2 Department of Cardiology, The University of Chicago Medicine, Chicago, IL, USA.;2 Department of Cardiology, The University of Chicago Medicine, Chicago, IL, USA.", "authors": "Minner|Sarah A|SA|;Simone|Pamela|P|;Chung|Benjamin B|BB|;Shah|Atman P|AP|", "chemical_list": "D058915:Purinergic P1 Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D000628:Aminophylline; D000077486:Ticagrelor; D000241:Adenosine", "country": "United States", "delete": false, "doi": "10.1177/0897190016680978", "fulltext": null, "fulltext_license": null, "issn_linking": "0897-1900", "issue": "31(1)", "journal": "Journal of pharmacy practice", "keywords": "acute coronary syndrome; aminophylline; bradyarrhythmia; dyspnea; ticagrelor/adverse effects", "medline_ta": "J Pharm Pract", "mesh_terms": "D000241:Adenosine; D000368:Aged; D000628:Aminophylline; D001919:Bradycardia; D004417:Dyspnea; D006801:Humans; D008297:Male; D058915:Purinergic P1 Receptor Antagonists; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor", "nlm_unique_id": "8900945", "other_id": null, "pages": "112-114", "pmc": null, "pmid": "27920235", "pubdate": "2018-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful Reversal of Bradycardia and Dyspnea With Aminophylline After Ticagrelor Load.", "title_normalized": "successful reversal of bradycardia and dyspnea with aminophylline after ticagrelor load" }

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SUCCESSFUL REVERSAL OF BRADYCARDIA AND DYSPNEA WITH AMINOPHYLLINE AFTER TICAGRELOR LOAD. 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SUCCESSFUL REVERSAL OF BRADYCARDIA AND DYSPNEA WITH AMINOPHYLLINE AFTER TICAGRELOR LOAD. 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SUCCESSFUL REVERSAL OF BRADYCARDIA AND DYSPNEA WITH AMINOPHYLLINE AFTER TICAGRELOR LOAD. JOURNAL OF PHARMACY PRACTICE 2018?31(1):112-114.", "literaturereference_normalized": "successful reversal of bradycardia and dyspnea with aminophylline after ticagrelor load", "qualification": "2", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180307", "receivedate": "20180307", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14607125, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" } ]

{ "abstract": "Left atrial appendage closure (LAAC) has evolved as a safe alternative to oral anticoagulation therapy for stroke prophylaxis. However, the presence of a patent foramen ovale (PFO) occluder device is considered a relative contraindication. Here we report a successful case of LAAC in the presence of a PFO occluder device. (Level of Difficulty: Beginner.).", "affiliations": "Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.;Department of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.", "authors": "Kousa|Omar|O|;Mahfood-Haddad|Toufik|T|;Patil|Shantanu M|SM|;Agarwal|Himanshu|H|;Abuissa|Hussam|H|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaccas.2021.01.017", "fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(21)00110-8\n10.1016/j.jaccas.2021.01.017\nMini-Focus Issue: Electrophysiology\nCase Report: Clinical Case\nLeft Atrial Appendage Closure in a Patient With a Patent Foramen Ovale Septal Occluder Device\nKousa Omar MD [email protected]\n@OmarKousa12\n∗\nMahfood-Haddad Toufik MD\nPatil Shantanu M. MD\nAgarwal Himanshu MD\nAbuissa Hussam MD\nDepartment of Medicine, Creighton University Medical Center, Omaha, Nebraska, USA\n∗ Address for correspondence: Dr. Omar Kousa, Department of Medicine, Creighton University, 7710 Mercy Road, Suite 202, Omaha, Nebraska 68124, USA. [email protected]@OmarKousa12\n17 3 2021\n3 2021\n17 3 2021\n3 3 508511\n1 6 2020\n22 12 2020\n8 1 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nLeft atrial appendage closure (LAAC) has evolved as a safe alternative to oral anticoagulation therapy for stroke prophylaxis. However, the presence of a patent foramen ovale (PFO) occluder device is considered a relative contraindication. Here we report a successful case of LAAC in the presence of a PFO occluder device. (Level of Difficulty: Beginner.)\n\nGraphical abstract\n\nKey Words\n\nanticoagulation\natrial fibrillation\nelectrophysiology\ninterventional cardiology\nleft atrial appendage closure\npatent foramen ovale\nAbbreviations and Acronyms\n\nICE, intracardiac echocardiogram\nLAAC, left atrial appendage closure\nPFO, patent foramen ovale\nTEE, transesophageal echocardiogram\n==== Body\nHistory of presentation\n\nA 72-year-old woman was seen in our clinic for consideration of left atrial appendage closure (LAAC). She had an acute right parietal stroke 4 years earlier and underwent patent foramen ovale (PFO) closure using a 30-mm Amplatzer septal occluder device (Abbott, Abbott Park, Illinois) at an outside facility; cryptogenic stroke was the suspected underlying cause. Shortly after undergoing PFO closure, she reported episodes of palpitations and received a diagnosis of paroxysmal atrial fibrillation noted on an event monitor. She was managed with flecainide (50 mg, 2 times a day) for rhythm control and was started on oral anticoagulation therapy with warfarin (CHA2DS2-VASc score of 5: age, previous stroke, female sex, hypertension). Three years later, the patient received a diagnosis of chronic peptic ulcer disease evident on upper gastric endoscopy and had occult gastrointestinal bleeding (HAS- BLED score of 4: age, stroke, receiving anticoagulation therapy, previous major bleeding or predisposition to bleeding). Given her high risk of cardioembolic stroke and contraindication to anticoagulation, she was referred to our structural heart clinic for elective LAAC. On examination, she was afebrile, with a blood pressure of 127/60 mm Hg, a heart rate of 91 beats/min, a respiratory rate of 18 breaths/min, and oxygen saturation of 96% on room air. She had normal heart sounds, no murmurs, normal jugular venous pressure, and no peripheral edema.Learning Objectives\n\n• To understand the role of LAAC as an acceptable alternative to anticoagulation in nonvalvular atrial fibrillation patients who have bleeding complications that develop during anticoagulation therapy and who have a prior history of a PFO septal occluder device.\n\n• To emphasize on the role of ICE in performing precise transseptal puncture in the presence of a septal occluder device.\n\nPast Medical History\n\nHer past medical history consisted of stroke, PFO, atrial fibrillation, and chronic peptic ulcer disease.\n\nDifferential Diagnosis\n\nThe differential diagnosis was ischemic stroke secondary to atrial fibrillation versus PFO.\n\nInvestigations\n\nShe underwent a transesophageal echocardiogram (TEE), which showed normal left ventricular systolic function with a well-seated PFO closure device. The left atrial appendage displayed a “windsock” morphology. A shared decision-making discussion was made, and the patient elected to proceed with LAAC.\n\nManagement\n\nDuring the procedure, it was difficult to visualize the inferior part of the interatrial septum below the Amplatzer device by using the TEE, and we therefore decided to use an intracardiac echocardiogram (ICE). Multiple images were obtained, and they confirmed the presence of an adequate area inferior and posterior to the Amplatzer device (Figure 1, Video 1). Using ICE, TEE, and fluoroscopy, transseptal puncture was successfully performed. The needle was then removed and exchanged for a ProTrack Pigtail Wire (Baylis Medical, Austin, Texas), which was then advanced into the left atrium (Figure 2, Video 2). The dilator and sheath were then removed and exchanged for a HeartSpan MR0 transseptal sheath (Merit Medical, South Jordan, Utah), which was advanced into the left atrium. The dilator and sheath were then removed and exchanged for a 14-F double-curve Watchman Access System (Boston Scientific, Marlborough, Massachusetts), which was advanced over the ProTrack Pigtail Wire into the left atrium (Figure 3). A pigtail catheter was advanced into the sheath, and the latter wire was removed. We then advanced the 14-F Watchman Access System into the left atrial appendage over the pigtail catheter (Figure 4A, Video 3) and carefully removed the latter from the body while making sure to keep the catheter in position. A 27-mm Watchman left atrial appendage device attached to the Watchman delivery system was advanced through the sheath. The device was then deployed carefully under fluoroscopic (Figure 4B) and echocardiographic guidance using the standard technique. The device was released in the standard fashion after meeting the PASS (position, anchor, size, and seal) criteria.Figure 1 Intracardiac Echocardiogram Image Showing the Small Inferior Septal Space Below the PFO Occluder Device\n\nPFO = patent foramen ovale.\n\nFigure 2 Fluoroscopy Image Showing Transseptal Puncture Inferior to the PFO Occluder Device in the AP View and the ProTrack Pigtail Wire (Baylis Medical, Austin, Texas) in the Left Atrium\n\nAP = anteroposterior; TEE = transesophageal echocardiogram; other abbreviations as in Figure 1.\n\nFigure 3 TEE Image at the Midesophageal Level Showing the Transseptal Puncture Site and the Watchman Access System (Boston Scientific, Marlborough, Massachusetts) Below the PFO Occluder Device\n\nAbbreviations as in Figures 1 and2.\n\nFigure 4 Fluoroscopy Imaging Showing the Delivery Sheath and Watchman Device (Boston Scientific, Marlborough, Massachusetts)\n\n(A) Fluoroscopy image in the RAO caudal view confirming the position of the delivery sheath in the left atrial appendage. (B) Fluoroscopy image in the AP caudal view showing the Watchman device in the left atrial appendage. AP = anteroposterior; RAO = right anterior oblique; other abbreviations as in Figures 1 and2.\n\nDiscussion\n\nAtrial fibrillation is prevalent in the United States and is a common cause of thromboembolic events. The risk of thromboembolism increases with older age, female sex, and the presence of comorbidities. Oral anticoagulation agents are widely used to prevent stroke in patients with nonvalvular atrial fibrillation (1). However, these agents can cause bleeding complications in patients with older age, history of bleeding or falls, malignant disease, chronic renal and liver disease, alcohol abuse, thrombocytopenia, and concurrent use of antiplatelet agents. The left atrial appendage accounts for 90% of thrombi formed in the heart (2). The newer technique of LAAC is growing as a safe alternative option to anticoagulation. Studies have shown that it is noninferior to vitamin K antagonists in stroke risk reduction (3,4). Precise transseptal puncture is an essential limiting step for successful deployment of the LAAC device. The presence of a previous PFO closure device makes it challenging because it would reduce the operator maneuverability of access systems and safe deployment of the device in the left atrial appendage (5,6). Currently, there are 2 U.S. Food and Drug Administration–approved devices in the United States: the Amplatzer device by Abbott and Gore Cardioform Septal Occluder by Gore Medical (W. L. Gore and Associates, Newark, Delaware). The Amplatzer device is made of 2 discs connected by a bond bridge. Each disc consists of a nitinol wire mesh that makes it more difficult to puncture. In contrast, the Gore Cardioform Septal Occluder device is made of polytetrafluoroethylene fabric on a nitinol framework and offers a more favorable medium to puncture (7,8). To our knowledge, only 2 cases of LAAC in patients with previous septal occluder device implantation have been published. Nadel et al. (5) have reported a successful transseptal puncture inferior and anterior to the device, whereas Gafoor et al. (6) have reported successful LAAC after PFO occlusion through an inferior and posterior approach. In our case, we used ICE because it was difficult to visualize the inferior part of the interatrial septum below the PFO occluder device when using only the TEE. Of note, computed tomography imaging may be performed to complement TEE imaging; however, this could not be used in our particular case secondary to potential artifact caused by the device. An inferior and posterior approach was used and proved to be a very satisfactory position despite the large size of the device. To our knowledge, this is the first case of ICE use to facilitate transseptal puncture in patients with an existing PFO closure device.\n\nFollow-Up\n\nA TEE was performed after 6 weeks, and it showed a well-seated device in the left atrial appendage with a nonsignificant 2-mm peridevice leak. There was no thrombus or residual interatrial shunt, and warfarin was discontinued. She was subsequently maintained on dual antiplatelet therapy for 4.5 months and on aspirin 325 mg daily thereafter.\n\nConclusions\n\nLAAC is a good alternative in patients with nonvalvular atrial fibrillation who are at high risk for thromboembolism and have a contraindication to anticoagulation. A previous history of atrial septal closure should not preclude proceeding with LAAC. By using appropriate imaging techniques, including ICE, transseptal puncture can be safely performed.\n\nFunding Support and Author Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nICE Showing the Small Inferior Septal Space Below the PFO Occluder Device\n\nSupplemental Video 2\n\nProTrack Pigtail Wire (Baylis Medical, Austin, Texas) in the Left Atrium After Successful Transseptal Puncture\n\nSupplemental Video 3\n\nLeft Atrial Appendage Angiogram After Successful Watchman Device (Boston Scientific, Marlborough, Massachusetts) Deployment\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 January C.T. Wann L.S. Alpert J.S. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society J Am Coll Cardiol 64 2014 e1 e76 24685669\n2 Blackshear J.L. Odell J.A. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation Ann Thorac Surg 61 1996 755 759 8572814\n3 Holmes D.R. Doshi S.K. Kar S. Left atrial appendage closure as an alternative to warfarin for stroke prevention in atrial fibrillation: a patient-level meta-analysis J Am Coll Cardiol 65 2015 2614 2623 26088300\n4 Holmes D.R. Kar S. Price M.J. Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial J Am Coll Cardiol 64 2014 1 2 24998121\n5 Nadel J. Subbiah R. Jacobs N. Muller D.W. Gunalingam B. Successful left atrial appendage closure in a patient with prior patent foramen ovale occlusion HeartRhythm Case Rep 5 2019 183 30997330\n6 Gafoor S. Franke J. Boehm P. Leaving no hole unclosed: left atrial appendage occlusion in patients having closure of patent foramen ovale or atrial septal defect J Interv Cardiol 27 2014 414 422 25059287\n7 Messas N. Ibrahim R. The Amplatzer Amulet Device: technical considerations and procedural approach Interv Cardiol Clin 7 2018 213 218 29526289\n8 Thomson J.D. Hildick-Smith D. Clift P. Patent foramen ovale closure with the Gore septal occluder: initial UK experience Catheter Cardiovasc Interv 83 2014 467 473 23766247\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2666-0849", "issue": "3(3)", "journal": "JACC. Case reports", "keywords": "ICE, intracardiac echocardiogram; LAAC, left atrial appendage closure; PFO, patent foramen ovale; TEE, transesophageal echocardiogram; anticoagulation; atrial fibrillation; electrophysiology; interventional cardiology; left atrial appendage closure; patent foramen ovale", "medline_ta": "JACC Case Rep", "mesh_terms": null, "nlm_unique_id": "101757292", "other_id": null, "pages": "508-511", "pmc": null, "pmid": "34317569", "pubdate": "2021-03", "publication_types": "D002363:Case Reports", "references": "23766247;29526289;8572814;26088300;25059287;30997330;24998121;24685669", "title": "Left Atrial Appendage Closure in a Patient With a Patent Foramen Ovale Septal Occluder Device.", "title_normalized": "left atrial appendage closure in a patient with a patent foramen ovale septal occluder device" }

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LEFT ATRIAL APPENDAGE CLOSURE IN A PATIENT WITH A PATENT FORAMEN OVALE SEPTAL OCCLUDER DEVICE. JACC: CASE REPORTS. 2021?3(3):508?11", "literaturereference_normalized": "left atrial appendage closure in a patient with a patent foramen ovale septal occluder device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210415", "receivedate": "20210415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19137983, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Several fluoroquinolone antibiotics have been associated with cardiac adverse effects, leading to the withdrawal of some of these agents from the market. Cardiac side effects such as QT prolongation and torsades de pointes (TdP) have also been observed with fluoroquinolones currently on the market. In order to evaluate the cardiac risk of fluoroquinolones as a class, and the comparative risk for each individual drug, we conducted a systematic review, meta-analysis, and network meta-analysis.\n\n\n\nMEDLINE, EMBASE and the Cochrane Library were searched, up to March 2018, for randomized controlled trials, cohort studies, and case-control studies that investigated the association between fluoroquinolone treatment and the risk of cardiovascular events and cardiovascular mortality. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random effects models. Direct and indirect comparisons in network meta-analysis were performed using frequentist methods.\n\n\n\nThirteen studies were included in our analyses. Fluoroquinolone use was associated with a statistically significant 85% increase in the risk for arrhythmia (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.22-2.81) and 71% increase in the risk for cardiovascular mortality (OR 1.71; 95% CI 1.39-2.09). Moxifloxacin ranked most likely to have the highest risk for arrhythmia (P-score 0.99) and for cardiovascular mortality (P-score 0.95) by network meta-analysis.\n\n\n\nOur findings show a significant association between fluoroquinolone use and an increased risk for arrhythmia and cardiovascular mortality. Moxifloxacin ranked with the highest probability for cardiovascular adverse events. Further study is required to determine how to reduce the risk for fluoroquinolone-associated cardiac toxicity.", "affiliations": "Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel.;The Department of Medicine, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.;The Department of Medicine, Hadassah University Hospital, Mt. Scopus, Jerusalem, Israel.;Division of Clinical Pharmacy, School of Pharmacy, The Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, 9112001, Jerusalem, Israel. [email protected].", "authors": "Gorelik|Einat|E|;Masarwa|Reem|R|;Perlman|Amichai|A|;Rotshild|Victoria|V|;Abbasi|Momen|M|;Muszkat|Mordechai|M|;Matok|Ilan|I|", "chemical_list": "D024841:Fluoroquinolones", "country": "New Zealand", "delete": false, "doi": "10.1007/s40264-018-0751-2", "fulltext": null, "fulltext_license": null, "issn_linking": "0114-5916", "issue": "42(4)", "journal": "Drug safety", "keywords": null, "medline_ta": "Drug Saf", "mesh_terms": "D002318:Cardiovascular Diseases; D002319:Cardiovascular System; D016022:Case-Control Studies; D015331:Cohort Studies; D024841:Fluoroquinolones; D006801:Humans; D000071076:Network Meta-Analysis; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors", "nlm_unique_id": "9002928", "other_id": null, "pages": "529-538", "pmc": null, "pmid": "30368737", "pubdate": "2019-04", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D000078182:Systematic Review", "references": "19622511;21079043;16331522;24428853;29095256;15687478;24615307;25409476;29625780;17241772;26011799;18478129;16510739;19236122;11909831;22865870;8203853;26920666;19680025;10671353;22008217;15891266;11779516;26227148;12832320;15843667", "title": "Fluoroquinolones and Cardiovascular Risk: A Systematic Review, Meta-analysis and Network Meta-analysis.", "title_normalized": "fluoroquinolones and cardiovascular risk a systematic review meta analysis and network meta analysis" }

[ { "companynumb": "IL-JNJFOC-20181101203", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "020634", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myocardial infarction", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cardiac death", "reactionmeddraversionpt": "21.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Disease risk factor", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GORELIK E, MASARWA R, PERLMAN A, ROTSHILD V, ABBASI M, MUSZKAT M, ET AL. FLUOROQUINOLONES AND CARDIOVASCULAR RISK: A SYSTEMATIC REVIEW, META-ANALYSIS AND NETWORK META-ANALYSIS. SPRINGER NATURE SWITZERLAND AG 2018 27-OCT-2018:-.", "literaturereference_normalized": "fluoroquinolones and cardiovascular risk a systematic review meta analysis and network meta analysis", "qualification": "3", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20181109", "receivedate": "20181109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15603095, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190205" } ]

{ "abstract": "The objective of this study was to characterize the clinical features, course, and treatment of essential tremor (ET) in children.\nA retrospective chart review was conducted over 25 years (1984-2011). Inclusion criteria were age <21 years and satisfying the core diagnostic criteria for ET. Primary exclusion criteria included other neurological findings, tremorogenic medications, sudden onset/stepwise progression, primary orthostatic tremor, and isolated task specificity; and secondary exclusion criteria were abnormal neuroimaging or metabolic/thyroid studies. Cases were reviewed for age, sex, family history, tremor characteristics, functional impairment, treatment, and follow-up.\nIn total, 211 children had ET, including 130 males and 81 females. The mean ± standard deviation age was at diagnosis was 14.09 ± 5.0 years, the age of onset was 9.71 ± 5.62 years, and the age of onset was birth in 7 children. One hundred ninety-nine children had bilateral hand tremor, 34 had asymmetry, 9 had unilateral onset but later became bilateral. Twelve children had voice tremors, 13 had leg tremors, 5 had head tremors, and 7 had trunk tremors. Tremor at rest was present in 20 children. Thirty-five percent of the children had a family history of ET, including in a father (n = 21), mother (n = 13), brother (n = 6), sister (n = 3), and other family member (n = 28). Fifty-five percent of patients had functional disabilities, including writing (n = 66), eating (n = 28) drinking from a cup (n = 13), typing (n = 4), playing instruments (n = 6), buttoning (n = 6), and playing (n = 3). For treatment, 33 patients received propranolol, 1 received atenolol, 13 received primidone, 3 received metoprolol, and 1 received nadolol. In total, 99 patients were followed for a mean ± standard deviation of 1.82 ± 2.21 years.If left untreated, tremor remained unchanged in 33 patients, and 7 had an apparent short-term improvement. On propranolol, 15 of 20 patients significantly improved.\nThis is the largest series to date of ET in children. The current findings indicate that onset at birth is possible, family history is less common in children than in adults, and tremor at rest is possible. Functional disability was noted in 55% of children, and 29.4% required medication.", "affiliations": "Departments of Neurology and Pediatrics Nationwide Children's Hospital Ohio State University Medical Center Columbus Ohio USA.;Pediatric Neurology Center Children's Hospital Cleveland Clinic Cleveland Ohio USA.;Department of Pediatrics New York Metropolitan Hospital New York New York USA.;Pediatric Neurology Center Children's Hospital Cleveland Clinic Cleveland Ohio USA.;Pediatric Neurology Center Children's Hospital Cleveland Clinic Cleveland Ohio USA.", "authors": "Ghosh|Debabrata|D|;Brar|Harmeet|H|;Lhamu|Ugen|U|;Rothner|A David|AD|;Erenberg|Gerald|G|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/mdc3.12385", "fulltext": null, "fulltext_license": null, "issn_linking": "2330-1619", "issue": "4(2)", "journal": "Movement disorders clinical practice", "keywords": "action tremor; parkinsonism; postural tremor; rest tremor; voice tremor", "medline_ta": "Mov Disord Clin Pract", "mesh_terms": null, "nlm_unique_id": "101630279", "other_id": null, "pages": "231-236", "pmc": null, "pmid": "30363473", "pubdate": "2017", "publication_types": "D016428:Journal Article", "references": "10854345;18973247;12671944;9452318;23064782;19795473;9115044;17043291;15834855;19473370;11746623;3975748;15133816;19725596;18344392;11487191;16721753;17116212;16991147;8628453;15520096;6736976", "title": "A Series of 211 Children with Probable Essential Tremor.", "title_normalized": "a series of 211 children with probable essential tremor" }

[ { "companynumb": "US-DRREDDYS-USA/USA/17/0091734", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PRIMIDONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040862", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL TREMOR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PRIMIDONE TABLETS" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Somnolence", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GHOSH D, BRAR H, LHAMU U, ROTHNER A, ERENBERG G. A SERIES OF 211 CHILDREN WITH PROBABLE ESSENTIAL TREMOR. MOV DISORD CLIN PRACT. 2017;4(2):231-6.", "literaturereference_normalized": "a series of 211 children with probable essential tremor", "qualification": "1", "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20171129", "receivedate": "20171129", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14235512, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180321" } ]

{ "abstract": "Pathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.", "affiliations": "Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.;Pediatric Nephrology Service, La Paz University Hospital, Madrid, Spain.;Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.;Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.;Pediatric Hepatology Service, La Paz University Hospital, Madrid, Spain.;Pathology Department, La Paz University Hospital, Madrid, Spain.;Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.;Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.", "authors": "López-Trascasa|Margarita|M|;Alonso-Melgar|Ángel|Á|;Melgosa-Hijosa|Marta|M|;Espinosa-Román|Laura|L|;Lledín-Barbancho|María Dolores|MD|;García-Fernández|Eugenia|E|;Rodríguez de Córdoba|Santiago|S|;Sánchez-Corral|Pilar|P|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fimmu.2021.751093", "fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.751093\nImmunology\nCase Report\nCase Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient\nLópez-Trascasa Margarita 1 2 *\n\nAlonso-Melgar Ángel 3\nMelgosa-Hijosa Marta 2 3\n\nEspinosa-Román Laura 2 3\n\nLledín-Barbancho María Dolores 4\nGarcía-Fernández Eugenia 5\nRodríguez de Córdoba Santiago 6 7\n\nSánchez-Corral Pilar 2 7\n\n1 Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain\n2 Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain\n3 Pediatric Nephrology Service, La Paz University Hospital, Madrid, Spain\n4 Pediatric Hepatology Service, La Paz University Hospital, Madrid, Spain\n5 Pathology Department, La Paz University Hospital, Madrid, Spain\n6 Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain\n7 Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain\nEdited by: Guido Moll, Charité–Universitätsmedizin Berlin, Germany\n\nReviewed by: Giuseppe Remuzzi, Istituto di Ricerche Farmacologiche Mario Negri (IRCCS), Italy; Johan Vande Walle, Ghent University, Belgium\n\n*Correspondence: Margarita López-Trascasa, [email protected]\nThis article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology\n\n14 10 2021\n2021\n12 75109331 7 2021\n27 9 2021\nCopyright © 2021 López-Trascasa, Alonso-Melgar, Melgosa-Hijosa, Espinosa-Román, Lledín-Barbancho, García-Fernández, Rodríguez de Córdoba and Sánchez-Corral\n2021\nLópez-Trascasa, Alonso-Melgar, Melgosa-Hijosa, Espinosa-Román, Lledín-Barbancho, García-Fernández, Rodríguez de Córdoba and Sánchez-Corral\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nPathogenic gain-of-function variants in complement Factor B were identified as causative of atypical Hemolytic Uremic syndrome (aHUS) in 2007. These mutations generate a reduction on the plasma levels of complement C3. A four-month-old boy was diagnosed with hypocomplementemic aHUS in May 2000, and he suffered seven recurrences during the following three years. He developed a severe hypertension which required 6 anti-hypertensive drugs and presented acrocyanosis and several confusional episodes. Plasma infusion or exchange, and immunosuppressive treatments did not improve the clinical evolution, and the patient developed end-stage renal disease at the age of 3 years. Hypertension and vascular symptoms persisted while he was on peritoneal dialysis or hemodialysis, as well as after bilateral nephrectomy. C3 levels remained low, while C4 levels were normal. In 2005, a heterozygous gain-of-function mutation in Factor B (K323E) was found. A combined liver and kidney transplantation (CLKT) was performed in March 2009, since there was not any therapy for complement inhibition in these patients. Kidney and liver functions normalized in the first two weeks, and the C3/C4 ratio immediately after transplantation, indicating that the C3 activation has been corrected. After remaining stable for 4 years, the patient suffered a B-cell non-Hodgkin lymphoma that was cured by chemotherapy and reduction of immunosuppressive drugs. Signs of liver rejection with cholangitis were observed a few months later, and a second liver graft was done 11 years after the CLKT. One year later, the patient maintains normal kidney and liver functions, also C3 and C4 levels are within the normal range. The 12-year follow-up of the patient reveals that, in spite of severe complications, CLKT was an acceptable therapeutic option for this aHUS patient.\n\natypical hemolytic uremic syndrome\ncomplement\nfactor B\ncombined liver-kidney transplantation\nrare diseases\n==== Body\npmcIntroduction\n\nHemolytic uremic syndrome (HUS) is characterized by the triad of hemolytic anemia, acute kidney failure, and thrombocytopenia. Most cases are children with infections by Escherichia Coli 0157:H7, Shigella or Salmonella, and generally evolve satisfactorily in a few weeks. Less frequently, HUS develops in the absence of a clear etiologic agent and has a worse evolution; these cases are denominated as atypical Hemolytic Uremic Syndrome (aHUS), which is very uncommon and is considered an ultrarare disease (1). Around 50-60% of aHUS patients have pathogenic variants in the complement genes CFH, MCP, CFI, C3 and CFB, or circulating anti-factor H autoantibodies (2). Moreover, pathogenic variants outside the complement system have been described in thrombomodulin, DGKE and plasminogen genes.\n\nMutations in complement CFH, CFI, C3 or CFB generate anomalies in the corresponding proteins, which are mainly produced in the liver and secreted into plasma; these anomalies persist after kidney transplantation, a reason that can explain the high level of disease recurrence in transplanted patients. Most of these complement pathogenic variants were described on the beginning of this century, when the complement inhibitor Eculizumab was not yet accessible, and combined liver-kidney transplantation was considered a therapy to cure HUS in patients with mutations in CFH or CFI (3).\n\nCFB mutations were first described in aHUS patients in 2007 (4). In this paper, two different mutations in complement factor B (FB) were identified. A pedigree with several members affected shared mutation F286L, while the second mutation, K323E, was a “de novo” mutation in an unrelated patient. The two mutations generated hyperfunctional FB proteins which gave rise to a more active C3bBb convertase and an important C3 consumption in plasma, which was particularly evident in the patient carrying the K323E mutation. The follow-up of one patient from the F286L pedigree has been recently described (5); this patient underwent a kidney transplant without Eculizumab treatment in 2011 and has not suffered HUS relapses.\n\nThe patient carrying the K323E mutation underwent a combined liver kidney transplantation (CLKT) in March 2009; a short summary of the evolution during the first three months post-transplantation has been previously reported (6). In this work, we fully describe the clinical evolution, transplantation history and complement levels of this patient, throughout his 20 years of life. The patient presented HUS when he was 4-months old, suffered multiple recurrences and incidents for 8 years, and received a combined liver kidney transplantation (CLKT) at the age of 9 years. This CLKT restored complement levels as well as kidney and liver functions after the transplant surgery. The patient had several transplant related complications such as a B-cell non-Hodgkin lymphoma, and a chronic liver rejection that required a second liver graft 11 years after CLKT. In spite of these complications, CLKT was at that time the only opportunity for improving the critical situation of the patient, and the function of the kidney graft has remained normal all the time.\n\nCase Description, Diagnostic Assessment, Therapeutic Intervention, Follow-Up and Outcomes\n\nA 4-month-old male was diagnosed with HUS and treated with peritoneal dialysis from the 5th day of disease onset. The patient had a bad evolution, with renal failure, anemia, severe hypertension, and peritonitis by Staphylococcus Epidermidis, and after 20 days he suffered a second HUS episode and was transferred to our Hospital. At that moment, in addition to altered hematologic parameters, complement analysis indicated very low C3 levels (35,4 mg/dL; normal range: 77-135) with normal C4 (43,8 mg/dL; normal range: 14-60); Factor H, Factor I, and MCP levels were on the normal range. Hematological parameters and glomerular filtration normalized after 1 month, but hypertension remained partially uncontrolled and hemolysis markers such as haptoglobin were persistently low. After 6 months, the patient suffered a third episode with severe hypertension which required as many as six hypotensive drugs. Moreover, he endured two episodes of acute pulmonary edema with respiratory distress caused by hypertensive crisis. He developed a severe anemia that required 17 erythrocyte concentrates, mild thrombocytopenia, proteinuria in the nephrotic range, and cardiac insufficiency. He also suffered acute renal failure which required diuretic and hemodialysis support. A renal biopsy performed during this episode indicated thrombotic microangiopathy, with major vascular involvement and mild glomerular damage ( Supplementary Figure 1 ).\n\nThe patient suffered 5 subsequent HUS episodes; treatment with immunosuppressive drugs (vincristine and prednisone) and several plasma exchanges courses were tried without success. Uncontrolled hypertension with hemodynamic instability required prolonged hospitalizations. He underwent chronic dialysis at the age of three years, and 10 months later both kidneys were removed in an attempt to avoid the severe complications associated to HUS episodes ( Figure 1 ). Nonetheless, the hypertension continued after bilateral nephrectomy, and the patient had several episodes of acrocyanosis on all the fingers of the lower extremities (Raynaud’s phenomenon) because of systemic microangiopathy ( Supplementary Figure 2 ).\n\nFigure 1 Clinical evolution since HUS onset to bilateral nephrectomy. Timeline of HUS episodes, treatments and renal outcome along the first four years of life of the patient. Supportive treatments included blood transfusions and plasma therapy, as well as different combinations of hypotensive drugs (Hydralazine, Atenolol, Furosemide, Nifedipine, Minoxidil and Enalapril); immunosuppressive drugs (Vincristine and M-Prednisolone) were used occasionally. The patient entered into chronic dialysis at the age of 36 months, and at the age of 46 months both kidneys had to be removed to avoid further HUS episodes. PD, Peritoneal Dialysis; HD, Hemodialysis; PE, Plasma Exchange; PI, Plasma Infusion.\n\nAlthough hematological parameters normalized after bilateral nephrectomy, the clinical course of the patient under chronic hemodialysis continued to be torpid, with severe hypertension with cardiac repercussion, stroke-like episodes not clearly explained, and bad tolerance to hemodialysis sessions. All the time, plasma levels of complement C3 were low, while levels of C4 and C5 were normal. When he was 5 years-old, a pathogenic gain-of-function variant in complement Factor B (FB) was identified (4); genetic studies also showed the presence of the two aHUS-risk haplotypes CFH(H3) y MCPggaac in heterozygosis. This molecular diagnosis opened the possibility of a combined liver kidney transplantation (CLKT), since by that time complement inhibition with Eculizumab was not available. While waiting for CLKT, the patient continued with a regimen of hemodialysis and plasma infusions.\n\nAt the age of 9 years, the patient received a CLKT from an 8-year-old child. Immediately before the surgery, he was treated with intensive plasma exchange to ensure removal of his circulating FB; two other plasma exchange sessions were performed the third- and fourth-days post-transplantation, coinciding with mild anemization without signs of hemolysis. Systemic heparinization was used as part of our liver transplant protocol. Normal kidney and liver functions were evident 2 weeks post-transplantation ( Figure 2 ), and plasma levels of complement C3 reached normal values for the first time in the patient’s life ( Figure 3 ). The patient remained in hospital for 30 days. Suspicion of hepatic acute rejection in early postoperative period was treated with a pulse of metilprednisolone, with good response; histopathology of the biopsy discarded the rejection. The patient continued stable for 4 years under immunosuppressive treatment (induction with Basiliximab, and maintenance with corticosteroids, tacrolimus and mycophenolate mofetil).\n\nFigure 2 Evolution of renal and hepatic function after combined liver-kidney transplantation. Follow up of Creatinine, Prothrombin and Alaninaminotransferase (ALT) levels in the patient before and after transplantation. Creatinine levels dropped immediately after transplant surgery, reaching normal levels 5 days later. The hepatic function normalized during the second week.\n\nFigure 3 Complement profile from 2000 to 2020. Evolution of C3 and C4 levels, and of the C3/C4 ratio, in plasma samples from patient HUS21 since HUS onset in 2000, at the age of 4 months. The horizontal dashed lines indicate the lower limit of normal values. The boxes in the X axis mark the dates of the liver-kidney transplantation (March 2009), and of the second liver transplant (February 2020).\n\nOn September 2013, the patient was diagnosed with a diffuse large B cell non-Hodgkin’s lymphoma stage 3, with infiltration in scalp and skull, and was treated with chemotherapy (R-CHOP/R-COPDAM) and rituximab. At the beginning of the treatment, he suffered a septic shock and endured at Intensive Care Unit for 9 days. The infectious episode induced coagulopathy and multiorgan failure (with hepatic, kidney, and cardiac involvement) with good outcome. After 3 months, the chemotherapy was ended with evident signs of remission. All along the chemotherapy treatment, tacrolimus and mycophenolate mofetil were stopped and only corticosteroids were maintained.\n\nOn February 2014, he suffered from a liver graft dysfunction with a light increase of transaminases without ultrasonographic signs of dilated biliary tract. He received intravenous antibiotics and ursodeoxycholic acid by suspicion for cholangitis. Liver biopsy showed moderate periportal fibrosis, but no histological features of chronic rejection. Subsequently to liver rejection in 2014, the patient developed high levels of de novo donor-specific antibodies (DSA) against DQ9 (MFI: 21705). These DSA were maintained with a similar MFI (between 21000 and 32000) at least until February 2020, just before the second liver graft; moreover, serological viral studies were negative. Sirolimus was included in the immunosuppressive treatment, and the corticosteroids and ursodeoxycholic acid doses were increased. Following several cholangitis and infectious episodes, in 2018 a second liver biopsy showed ductal proliferation with inflammation and branding fibrosis. Diagnosis of chronic liver rejection was established, and tacrolimus and mycophenolate mofetil were reintroduced. Percutaneous transhepatic cholangiography showed multiple biliary structures of the biliary tree without obstruction in the anastomotic site. Several biliary dilatations and external biliary drainage were performed, and finally, a biliary stent was positioned. However, the patient continued suffering cholangitis episodes by multidrug-resistant bacteria, requiring frequent hospitalization. During all this period, the glomerular filtration rate decreased during the acute infection episodes but normalized afterwards, with no signs of kidney rejection. On February 2020, the patient received a second cadaveric liver graft. By that moment, creatinine-based glomerular filtration rate was normal (> 90 ml/min/1.73 m2).\n\nCurrently, the patient has a good clinical condition, although he displays a low height for its expected genetic height (height: 158.5 cm (-3.18SD); weight: 56.2Kg (-1.79 SD); data related to Spanish population). He receives immunosuppressive treatment with corticosteroids, tacrolimus and mycophenolate mofetil, with maintained hepatic function after his second liver graft: AST 34 UI/L (<40); ALT 48 UI/L (<35); GGT 30 UI/L (<73); total bilirubin 0.79 mg/dL (0.30-1.20), albumin 4.3 g/dL (2.9-5.2). Kidney function is also good, with a normal GFR calculated both by Creatinine and by Cystatin C (creatinine 1 mg/dl (0.70-1.30); GFR calculated by CKD-EPI >90 ml/min/1.73 m2 (N >75); Cystatin C 1.20 mg/L (0.64-1.23); GFR calculated by CKD-EPI Cyst C 72 mL/min/1.73m2 (N>60); protein/creatinine ratio 0.08 (N<0.2).\n\nThe main clinical and treatment events after CLKT are shown in Figure 4 ; as shown in Figure 3 , plasma levels of C3, C4, and the C3/C4 ratio, have always remained within the normal range. Now, the patient is under the supervision on a different hospital (adult section) for the hepatic and kidney post-transplantation follow-up.\n\nFigure 4 Post-transplant clinical evolution. The main clinical episodes after combined liver-kidney transplantation (CLKT) are indicated. The first complication, 4 years after transplantation, was a lymphoproliferative disease, which was treated with chemotherapy and reduction/abrogation of the immunosuppressive regimen. Immunosuppression was reintroduced 5 months later, after a hepatic failure and detection of high levels of anti-HLA-II antibodies. Taking into account the bad evolution of the liver graft, the patient underwent a second liver transplant in 2020, which remains functional until now. In spite of these findings, the renal function has remained stable since the CLKT in 2009.\n\nDiscussion, Take-Away Lessons\n\nIn the last 20 years, there has been an important improvement in the comprehension of the molecular bases underlying atypical Hemolytic Uremic Syndrome. The complement system was initially considered an important mediator of the endothelial damage characteristic of this rare disease, and the subsequent identification of pathogenic variants and/or polymorphisms in one or more complement genes further strengthen its role as disease causative (2). In the aHUS patient described here, the identification of a gain-of-function mutation in complement Factor B explained the high and constitutive consumption of complement C3 in the patient´s plasma.\n\nThe fact that the liver is the main source of plasma Factor B (7) anticipated HUS recurrence after an isolated kidney transplantation, thus hampering this possibility for our patient. By that time, several aHUS patients with mutations in Factor H, most of them children, underwent CLKT. Although initial experiences had a fatal outcome (8–10), the introduction of pre-emptive plasmapheresis with plasma exchange proved to be very successful (11–13). At the light of these experiences, and in the absence of other therapies, it was decided that the CKLT was the only curative option for our patient with the Factor B mutation. This decision was adopted after a consensus meeting between nephrologists, hepatologists, surgeons, and immunologists from Hospital La Paz, and complement researchers involved in the case. In spite of its risks, the intervention was accepted by the patient’s parents, and it could be done in 2009, upon the availability of liver and kidney grafts from a donor of the same age that the patient. The CLKT allowed immediate restoration of the renal function in the patient, who remained without problems under immunosuppressive treatment for four years.\n\nA B-cell lymphoma was the first complication of the patient. The B-cell lymphoma could be related with the immunosuppressive treatment, but the association of immunosuppression with subsequent complications after CLKT is only partially understood (14–16). The risk of tumor appearance induced by the immunosuppression treatment increases with postransplantation time. The overall incidence of tumors in the pediatric age after a solid organ transplantation is around 6%, with values of 7% in liver and around 3% in renal grafts. There are few data on combined transplantation, but tumor incidence seems to be like that of single liver transplantation, around 8% (17). These percentages raise when the follow-up is prolonged into adulthood. In all solid organ transplantation, between 80 and 90% of the tumors are of lymphoid origin. In addition, in our patient, the immunosuppression received prior to transplantation could increase the tumor risk.\n\nThe immunosuppression regimes in CLKT and isolated kidney transplantation are very similar; moreover, in CLKT the liver graft confers immunoprotection to the kidney graft. This effect was first observed in experimental animals (18) and later on in patients (19). The presence of DSA was considered a predisposition factor to graft rejection in isolated kidney transplantation (20, 21). However, in the case of CLKT, the liver graft protects the kidney from the hyperacute reaction, and it also decreases the acute cellular response (22). In a more recent cooperative study, the authors evidenced that the presence of DSA antibodies in CLKT rises the mortality, but they did not find a clear relationship with the kidney and liver graft evolution (23).\n\nCholangitis associated to chronic liver rejection was an additional and severe complication in the patient, with a 6-year evolution that conducted to a second liver graft in 2020 that remains functional. Although the patient suffered several complications along the post-transplant period, in 2009 CLKT was the only therapeutic approach, since complement inhibitors such as Eculizumab were not available. The combined transplantation allowed the patient to leave dialysis and to improve his social and academic life; currently, he is enrolled on a university degree. Further complications were solved in a tertiary hospital, and the patient continues under immunosuppressive therapy with adequate follow-up.\n\nTo correct the complement dysregulation and the very low C3 levels caused by the gain-of-function mutation in Factor B was an important consideration when discussing the therapeutic options for our patient. Our conclusion was that, although liver transplantation would add additional risks to kidney transplantation, the CLKT was the only available option to completely normalize complement activation. Nowadays, our patient would have likely been approached with an isolated kidney transplantation and the use of Eculizumab. However, during the last 15 years it has been an extraordinary progress in the development of drugs inhibiting different levels of the complement cascade, providing novel therapeutic options to aHUS patients. In this changing scenario, a next generation of complement inhibitors acting upstream of C5 activation would soon be available for the treatment of complement dysregulation disorders. One of these novel drugs, which may be better and more appropriate than Eculizumab for some patients, is Pegcetacoplan (24, 25), a PEGylated pentadecapeptide that binds to C3 and C3b, and regulates the activation of C3 and the activity of the AP C3 convertase. Pegcetacoplan has been recently approved by the FDA for the treatment of adults with paroxysmal nocturnal hemoglobinuria (26).\n\nCLKT is still nowadays a valid therapeutic option for aHUS patients. Thus, the experts recommend not to completely discard CLKT (which could be the only option in countries or situations where Eculizumab is not available), and to discuss all the options with patients and families (27). CLKT in aHUS patients with complement mutations has been extensively reviewed by Zuber et al. in 2013 (28), and by Saland et al. in 2014 (29); these papers included 16 cases with CFH mutations (14 successful), one with C3 mutation (unsuccessful), one with CFB mutation (this patient), 2 cases with a hybrid CFH::CFHR1 gene (one successful), and an additional case as personal communication (28).\n\nFunctional characterization of the Factor B K323E variant purified from the patient’s plasma showed increased resistance of the C3 convertase to dissociation by the complement regulators Factor H and DAF (4). The gain-of-function consequences of the K323E variant were confirmed in another study where Factor B pathogenic variants identified in other aHUS patients were functionally characterized (30). Further characterization of recombinant Factor B K323E showed that it is functionally very similar to a C3 nephritic factor, which most of the times does not allow activation of the complement terminal pathway (31). Two aHUS patients with another Factor B pathogenic variant and very low C3 levels in plasma have been recently described (32), and the authors consider that the excessive activation of the fluid-phase C3 convertase could predispose to aHUS or to C3 glomerulonephritis, depending on the presence of additional predisposing genes or environmental factors. In this context, it could be relevant that the aHUS-risk haplotype MCPgggac is present in our patient with the K323E mutation in Factor B, and in all the affected members of the family carrying the F286L mutation (4). One of the members of that family is a girl who presented HUS at the age of 3 months and had a bad clinical evolution, comparable in many aspects to the evolution of our patient with the K323E mutation. Nonetheless, C3 levels in the girl’s plasma were never as low as observed in our patient; this could reflect that the K323E mutation is more pathogenic for Factor B function than the F286L mutation. The girl with the F286L mutation received a kidney graft in 2011 and has remained stable without Eculizumab prophylaxis (5). It is likely that the absence of the MCPggaac aHUS-risk haplotype in the kidney graft have contributed to the successful evolution of this patient after transplantation. In the case of the patient with the K323E mutation, further genetic studies showed that donor and receptor shared the MCPggaac aHUS-risk haplotype but not the CFH(H3) haplotype; the absence of the CFH-risk polymorphism in addition to the presence of wild-type Factor B in the liver graft likely contributed to a better regulation of the C3 convertase in the receptor.\n\nIn conclusion, we describe the clinical evolution and therapeutic strategy in a boy with a gain–of-function mutation in complement Factor B. CLKT as a therapeutic option was justified because of a torpid evolution during 8 years, with several life-threatening events and the unavailability of complement-inhibiting drugs at that time. CLKT allowed the immediate restauration of kidney function and a stable evolution for four years, but after a B-cell lymphoma and a liver rejection, the patient needed a second liver graft 11 years later. Renal function and complement levels have remained normal all the time since the CKLT, and the patient has not suffered any aHUS recurrence.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Comité de Ética del Hospital Universitario “La Paz”. Hospital La Paz. Madrid. Spain. Written informed consent to participate in this study was provided by the patient or their parents.\n\nAuthor Contributions\n\nÁA-M, MM-H, LE-R, and DL-B gathered clinical data. EG-F contributed to the analysis of the biopsy. PS-C, ÁA-M, MM-H, and ML-T prepared figures. ML-T compiled the data for the case-study, and wrote the first draft of the manuscript. SRC and PS-C revised the initial draft of the paper. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nML-T, SRC, and PS-C are supported by the Spanish Autonomous Region of Madrid (Complement II-CM network; B2017/BMD-3673).\n\nAuthor Disclaimer\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe thank Irene Delgado and Fernando Corvillo for helpful contribution on the preparation of graphic materials. We want to especially acknowledge all the clinicians from Hospital Infantil La Paz who were involved in the treatment of this patient along these years. We also appreciate the support from doctors Mercedes Navarro and Paloma Jara, two mentors of our hospital, who were pioneers in the Paediatrics field, and encouraged all the clinical decisions on the patient’s treatment. We acknowledge Dr. Esther Mancebo (Immunology Department. Hospital 12 de Octubre. Madrid) for the valued contribution on the anti-HLA antibodies studies. Finally, we would like to thank the patient and his family for their confidence on the medical decisions, and for their admirable attitude towards the difficult and critical experiences during all this time.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021.751093/full#supplementary-material\n\nSupplementary Figure 1 Kidney biopsy. (A) Hematoxylin and Eosin staining of a glomerulus, showing mesangiolysis with fragmented red blood cells and double contours in capillary walls. (B) Masson trichrome staining, showing small arteries with intimal thickening, mucoid intimal edema, and endothelial swelling.\n\nClick here for additional data file.\n\nSupplementary Figure 2 Acrocyanosis on the feet fingers. The two images correspond to a microangiopathy episode occurring after the patient underwent bilateral nephrectomy.\n\nClick here for additional data file.\n\nAbbreviations\n\naHUS, atypical Hemolytic Uremic syndrome; DGKE, Diacylglycerol kinase Epsilon; CLKT, combined liver kidney transplantation; DSA, donor specific antibodies; MFI, median fluorescence intensity.\n==== Refs\nReferences\n\n1 Cody EM Dixon BP . Hemolytic Uremic Syndrome. Pediatr Clin North Am (2019) 66 (1 ):235–46. doi: 10.1016/j.pcl.2018.09.011\n2 Nester CM Barbour T de Cordoba SR Dragon-Durey MA Fremeaux-Bacchi V Goodship TH . Atypical aHUS: State of the Art. Mol Immunol (2015) 67 (1 ):31–42. doi: 10.1016/j.molimm.2015.03.246 25843230\n3 Saland JM Ruggenenti P Remuzzi G Consensus Study Group. Liver-Kidney Transplantation to Cure Atypical Hemolytic Uremic Syndrome. J Am Soc Nephrol (2009) 20 (5 ):940–9. doi: 10.1681/ASN.2008080906\n4 Goicoechea de Jorge E Harris CL Esparza-Gordillo J Carreras L Arranz EA Garrido CA . Gain-Of-Function Mutations in Complement Factor B Are Associated With Atypical Hemolytic Uremic Syndrome. Proc Natl Acad Sci U S A (2007) 104 (1 ):240–5. doi: 10.1073/pnas.0603420103\n5 Sánchez-Moreno A de la Cerda F Rodríguez-Barba A Fijo J Bedoya R Arjona E . Is the Atypical Hemolytic Uremic Syndrome Risk Polymorphism in Membrane Cofactor Protein MCPggaac Relevant in Kidney Transplantation? A Case Report. Pediatr Transplant (2021) 25 (3 ):e13903. doi: 10.1111/petr.13903 33217135\n6 Alonso Melgar A Melgosa M López-Trascasa M Navarro M de la Vega A and Sánchez-Corral P . Successful Combined Liver and Kidney Transplantation in a Child With Hypocomplementemic Atypical Haemolytic Uremic Syndrome (aHUS) Due to a Factor B Mutation. 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Kidney Int (2016) 89 (4 ):909–17. doi: 10.1016/j.kint.2015.10.016\n23 Del Bello A Thaunat O Le Quintrec M Bestard O Durrbach A Perrin P . Combined Liver-Kidney Transplantation With Preformed Anti-Human Leukocyte Antigen Donor-Specific Antibodies. Kidney Int Rep (2020) 5 (12 ):2202–11. doi: 10.1016/j.ekir.2020.09.018\n24 de Castro C Grossi F Weitz IC Maciejewski J Sharma V Roman E . C3 Inhibition With Pegcetacoplan in Subjects With Paroxysmal Nocturnal Hemoglobinuria Treated With Eculizumab. Am J Hematol (2020) 95 (11 ):1334–43. doi: 10.1002/ajh.25960\n25 Hillmen P Szer J Weitz I Röth A Höchsmann B Panse J . Pegcetacoplan Versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med (2021) 384 (11 ):1028–37. doi: 10.1056/NEJMoa2029073\n26 Hoy SM . Pegcetacoplan: First Approval. Drugs (2021) 81 (12 ):1423–30. doi: 10.1007/s40265-021-01560-8\n27 Bacchetta J Mekahli D Rivet C Demède D Leclerc AL . Pediatric Combined Liver-Kidney Transplantation: A 2015 Update. Curr Opin Organ Transplant (2015) 20 (5 ):543–9. doi: 10.1097/MOT.0000000000000225\n28 Zuber J Le Quintrec M Morris H Frémeaux-Bacchi V Loirat C Legendre C . Targeted Strategies in the Prevention and Management of Atypical HUS Recurrence After Kidney Transplantation. Transplant Rev (Orlando) (2013) 27 (4 ):117–25. doi: 10.1016/j.trre.2013.07.003\n29 Saland J . Liver-Kidney Transplantation to Cure Atypical HUS: Still an Option Post-Eculizumab? Pediatr Nephrol (2014) 29 (3 ):329–32. doi: 10.1007/s00467-013-2722-2\n30 Marinozzi MC Vergoz L Rybkine T Ngo S Bettoni S Pashov A . Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome-Disease-Relevant or Benign? J Am Soc Nephrol (2014) 25 (9 ):2053–65. doi: 10.1681/ASN.2013070796\n31 Urban A Borowska A Felberg A van den Heuvel L Stasiłojć G Volokhina E . Gain of Function Mutant of Complement Factor B K323E Mimics Pathogenic C3NeF Autoantibodies in Convertase Assays. Autoimmunity (2018) 51 (1 )18–24. doi: 10.1080/08916934.2017.1423286 29308663\n32 Zhang Y Kremsdorf RA Sperati CJ Henriksen KJ Mori M Goodfellow RX . Mutation of Complement Factor B Causing Massive Fluid-Phase Dysregulation of the Alternative Complement Pathway can Result in Atypical Hemolytic Uremic Syndrome. Kidney Int (2020) 98 (5 ):1265–74. doi: 10.1016/j.kint.2020.05.028\n\n", "fulltext_license": "CC BY", "issn_linking": "1664-3224", "issue": "12()", "journal": "Frontiers in immunology", "keywords": "atypical hemolytic uremic syndrome; combined liver-kidney transplantation; complement; factor B; rare diseases", "medline_ta": "Front Immunol", "mesh_terms": null, "nlm_unique_id": "101560960", "other_id": null, "pages": "751093", "pmc": null, "pmid": "34721423", "pubdate": "2021", "publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't", "references": "27105881;15816899;24362724;23380861;16889549;19092117;12020532;17182750;4988655;12614293;33730455;30454746;14986080;34342834;19235662;23160511;12451237;29308663;23937869;17973958;33217135;24652797;33305113;19005013;26270957;33464651;827931;26924059;32540405;25843230;19328954", "title": "Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.", "title_normalized": "case report combined liver kidney transplantation to correct a mutation in complement factor b in an atypical hemolytic uremic syndrome patient" }

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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "URSODIOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Liver transplant rejection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Liver transplant rejection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130901" } }, "primarysource": { "literaturereference": "Lopez-Trascasa M, Alonso-Melgar A, Melgosa-Hijosa M, Espinosa-Roman L, Lledin-Barbancho MD, Garcia-Fernandez E, et al. Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient. Front-Immunol 2021;12:1-8.", "literaturereference_normalized": "case report combined liver kidney transplantation to correct a mutation in complement factor b in an atypical hemolytic uremic syndrome patient", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20220107", "receivedate": "20211223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20224638, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20220423" }, { "companynumb": "ES-ROCHE-2962026", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, 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"URSODIOL" } ], "patientagegroup": null, "patientonsetage": "4", "patientonsetageunit": "802", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Complications of transplanted liver", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130901" } }, "primarysource": { "literaturereference": "Lopez-Trascasa M, Alonso-Melgar, A, Melgosa-Hijosa, M et al.. 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"drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, RCOPDAM REGIMEN", "drugenddate": null, "drugenddateformat": null, "drugindication": "B-cell lymphoma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2013", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, PULSE THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Liver transplant rejection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Liver transplant rejection", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS" } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Septic coagulopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20130101" } }, "primarysource": { "literaturereference": "Lopez-Trascasa M, Alonso-Melgar A, Melgosa-Hijosa M, Espinosa-Roman L, Lledin-Barbancho MD, Garcia-Fernandez E, et al.. Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.. Front-Immunol. 2021;121-8", "literaturereference_normalized": "case report combined liver kidney transplantation to correct a mutation in complement factor b in an atypical hemolytic uremic syndrome patient", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20211213", "receivedate": "20211213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20173792, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220304" }, { "companynumb": "ES-CELLTRION INC.-2021ES016628", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RITUXIMAB" }, 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Diffuse large B-cell lymphoma stage III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE\\DOXORUBICIN\\PREDNISONE\\RITUXIMAB\\VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "B-cell lymphoma", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Complications of transplanted liver", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Transaminases increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20140201" } }, "primarysource": { "literaturereference": "Lopez-Trascasa M, Alonso-Melgar, A, Melgosa-Hijosa, M et al. Case Report: Combined Liver-Kidney Transplantation to Correct a Mutation in Complement Factor B in an Atypical Hemolytic Uremic Syndrome Patient.. Frontiers in Immunology. 2021;12:1-8", "literaturereference_normalized": "case report combined liver kidney transplantation to correct a mutation in complement factor b in an atypical hemolytic uremic syndrome patient", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20211224", "receivedate": "20211214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20178475, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "Idarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran, a Direct Oral Anticoagulant. Despite recent trials demonstrating reversal of clinically relevant bleeding, there is a paucity of data on use outside the trial setting. This manuscript describes the use of Idarucizumab to reverse dabigatran in two patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH).\nPatients were identified through retrospective review of medication dispensing systems and electronic medical records.\nTwo cases of Idarucizumab use were identified. Case 1 was of a 63-year-old male who presented following a motorcycle crash. Case 2 was of a 77-year-old male who presented with a 3-week history of ataxia and recurrent falls. Both patients were taking dabigatran for atrial fibrillation (AF). CT Brain revealed acute SDH with clinical indications for urgent surgical evacuation. Serum dabigatran levels were obtained on arrival in the emergency department with levels of 155 ng/ml and 110 ng/ml (reference range 117-275 ng/ml). Idarucizumab for dabigatran reversal was commenced; Case 1 received 5 g Idarucizumab as an intravenous bolus dose, while Case 2 received 5 g Idarucizumab as two 2.5 g intravenous infusions. Serum dabigatran levels for Cases 1 and 2 were 0 ng/ml at 75 min and 340 min post Idarucizumab administration respectively. Both patients proceeded to craniotomy with evacuation of the SDH. There was no extension of the SDH in either case. Anticoagulation was withheld until outpatient clinic review, and both patients transferred for rehabilitation prior to discharge home.\nIdarucizumab was clinically effective for reversing dabigatran, resulting in undetectable serum levels, and should be considered in patients presenting to hospital with clinically significant bleeding associated with dabigatran therapy.", "affiliations": "Pharmacy Department, The Alfred Hospital, Melbourne, Australia.;Pharmacy Department, The Alfred Hospital, Melbourne, Australia.;Department of Neurosurgery, The Alfred Hospital, Melbourne, Australia.;Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia.", "authors": "Edwards|Gail|G|;Roman|Cristina|C|;Jithoo|Rondhir|R|;Mitra|Biswadev|B|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.tcr.2017.12.003", "fulltext": "\n==== Front\nTrauma Case RepTrauma Case RepTrauma Case Reports2352-6440Elsevier S2352-6440(17)30080-810.1016/j.tcr.2017.12.003ArticleUse of Idarucizumab for dabigatran reversal: Emergency department experience in two cases with subdural haematoma Edwards Gail [email protected]⁎Roman Cristina abJithoo Rondhir cMitra Biswadev bdea Pharmacy Department, The Alfred Hospital, Melbourne, Australiab Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australiac Department of Neurosurgery, The Alfred Hospital, Melbourne, Australiad Department of Epidemiology & Preventative Medicine, Monash University, Melbourne, Australiae National Trauma Research Institute, Melbourne, Australia⁎ Corresponding author at: Pharmacy Department, The Alfred Hospital, 55 Commercial Road, Melbourne 7000, Australia.Pharmacy DepartmentThe Alfred Hospital55 Commercial RoadMelbourne7000Australia [email protected] 12 2017 2 2018 29 12 2017 13 46 49 26 12 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Introduction\nIdarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran, a Direct Oral Anticoagulant. Despite recent trials demonstrating reversal of clinically relevant bleeding, there is a paucity of data on use outside the trial setting. This manuscript describes the use of Idarucizumab to reverse dabigatran in two patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH).\n\nMethods\nPatients were identified through retrospective review of medication dispensing systems and electronic medical records.\n\nResults\nTwo cases of Idarucizumab use were identified. Case 1 was of a 63-year-old male who presented following a motorcycle crash. Case 2 was of a 77-year-old male who presented with a 3-week history of ataxia and recurrent falls. Both patients were taking dabigatran for atrial fibrillation (AF). CT Brain revealed acute SDH with clinical indications for urgent surgical evacuation. Serum dabigatran levels were obtained on arrival in the emergency department with levels of 155 ng/ml and 110 ng/ml (reference range 117–275 ng/ml). Idarucizumab for dabigatran reversal was commenced; Case 1 received 5 g Idarucizumab as an intravenous bolus dose, while Case 2 received 5 g Idarucizumab as two 2.5 g intravenous infusions. Serum dabigatran levels for Cases 1 and 2 were 0 ng/ml at 75 min and 340 min post Idarucizumab administration respectively. Both patients proceeded to craniotomy with evacuation of the SDH. There was no extension of the SDH in either case. Anticoagulation was withheld until outpatient clinic review, and both patients transferred for rehabilitation prior to discharge home.\n\nConclusion\nIdarucizumab was clinically effective for reversing dabigatran, resulting in undetectable serum levels, and should be considered in patients presenting to hospital with clinically significant bleeding associated with dabigatran therapy.\n\nKeywords\nIdarucizumabDabigatranIntracranial haemorrhageWounds and injuriesEmergency department\n==== Body\nIntroduction\nIn-hospital mortality in the setting of disorders of coagulation and traumatic brain injury (TBI) has been reported to be approaching 50% [1] Timely normalization of coagulopathy has also been associated with improved outcomes [2] Dabigatran, a direct thrombin inhibitor, is a novel anticoagulant. Patients treated with dabigatran who present with major bleeding or need urgent surgical intervention are at risk of severe complications due to the anticoagulation effects [3] Idarucizumab is the first effective humanized monoclonal antibody fragment developed specifically as a reversal agent for dabigatran [4], [5], [6] The Therapeutic Goods Administration approved the use of Idarucizumab in Australia in June 2016.\n\nEarly studies in healthy young patients and those between 45 and 80 years old with mild to moderate renal impairment have demonstrated idarucizumab rapidly reverse the anticoagulant effects of dabigatran and achieve haemostasis without pro-thrombotic effects. However, the safety and efficacy in patients with serious bleeding or who require urgent surgery is not known.\n\nThis case series documents the use of Idarucizumab to reverse dabigatran in patients presenting to the emergency department of a major tertiary hospital with acute traumatic subdural haematomas (SDH).\n\nMethods\nPatients were identified through retrospective review of medication dispensing systems and electronic medical records. Two cases were identified from 1/1/2016 to 1/6/2016 and informed consent to present this report obtained. The study was approved by The Alfred Hospital Research and Ethics Committee.\n\nResults\nTwo cases were identified for inclusion. Case 1 was of a 63-year-old male who was transferred from a regional centre following a motorcycle crash. He had a history of atrial fibrillation for which he was prescribed dabigatran. Computed tomography (CT) imaging following the crash showed a SDH with mass effect. Fresh Frozen Plasma and a 3-factor prothrombin complex concentrate were administered prior to transfer. Upon arrival at our centre, and following analysis of laboratory data and multi-disciplinary medical team discussions, a decision to administer Idarucizumab was made. Laboratory results are listed in Table 1 and a timeline of events in Fig. 1. A single 5g-bolus dose of Idarucizumab was administered. The patient proceeded to the operating theatre where he underwent a craniotomy and evacuation of the SDH. Surgery was successful and haemostasis was achieved. Post-operative complications involved residual dysphasia, which resolved within 2 weeks post discharge. There was evidence of residual SDH on CT scans performed at 2 and 4 weeks post the crash but with no acute component. Anticoagulation was withheld and the patient was discharged into the care of his local medical officer who was advised to restart anticoagulation if there had been no extension of SDH on a follow-up CT scan to be performed 6 weeks post crash.Fig. 1 Case 1 Timeline.\n\nFig. 1Table 1 Case 1 laboratory data.\n\nTable 1Laboratory markers (reference ranges)\tAdmission\tPost Idarucizumab Administration\n(T = 75 min from administration)\t\nDabigatran\n(117–275 ng/ml)\t155\t0\t\nPT*\n(10.6–15.3 s)\t17.4\t14.1\t\nAPTT*\n(26–38 s)\t63\t35.5\t\nINR*\n(0.9–1.3)\t1.4\t1.1\t\nTCT*\n(14–24 s)\t133.4\t18.1\t\n\n\nCase 2 was of a 77-year-old male who presented with an ataxic gait and recurrent falls, increasing in frequency in the preceding 3 days. He had a history of atrial fibrillation for which he was prescribed dabigatran. CT imaging revealed an acute on chronic SDH. Laboratory investigations confirmed active anticoagulation (Table 2) and a timeline of events outlined in Fig. 2. Multi-disciplinary medical discussions resulted in a decision to administer Idarucizumab. The patient was prescribed a 5 g dose of Idarucizumab, administered as two 2.5 g bolus doses spaced 5 min apart. No other blood products were administered to achieve haemostasis. The patient proceeded to the operating theatre for a frontoparietal mini craniotomy and evacuation of the SDH. The post-operative course was uncomplicated but routine CT follow-up at 4 weeks showed some residual SDH, although the patient was asymptomatic. A decision was made to remain off anticoagulation until a repeat CT was performed in 8 weeks time. CT scans performed seven months following injury show near complete resolution of SDH. However, the patient remained off anticoagulation under the guidance of the neurosurgical and cardiology teams.Fig. 2 Case 2 Timeline.\n\nFig. 2Table 2 Case 2 laboratory results.\n\nTable 2Laboratory markers (reference ranges)\tAdmission\tPost Idarucizumab Administration\n(T = 340 min from administration)\t\nDabigatran\n(117–275 ng/ml)\t110\t0\t\nPT*\n(10.6–15.3 s)\t17.2\t15\t\nAPTT*\n(26–38 s)\t48.4\t28.6\t\nINR*\n(0.9–1.3)\t1.4\t1.2\t\nTCT*\n(14–24 s)\tN/A\t16.5\t\n*PT = prothrombin time, APTT = activated partial thromboplastin time, INR = International normalised Ratio, TCT = thrombin clotting time.\n\n\n\nDiscussion\nThis manuscript describes two cases of successful reversal of the effects of dabigatran following administration of Idarucizumab. Both patients were taking dabigatran and sustained severe traumatic brain injuries requiring urgent surgical intervention. There were no obvious adverse effects observed.\n\nAlternate options for reversal of the effects of dabigatran such as haemodialysis or waiting until anticoagulation effects cease by normal elimination, were not feasible in these cases, as rapid return to haemostasis was required. In patients with normal renal function dabigatran has a half-life of 12–14 h extending in those with renal impairment [7]. Therefore, ceasing treatment 24–48 h prior to planned procedures is a valid treatment strategy. Similarly, haemodialysis can be also considered for reversal of dabigatran effects in specific patient scenarios [8].\n\nIdarucizumab has been developed as a specific antidote to dabigatran and is approved for use when the rapid reversal of anticoagulation effects is required for emergency surgery, urgent procedures, and in life threatening or uncontrollable bleeding. It is a humanized monoclonal antibody that binds specifically and potently to dabigatran to neutralise its effects [9]. The affinity of Idarucizumab binding to dabigatran is around 350 times greater than that of dabigatran for thrombin [9], [10]. Both free and thrombin-bound dabigatran can be bound by Idarucizumab to neutralise anticoagulation activity [10]. Idarucizumab does not bind thrombin or its substrates nor does it activate platelets or convert fibrinogen to fibrin [4]. Benefits of Idarucizumab include a low rate of adverse effects, no increase risk of thrombosis and its short half-life allows for the resumption of anticoagulation therapy early after the acute episode of bleeding has resolved [6].\n\nAn important consideration when deciding on the use of Idarucizumab is the timing of the last dabigatran dose. It was confirmed with both cases that doses had been taken on the morning of their presentations and this was reflected through serum dabigatran levels measured on admission. Given the short half-life of dabigatran, if doses had been missed, it is possible that it no longer contributes to bleeding.\n\nReversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) is a prospective cohort study to examine the efficacy and safety of idarucizumab for the reversal of the anticoagulant effects of dabigatran in patients who presented with serious bleeding or who required urgent surgery or intervention. In the interim analysis of the RE-VERSE AD study, Idarucizumab was administered to around 25% of patients who had normal coagulation tests making it difficult to ascertain the benefit gained from Idarucizumab in this cohort [4], [10].\n\nThe dose prescribed and administered of Idarucizumab varied between our two cases with one patient receiving a 5 g intravenous bolus dose and the other patient receiving two 2.5 g intravenous bolus doses. It is believed a 5 g total dose of Idarucizumab will reverse all available dabigatran up to the 99th percentile of dabigatran plasma concentrations measured in patients enrolled in the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial [4], [10]. RE-VERSE ED administers Idarucizumab as two 2.5 g intravenous bolus doses no more than 15 min apart. While dosing of Idarucizumab in our case series did not follow the regimen of this current Phase 3 trial, it still produced undetectable serum dabigatran levels and improvement in other markers of coagulation post administration. A study by Glund et al. conducted in healthy elderly or with mild-moderate renal impairment found that administration of 5 g or two 2.5 g Idarucizumab doses led to the sustained reversal of dabigatran induced anticoagulation [5]. Standardised dosing of Idarucizumab is of benefit in the busy clinical environment and future research could assess the efficacy of a single 5 g Idarucizumab doses to further simplify treatment.\n\nOngoing assessment will provide better understanding of optimal timing of serum dabigatran and coagulation laboratory tests. Timing of post Idarucizumab administration laboratory data varied in our two cases. RE-VERSE AD is performing measures between 10 and 30 min and at 1, 2, 4, 12, and 24 h following the second infusion [10]. In the busy clinical setting of an emergency department or theatre suite it may not be practical or achievable to perform laboratory testing as frequently as this. Thus, clear guidelines need to be established for clinical practice reflecting both real life data and clinical trial literature.\n\nConclusion\nThe two cases described support the use of Idarucizumab, rapidly reversing the anticoagulant effects of dabigatran. Idarucizumab can be considered in patients treated with dabigatran who present with uncontrollable or life-threatening bleeding or in need of urgent surgical intervention.\n==== Refs\nReferences\n1 Epstein D.S. Mitra B. Cameron P.A. Fitzgerald M. Rosenfeld J.V. Acute traumatic coagulopathy in the setting of isolated traumatic brain injury: definition, incidence and outcomes Br. J. Neurosurg. 2014 1 5 \n2 Epstein D.S. Mitra B. Cameron P.A. Fitzgerald M. Rosenfeld J.V. Normalization of coagulopathy is associated with improved outcome after isolated traumatic brain injury J. Clin. Neurosci. 29 2016 64 69 26947341 \n3 Thomas P.A. Schaerf N.B. Rosenfeld J.V. Dabigatran-neurosurgical anathema? Med. J. Aust. 199 4 2013 238 240 \n4 Eikelboom J.W. Quinlan D.J. van Ryn J. Weitz J.I. Idarucizumab Circulation 132 25 2015 2412 2422 26700008 \n5 Glund S. Stangier J. Schmohl M. Moschetti V. Haazen W. De Smet M. Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects Blood 124 21 2014 344 24914142 \n6 Gottlieb M. Khishfe B. Idarucizumab for the reversal of dabigatran Ann. Emerg. Med. 69 2017 554 558 28110992 \n7 Dabigatran Boehringer Ingelheim Inc. [Available from] http://files.boehringer.com.au/files/PI/Pradaxa \n8 Chang D.N. Dager W.E. Chin A.I. Removal of dabigatran by hemodialysis Am. J. Kidney Dis. 61 3 2013 487 489 23219111 \n9 Glund S. Stangier J. Schmohl M. Gansser D. Norris S. van Ryn J. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial Lancet 386 9994 2015 680 690 26088268 \n10 Pollack C.V. Jr. Reilly P.A. Eikelboom J. Glund S. Verhamme P. Bernstein R.A. Idarucizumab for dabigatran reversal N. Engl. J. Med. 373 6 2015 511 520 26095746\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2352-6440", "issue": "13()", "journal": "Trauma case reports", "keywords": "Dabigatran; Emergency department; Idarucizumab; Intracranial haemorrhage; Wounds and injuries", "medline_ta": "Trauma Case Rep", "mesh_terms": null, "nlm_unique_id": "101711730", "other_id": null, "pages": "46-49", "pmc": null, "pmid": "29644298", "pubdate": "2018-02", "publication_types": "D002363:Case Reports", "references": "23219111;26700008;28110992;26095746;26947341;25153987;26088268;23984772", "title": "Use of Idarucizumab for dabigatran reversal: Emergency department experience in two cases with subdural haematoma.", "title_normalized": "use of idarucizumab for dabigatran reversal emergency department experience in two cases with subdural haematoma" }

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{ "abstract": "The occurrence of a pneumothorax using supraglottic device is a rare complication during general anesthesia. Moreover, less than 2% of pneumothoraxes can be related to lung metastases, most due to soft tissue sarcoma. We present the case of a 45-year-old female diagnosed with metastatic sarcoma who developed a bilateral pneumothorax after general anesthesia with supraglottic device. Different causes of pneumothorax were discussed.", "affiliations": "Department of Anesthesia and Intensive Care, Careggi University Hospital, Florence, Italy.;Department of Anesthesia and Intensive Care, Careggi University Hospital, Florence, Italy.;Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.", "authors": "Gianesello|Lara|L|;Boccaccini|Alberto|A|;Rostagno|Carlo|C|https://orcid.org/0000-0002-7764-8919", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/2050313X19833258", "fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1983325810.1177_2050313X19833258Case ReportBilateral pneumothorax after general anesthesia in patient with pleomorphic sarcoma of soft tissue Gianesello Lara 1Boccaccini Alberto 1https://orcid.org/0000-0002-7764-8919Rostagno Carlo 21 Department of Anesthesia and Intensive Care, Careggi University Hospital, Florence, Italy2 Department of Experimental and Clinical Medicine, University of Florence, Florence, ItalyCarlo Rostagno, AOU Careggi, Largo Brambilla 3, 50134 Firenze, Italy. Email: [email protected] 2 2019 2019 7 2050313X1983325813 9 2018 29 1 2019 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).The occurrence of a pneumothorax using supraglottic device is a rare complication during general anesthesia. Moreover, less than 2% of pneumothoraxes can be related to lung metastases, most due to soft tissue sarcoma. We present the case of a 45-year-old female diagnosed with metastatic sarcoma who developed a bilateral pneumothorax after general anesthesia with supraglottic device. Different causes of pneumothorax were discussed.\n\nPneumothoraxmetastatic sarcomamechanical ventilationcover-dateJanuary-December 2019\n==== Body\nIntroduction\nSecondary pneumothorax due to metastatic sarcoma is often associated with advanced disease or systemic chemotherapy.1,2 From the case series reported in the literature, the prevalence of spontaneous pneumothorax in sarcoma is 1.9%.3 The first case was described by De Barrin4 in 1937 associated with advanced disease-metastatic osteosarcoma. We present a case of a 45-year-old female suffering from metastatic sarcoma who developed a bilateral pneumothorax after general anesthesia with supraglottic device.\n\nCase report\nA 45-year-old female, with a history of thyroid nodules, noticed 2 months before hospitalization a tumefaction of her right thigh. Magnetic resonance (MR) imaging showed a vascularized mass measuring 20 × 8.5 × 7 cm3 with intra-fascial edema of vastus lateralis and vastus medialis.\n\nThree weeks later, a new MR showed an increase in the size of the mass surrounding the femur with irregular profile of the femoral cortical. Computed tomographic (CT) scan of the chest did not show lung metastasis. An incisional biopsy of the mass demonstrated a high-grade pleomorphic sarcoma.\n\nResection of the femur with quadriceps muscle was performed and a total femoral prosthesis was implanted. Pathologic diagnosis was high-grade pleomorphic sarcoma with widespread necrotic-bleeding aspects and infiltration of striated muscle and bone tissue.\n\nForty days later, she was readmitted for the treatment two eschars within the surgical scar associated with peri-prosthetic abscess. No other pulmonary CT scan was performed before re-admission. Arthrocentesis and superficial debridement were conducted under general anesthesia. A lubricated laryngeal mask airway (LMA) Supreme™ n.4 was inserted successfully at the first attempt without difficulty using the standard insertion technique (The LMA Supreme Instruction Manual, Intravent Orthofix Ltd, Maidenhead, 2007). The cuff of the LMA Supreme was inflated with air (30 mL) to obtain a pressure of 60 cm H2O. After insertion, the device was connected to a closed-circuit breathing system under pressure-controlled ventilation (PCV) with an inspiratory pressure 16 cm H2O, a positive end-expiratory pressure (PEEP) of 5 cm H2O, a respiration rate (RR) of 12 breaths/min, an inspiratory ratio of 1:2 and fresh gas flow (oxygen/air) of 3 L/min. Successful placement was defined as a square wave tracing on the capnography with an end-tidal CO2 (EtCO2) value of 32–35 mmHg. There was not gas leakage at a positive pressure. Anesthesia was maintained with sevoflurane (end-tidal concentration of 2.5%) and remifentanil (0.15–0.20 µg/kg/min). The patient was in the supine position and hemodynamic and respiratory parameters were stable during the surgery. The surgery was uneventful and the duration of anesthesia was 60 min. After surgery, the patient was admitted to post-anesthesia care unit for postoperative monitoring and thereafter transferred to the ward in stable conditions.\n\nNext morning, she developed respiratory distress with sudden desaturation (SpO2 85%) associated with intense thoracic pain located in right scapular area. CT scan showed right massive pneumothorax and left pneumothorax of 6 cm depth (Figure 1). Bilateral thoracic drainage was needed. Following lung re-expansion, a CT scan of the chest showed bilateral lung pulmonary metastasis, some of these located in sub-pleural region (Figure 2). No further complications occurred and the patient was discharged after 10 days of hospitalization with indication to chemotherapy and radiotherapy.\n\nFigure 1. CT scan with right massive pneumothorax and left pneumothorax.\n\nFigure 2. CT scan. Black arrow shows a sub-pleural metastasis.\n\nDiscussion\nPneumothorax is a rare complication during general anesthesia. It can be due to surgical or anesthetic procedures that damage the pleural surface. The incidence of barotrauma in postoperative patients has been reported to be as low as 0.5%.5 Several studies reported that a peak airway pressure above 50 cm H2O is associated with increased risk of alveolar rupture during ventilation.6 Although high PEEP values had been reported to be associated with pneumothorax,7 contrasting data have been reported.8,9\n\nThe development of the pneumothorax during general anesthesia with supraglottic devices is rarer than general anesthesia with endotracheal intubation; it has previously been reported only twice in the medical literature. Choy and Pescod10 described a case of spontaneous pneumothorax during general anesthesia while a patient was breathing spontaneously through a supraglottic airway device. Similar experience was reported by Sandor and Tolas.11 In both cases, the patient responded to surgical stimulation with an episode of cough which preceded the onset of the pneumothorax. Cough may generate intrapleural and intra-alveolar pressures up to 400 cm H2O12 and cause sub-pleural bleb rupture, resulting in a pneumothorax.\n\nOur patient was suffering from sarcoma that is a neoplasm originating from tissue of mesenchymal origin.13 Metastatic soft tissue sarcoma is often exclusively located in the lung. The time from presentation to development of pulmonary metastases is difficult to ascertain. Most patients developed lung metastases within 1 year after presentation. Metastases-free intervals were significantly lower with the increase in the grade of disease.14 Secondary pneumothorax due to metastatic sarcoma is often associated with advanced disease or systemic chemotherapy and these patients have poor prognoses unless promptly treated.1 The incidence of spontaneous pneumothorax is difficult to ascertain from the literature, but several case series report a prevalence in sarcoma of 1.9%.3 The first patient was described by De Barrin in 1937.4 Tariq et al.15 reported a case of simultaneous bilateral spontaneous pneumothorax in a young patient with fibular osteosarcoma. Gan et al.16 described a similar case of a patient with osteosarcoma of the right mandible who developed bilateral pneumothorax. In both cases, the formation of bullae in pulmonary metastases and bilateral pneumothorax was produced after chemotherapy.\n\nIn the literature, several hypotheses were made to understand the pathophysiological mechanism of metastasis-related pneumothorax. Necrosis of metastatic nodules, spontaneous or induced by chemotherapy, may be followed by rupture in the pleural space. Moreover, patients who receive chemotherapy have a higher risk of spontaneous pneumothorax than those who do not.17 It has been hypothesized that pneumothorax was the result of ruptures of the necrotic sub-pleural micrometastasis in patients treated with chemiotherapy.18 Other mechanism may be the compression by neoplastic nodules that determine a valve stenosis mechanism of peripheral bronchi with hyperinflation and subsequent rupture in pleura. Finally, infiltration of a pre-existing benign cysts may be responsible for the development of a solution of continuity of the visceral pleura.1,19\n\nIn our case, at the time of spontaneous pneumothorax, the patient had not yet been undergoing chemotherapy. During the surgery, we used protective mechanical ventilation; it is unlikely that a sub-pleural bleb may rupture at low inflation pressures. Furthermore, whether the development of pneumothorax occurred during ventilation with laryngeal mask, it should have been associated with intraoperative hypoxemia.\n\nThe pneumothorax developed the following day; probably, the irritation of the oropharynx, determined by the supraglottic device, induced the cough that caused the bubbles’ breaking.\n\nIn conclusion, in our patient, pneumothorax is likely due to the progression of the disease with the presence of lung metastases rather than a barotrauma due to general anesthesia. Malignancies, in patient with sarcoma of soft tissue, should be considered in the differential diagnosis of pneumothorax after general anesthesia. We should take into account that supraglottic device could trigger an irritative cough which can cause the sub-pleural bleb rupture.\n\nL.G. and C.R. contributed to the concept; L.G. and A.B. designed the study; L.G. and C.R. performed data collection and/or processing; L.G. performed the literature search; L.G and C.R. wrote the manuscript; and A.B and C.R. performed critical reviews.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient for his anonymized information to be published in this article.\n\nORCID iD: Carlo Rostagno \nhttps://orcid.org/0000-0002-7764-8919\n==== Refs\nReferences\n1 \nFurrer M Althaus U Ris HB. \nSpontaneous pneumothorax from radiographically occult metastatic sarcoma . Eur J Cardiothorac Surg \n1997 ; 11 (6 ): 1171 –1173 .9237605 \n2 \nUpadya A Amoateng-Adjepong Y Haddad RG. \nRecurrent bilateral spontaneous pneumothorax complicating chemotherapy for metastatic sarcoma . South Med J \n2003 ; 96 (8 ): 821 –823 .14515929 \n3 \nHoag JB Sherman M Fasihuddin Q et al \nA comprehensive review of spontaneous pneumothorax complicating sarcoma . Chest \n2010 ; 138 (3 ): 510 –518 .20382720 \n4 \nDe Barrin MJ \nHemopneumothorax spontane dans une metastase pulmonaire de sarcoma osseux . Bul Mem Soc Rad Med Fr \n1937 ; 25 : 73 –76 .\n5 \nNoppen M Schramel F. \nPneumothorax . Eur Respir Rev \n2002 ; 7 : 279 –296 .\n6 \nPetersen GW Baier H. \nIncidence of pulmonary barotraumas in a medical ICU . Crit Care Med \n1983 ; 11 : 67 –69 .6337021 \n7 \nGammon RB Shin MS Buchalter SE. \nPulmonary barotraumas in mechanical ventilation. Patterns and risk factors . Chest \n1992 ; 102 : 568 –572 .1643949 \n8 \nCullen DJ Caldera DL. \nThe incidence of ventilator-induced pulmonary barotrauma in critically ill patients . Anesthesiology \n1979 ; 50 (3 ): 185 –190 .373507 \n9 \nKumar A Pontoppidan H Falke KJ et al \nPulmonary barotraumas during mechanical ventilation . Crit Care Med \n1973 ; 1 : 181 –186 .4587509 \n10 \nChoy MCK Pescod D \nPneumothorax in association with spontaneous ventilation general anesthesia . Anesth Intensive Care \n2007 ; 35 (2 ): 270 –273 .\n11 \nSandor GK Tolas A. \nSpontaneous tension pneumothorax following outpatient general anesthesia . J Oral Maxillofac Surg \n1982 ; 40 (9 ): 596 –600 .6955479 \n12 \nFontana GA. \nMotor mechanisms and the mechanics of cough . In: Chung KF Widdicombe JG Boushey HA (eds) Causes, mechanisms and therapy . Oxford : Blackwell , 2003 , pp. 193 –206 .\n13 \nMason RJ Broaddus VC Murray JF et al \nMurray and Nadel’s textbook of respiratory medicine . 4th ed \nPhiladelphia, PA : Elsevier Saunders , 2005 .\n14 \nSongur N Dinc M Ozdilekcan C et al \nAnalysis of lung metastasis in patients with primary extremity sarcoma . Sarcoma \n2003 ; 7 : 63 –67 .18521370 \n15 \nTariq U Sohail MS Fatima Z et al \nSimultaneous bilateral spontaneous pneumothorax: a rare complication of osteosarcoma . Cureus \n2018 ; 10 (6 ): e2745 .30087821 \n16 \nGan Z Lin S Han K et al \nBilateral spontaneous pneumothorax in an osteosarcoma patient with pulmonary metastases: a case report . Oncol Lett \n2016 ; 11 (2 ): 1179 –1180 .26893715 \n17 \nSmevik B Klepp O. \nThe risk of spontaneous pneumothorax in patients with osteogenic sarcoma and testicular cancer . Cancer \n1982 ; 49 (8 ): 1734 –1737 .6950803 \n18 \nD’Angiò GJ Iannoccone G. \nSpontaneous pneumothorax as a complication to pulmonary metastases in malignant tumors of childhood . Am J Roentgenol Radium Ther Nucl Med \n1961 ; 86 : 1092 –1102 .\n19 \nYamamoto T Mizuno K. \nSpontaneous pneumothorax without any detectable pulmonary metastasis in a patient with osteosarcoma . Int Orthop \n1999 ; 23 (6 ): 361 –362 .10741526\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2050-313X", "issue": "7()", "journal": "SAGE open medical case reports", "keywords": "Pneumothorax; mechanical ventilation; metastatic sarcoma", "medline_ta": "SAGE Open Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101638686", "other_id": null, "pages": "2050313X19833258", "pmc": null, "pmid": "30834120", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "10741526;13882968;14515929;1643949;17444319;18521370;20382720;26893715;30087821;373507;4587509;6337021;6950803;6955479;9237605", "title": "Bilateral pneumothorax after general anesthesia in patient with pleomorphic sarcoma of soft tissue.", "title_normalized": "bilateral pneumothorax after general anesthesia in patient with pleomorphic sarcoma of soft tissue" }

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{ "abstract": "The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5.", "affiliations": "Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.;Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan.;Morinomiya University of Medical Sciences, Osaka, Japan.", "authors": "Higaki|Jitsuo|J|;Komuro|Issei|I|;Shiki|Kosuke|K|;Lee|Ganghyuck|G|;Taniguchi|Atsushi|A|;Ikeda|Hiroshi|H|;Kuroki|Daisuke|D|;Nishimura|Seiichiro|S|;Ogihara|Toshio|T|", "chemical_list": "D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D004338:Drug Combinations; C548840:telmisartan amlodipine combination; D006852:Hydrochlorothiazide; D017311:Amlodipine; D000077333:Telmisartan", "country": "England", "delete": false, "doi": "10.1038/hr.2016.124", "fulltext": "\n==== Front\nHypertens ResHypertens. ResHypertension Research0916-96361348-4214Nature Publishing Group UK London 27761000BFhr201612410.1038/hr.2016.124ArticleEffect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study Higaki Jitsuo [email protected] 1Komuro Issei 2Shiki Kosuke 3Lee Ganghyuck 3Taniguchi Atsushi 3Ikeda Hiroshi 3Kuroki Daisuke 3Nishimura Seiichiro 3Ogihara Toshio 41 grid.255464.40000 0001 1011 3808Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime Japan 2 grid.26999.3d0000 0001 2151 536XDepartment of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo Japan 3 grid.459839.a0000 0004 4678 1308Medical Division, Nippon Boehringer Ingelheim, Tokyo, Japan 4 grid.440914.c0000 0004 0649 1453Morinomiya University of Medical Sciences, Osaka Japan 20 10 2016 20 10 2016 2017 40 3 251 258 20 4 2016 23 7 2016 18 8 2016 © The Author(s) 2017This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5.\n\nSupplementary information\nThe online version of this article (doi:10.1038/hr.2016.124) contains supplementary material, which is available to authorized users.\n\nKeywords\namlodipinecombination therapyhydrochlorothiazidetelmisartanSubject terms\nClinical pharmacologyRandomized controlled trialsHypertensionCombination drug therapyissue-copyright-statement© The Japanese Society of Hypertension 2017\n==== Body\nIntroduction\nAccording to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014), it is estimated that ∼43 million people are affected by hypertension in Japan.1 It is concerning that the number of people with hypertension may continue to increase with aging of the population. In a survey of 4000 hypertensive subjects, the proportion with controlled blood pressure was 34.9% in 2006, and this improved to 50% in 2009; however, blood pressure control remains inadequate.2 Another survey conducted in 3000 subjects in 1994, 2001 and 2010 showed that the mean number of prescribed agents per patient increased gradually from 1.64 in 1994 to 1.79 in 2001 and to 2.04 in 2010.3 For many patients, a combination of two or more treatments, or an increased dose of combination therapy, is required to achieve any antihypertensive effect.1\n\nAngiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors, calcium channel blockers (CCBs) and diuretics are first-line drugs for the management of hypertension.1 CCBs and ARBs lower blood pressure by vasodilating effects. Diuretics increase the excretion of excess water and sodium, thereby decreasing peripheral vascular resistance.\n\nAmong these first-line drugs, ARB/CCB combination therapy is widely used for hypertensive patients as a second-line treatment. In a phase III study, a combined antihypertension treatment containing 80 mg of the ARB telmisartan and 5 mg of the CCB amlodipine (Micamlo combination tablets BP; Nippon Boehringer Ingelheim) reduced diastolic blood pressure (DBP) to ⩽90 mm Hg in 70.1% of patients compared with 41.5% of patients taking telmisartan monotherapy (data on file, Nippon Boehringer Ingelheim, Tokyo, Japan).\n\nFor patients with hypertension refractory to ARB/CCB, the use of an additional antihypertensive drug with a different mode of action, such as a low dose of a diuretic, is recommended.1 However, diuretics are infrequently used to treat Japanese hypertensive patients. We designed this study to determine the effects of adding the diuretic hydrochlorothiazide to an ARB/CCB combination therapy.\n\nThe aim of this prospective, randomized, double-blind, active-control, parallel-group comparison study was to examine the efficacy and safety of telmisartan (80 mg), amlodipine (5 mg) and hydrochlorothiazide (12.5 mg) (T80/A5/H12.5) for the treatment of hypertensive patients whose hypertension is uncontrolled with telmisartan (80 mg) and amlodipine (5 mg) (T80/A5).\n\nMaterials and Methods\nPatients\nJapanese patients aged ⩾20 years were enrolled in this study if they had essential hypertension, were already taking two or three antihypertensive drugs (at the time of the visit for signing the informed consent form), had a mean (of three measurements in one visit) seated DBP ⩾90 and ⩽114 mm Hg at week −6 and week 0 (see Figure 1 for details of visits), had a mean seated systolic blood pressure (SBP) ⩽200 mm Hg at week −6 and week 0, were an outpatient, were able to stop all current antihypertensive drugs (other than study medication) from week −6 through to the end of the study without risk and if they provided informed consent. Patients were excluded if they had any of the following: known or suspected secondary hypertension, cardiac disorders, a history of stroke or transient ischemic attack within the past 6 months, hepatic or renal dysfunctions, biliary atresia or cholestasis, hyperkalemia, anuria or blood dialysis, hyponatremia, malignant tumor or a disease requiring immunosuppressants. Patients were also excluded if they were <80% or >120% compliant during the run-in period. The study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was acquired from all institutional review boards and all patients provided written informed consent that they were free to withdraw at any time during the study.Figure 1 Study design. DBP, diastolic blood pressure; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg/amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\n\n\nPrescribed treatments for concomitant diseases, except for those known to affect blood pressure, were not discontinued during the study. Patient compliance was measured at each visit by counting the number of tablets returned to the investigation and calculating the percentage of medication taken in relation to the amount that should have been taken.\n\nStudy design\nThis study was designed as an 8-week, multicenter (30 sites), randomized, double-blind, active-control, parallel-group comparative phase III clinical study conducted between 8 November 2013 and 12 July 2014 to verify the superiority of T80/A5/H12.5 over T80/A5 for the reduction in blood pressure. Patients entered a 6-week open-label run-in period that involved the oral administration of a once-daily T80/A5 fixed-dose combination tablet. At the end of the run-in period (week 0), patients whose trough-seated DBP remained ⩾90 mm Hg after treatment with T80/A5 were randomly assigned to one of two groups: once-daily, orally administered T80/A5 fixed-dose combination tablet+H12.5 (T80/A5/H12.5) or T80/A5 fixed-dose combination tablet+placebo (T80/A5). The treatment period lasted 8 weeks (Figure 1). Randomization and appropriate supply of study medication to patients was performed using Interactive Response Technology.\n\nStudy endpoints\nEfficacy\nThe primary endpoint of this study was the reduction from the reference baseline in mean seated DBP at trough after 8 weeks of the double-blind period. The key secondary endpoint was the reduction from the reference baseline in mean seated SBP at trough after 8 weeks of the double-blind period. The other secondary endpoint was the proportion of patients with seated DBP <90 mm Hg and seated SBP <140 mm Hg at trough after 8 weeks of the double-blind period. Other endpoints included the seated DBP control rate (percentage of patients with DBP <90 mm Hg) and SBP control rate (percentage of patients with SBP <140 mm Hg) at trough after 8 weeks of the double-blind period and seated DBP response rate (percentage of patients with DBP <90 mm Hg or a reduction in DBP of ⩾10 mm Hg) and SBP response rate (percentage of patients with SBP <140 mm Hg or a reduction in SBP of ⩾20 mm Hg) at trough after 8 weeks of the double-blind period from the reference baseline.\n\nBlood pressure and heart rate measurements\nAll blood pressure measurements were taken with a standard mercury sphygmomanometer, recorded on the same arm by the same operator where possible. Blood pressure and pulse rate at trough were measured ∼24 h (±3 h) after the last dose of the study drugs on the previous day. Seated blood pressure was calculated as the mean of three measurements.\n\nSeated blood pressure and pulse rate were measured at weeks −6, 0, 4 and 8. Blood pressure and pulse rate were measured in seated, supine and standing positions at weeks −6, 0 and 8. DBP was taken at the disappearance of repetitive sound (Korotkoff phase 5). In those in whom the sound continued until the zero point, the blood pressure at the distinct muffling of the repetitive sounds (Korotkoff phase 4) was to be recorded as the DBP.\n\nSafety\nTo ensure the safety of the study participants, the parameters were analyzed during the study, while maintaining blind, to identify potential safety concerns, including the incidence of adverse events, changes in blood pressure and pulse rate following position change, seated pulse rate and general laboratory tests (blood biochemistry, hematology and urinalysis).\n\nStatistical analyses\nThe sample size of 300 (150 per group; allocation ratio 1:1) was determined to achieve superiority of the T80/A5/H12.5 group to the T80/A5 group with two-sided significance level of 5% and power of >80% provided that the seated DBP reduction would differ between treatment groups by 2.8 mm Hg with s.d. of 8.5 mm Hg.\n\nIn this study, three analysis sets were defined for analyzing data, including the treated set, the full analysis set (FAS) and the per-protocol set (PPS). The treated set was defined as all patients (1) randomly assigned to one of two treatment groups and (2) taking at least one dose of T80/A5/H12.5 or T80/A5. The FAS was defined as all patients (1) included in the treated set and (2) taking measurements of seated DBP at reference baseline and at one or more time points during the double-blind period. The PPS was defined as a collection of patients (1) included in the FAS and (2) observing no important protocol violation that might affect the efficacy evaluation during the double-blind period.\n\nFor the primary and key secondary endpoints, an analysis of covariance (ANCOVA) was performed on the FAS to analyze the blood pressure reduction after 8 weeks of treatment in the T80/A5/H12.5 and T80/A5 groups. The model includes treatment and center as fixed effects, and reference baseline as a covariate. The last observation carried forward (LOCF) approach was used to impute missing data. The treatment effect was tested and estimated by the adjusted mean and its 95% confidence interval (CI) obtained from the model. The sensitivity analyses were performed using an ANCOVA on the PPS, and using mixed-effects model repeated measures (MMRM) on the FAS without the LOCF approach. The other secondary endpoint and other endpoints, including the proportion of patients with trough-seated DBP/SBP ⩽90/140 mm Hg, DBP/SBP control rates and DBP/SBP response rates after 8 weeks of the double-blind period, were analyzed by treatment group and compared between groups using logistic regression analysis with noncompleters considered failure imputation. (Clinical trial registration: NCT01975246.)\n\nResults\nPatients\nWe enrolled 442 male and female Japanese patients in this study. Of these, 309 patients had uncontrolled blood pressure despite treatment with T80/A5 during the run-in period (Figure 2). The study population consisted predominantly of males (83.2%) and people aged <65 years (85.4%), with the mean (s.d.) age of all patients being 54.7 (9.4) years (Table 1). The majority of patients had hypertension severity grade I or II (72.8% and 24.6%, respectively) according to JSH 2014.1 The mean (s.d.) body mass index of the study population was 26.92 (4.34) kg m−2 and the mean (s.d.) waist circumference was 92.90 (10.76) cm. In total, 73.8% of the treated patients had abdominal obesity. Overall, of the 309 patients in the treated set, 93.5% had at least one concomitant diagnosis; the most frequent was metabolic and nutrition disorders (72.2%), followed by hepatobiliary disorders (27.8%).Figure 2 Patient disposition. AE, adverse event; T80/A5, telmisartan 80 mg+amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\nTable 1 Demographic and reference baseline characteristics of the treated set\n\n\tT80/A5/H12.5\tT80/A5\tTotal\t\nN\t149\t160\t309\t\nGender, N (%)\t\n Male\t127 (85.2)\t130 (81.3)\t257 (83.2)\t\n Female\t22 (14.8)\t30 (18.8)\t52 (16.8)\t\nAge, years\t\n Mean (s.d.)\t54.4 (9.1)\t55.0 (9.7)\t54.7 (9.4)\t\n Median (range)\t54.0 (27–80)\t54.5 (30–83)\t54.0 (27–83)\t\nAge, N (%)\t\n <65 Years\t130 (87.2)\t134 (83.8)\t264 (85.4)\t\n ⩾65 Years\t19 (12.8)\t26 (16.3)\t45 (14.6)\t\nReference baseline BMI, kg m−2\t\n Mean (s.d.)\t27.10 (4.16)\t26.76 (4.51)\t26.92 (4.34)\t\n Median (range)\t26.96 (17.5–44.6)\t26.12 (16.8–43.8)\t26.66 (16.8–44.6)\t\nBMI, N (%)\t\n <25.0 kg m−2\t46 (30.9)\t67 (41.9)\t113 (36.6)\t\n ⩾25.0 To <30.0 kg m−2\t70 (47.0)\t60 (37.5)\t130 (42.1)\t\n ⩾30.0 kg m−2\t33 (22.1)\t33 (20.6)\t66 (21.4)\t\nAbdominal obesitya, N (%)\t\n No\t34 (22.8)\t47 (29.4)\t81 (26.2)\t\n Yes\t115 (77.2)\t113 (70.6)\t228 (73.8)\t\nReference baseline blood pressure (mm Hg)\t\n DBP mean (s.d.)\t96.5 (5.6)\t95.7 (5.1)\t96.1 (5.3)\t\n SBP mean (s.d.)\t142.3 (12.9)\t142.3 (12.1)\t142.3 (12.4)\t\nDuration of hypertension, N (%)\t\n ⩽1 Year\t11 (7.4)\t5 (3.1)\t16 (5.2)\t\n >1–5 Years\t36 (24.2)\t44 (27.5)\t80 (25.9)\t\n >5–10 Years\t46 (30.9)\t43 (26.9)\t89 (28.8)\t\n >10 Years\t56 (37.6)\t68 (42.5)\t124 (40.1)\t\nHypertension severityb\nat reference baseline, N (%)\t\n Grade I\t107 (71.8)\t118 (73.8)\t225 (72.8)\t\n Grade II\t36 (24.2)\t40 (25.0)\t76 (24.6)\t\n Grade III\t5 (3.4)\t2 (1.3)\t7 (2.3)\t\n Missing\t1 (0.7)\t0 (0.0)\t1 (0.3)\t\neGFR (ml min−1\n1.73 m−2), N (%)\t\n ⩾90 (Normal)\t24 (16.1)\t32 (20.0)\t56 (18.1)\t\n ⩾60 To <90 (mild)\t109 (73.2)\t104 (65.0)\t213 (68.9)\t\n ⩾30 To <60 (moderate)\t16 (10.7)\t24 (15.0)\t40 (12.9)\t\n <30 (Severe)\t0 (0.0)\t0 (0.0)\t0 (0.0)\t\nConcomitant diagnoses, N (%)\t137 (91.9)\t152 (95.0)\t289 (93.5)\t\nNumber of previous antihypertensives used, N (%)\t\n Two\t125 (83.9)\t129 (80.6)\t254 (82.2)\t\n Three\t24 (16.1)\t31 (19.4)\t55 (17.8)\t\nAbbreviations: BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg/amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\naAbdominal obesity: Yes= reference baseline waist circumference >85 cm (male) and >90 cm (female).\n\nbHypertension severity: grade I=seated SBP 140 to <160 mm Hg or seated DBP 90 to <100 mm Hg; Grade II=seated SBP 160 to <180 mm Hg or seated DBP 100 to <110 mm Hg; Grade III=seated SBP ⩾180 mm Hg or seated DBP ⩾110 mm Hg.\n\n\n\nIn accordance with the inclusion criteria, patients were previously treated with two (82.2%) or three (17.8%) antihypertensive drugs. In 74.4% of patients, this consisted of an ARB and a CCB, and for 10.7% it consisted of an ARB, a CCB and a diuretic. The mean (s.d.) seated DBP at reference baseline was 96.5 (5.6) mm Hg and 95.7 (5.1 mm Hg) in the T80/A5/H12.5 and the T80/A5 groups, respectively. The mean seated SBP at reference baseline was 142.3 (12.9) and 142.3 (12.1) mm Hg in the T80/A5/H12.5 and the T80/A5 groups, respectively. In general, the demographic and reference baseline characteristics of both groups were similar (Table 1).\n\nThe disposition of the study patients is shown in Figure 2. Of the 442 enrolled patients, 393 entered the run-in period and 49 were excluded, largely because of violations of the inclusion/exclusion criteria. Following the run-in period, 309 patients were randomly assigned to T80/A5/H12.5 (N=149) and T80/A5 (N=160) groups and 84 were excluded, mainly because of not meeting the blood pressure inclusion/exclusion criteria. Of the 309 patients who entered the treatment period, 303 (98.1%) patients completed the 8-week treatment period, and the proportion of patients who completed the study was similar between groups (145 [97.3%] and 158 [98.8%] for the T80/A5/H12.5 and T80/A5 groups, respectively). The most frequent cause for discontinuation was adverse events that occurred in 2 (1.3%) and 1 (0.6%) patients in the T80/A5/H12.5 and T80/A5 groups, respectively (Figure 2).\n\nDBP change\nAfter 8 weeks of treatment, the adjusted mean (s.e.) reduction in trough-seated DBP was 8.4 (0.6) mm Hg in the T80/A5/H12.5 group compared with 4.5 (0.5) mm Hg in the T80/A5 group in the FAS (ANCOVA with LOCF). The T80/A5/H12.5 group showed a statistically significantly greater adjusted mean reduction in seated DBP compared with the T80/A5 treatment group, with a difference of −3.9 mm Hg (95% CI: −5.3 to −2.4; P<0.0001). Figure 3a shows the results of a sensitivity analysis performed using a MMRM on the FAS that provided results that were consistent with those of the primary analysis. An ANCOVA on the PPS also provided results consistent with those of the primary analysis. In addition, the adjusted mean (s.e.) change from reference baseline in trough-seated DBP at week 4 based on the MMRM analysis was −6.6 (0.5) mm Hg in the T80/A5/H12.5 group and −3.2 (0.5) mm Hg in the T80/A5 group. Compared with T80/A5, T80/A5/H12.5 had a greater reduction in trough-seated DBP, with a treatment difference of −3.5 mm Hg (95% CI: −4.8 to −2.1; P<0.0001). These data indicate that treatment with the combination T80/A5/H12.5 achieved a superior reduction in seated DBP compared with treatment with T80/A5.Figure 3 Change in trough-seated DBP and SBP from reference baseline using a mixed-effects model for repeated measures on the full analysis set with no imputation. (a) Adjusted mean change in DBP compared with reference baseline at 4 and 8 weeks for both treatment groups in the FAS. (b) Adjusted mean change in SBP compared with reference baseline at 4 and 8 weeks of treatment for both treatment groups in the FAS. DBP, diastolic blood pressure; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg+amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg+amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\n\n\nSBP change\nFollowing 8 weeks of treatment, the adjusted mean (s.e.) reduction in trough-seated SBP was 12.3 (0.8) mm Hg in the T80/A5/H12.5 group compared with 6.9 (0.8) mm Hg in the T80/A5 group in the FAS (ANCOVA with LOCF). The T80/A5/H12.5 group showed a statistically significantly greater adjusted mean reduction in SBP compared with the T80/A5 group, with a difference of −5.3 mm Hg (95% CI: −7.6 to −3.1; P<0.0001). The sensitivity analysis, including a MMRM analysis on the FAS (Figure 3b), provided results that were consistent with those of the primary analysis. Furthermore, the adjusted mean (s.e.) change from reference baseline in trough-seated SBP at week 4 based on the MMRM analysis was −9.7 (0.8) mm Hg in the T80/A5/H12.5 group and −5.2 (0.8) mm Hg in the T80/A5 group. Compared with the T80/A5 group, the T80/A5/H12.5 group had a greater reduction in trough-seated SBP, with a treatment difference of −4.5 mm Hg (95% CI: −6.6 to −2.3; P<0.0001; MMRM analysis; Figure 3b). These data indicate that treatment with the combination T80/A5/H12.5 achieved a superior reduction in SBP compared with treatment with T80/A5.\n\nOther outcomes\nFollowing 8 weeks of treatment, the proportion of patients who achieved a trough-seated DBP/SBP of <90/140 mm Hg was 51.7% in the T80/A5/H12.5 group and 36.9% in the T80/A5 group (Table 2). Based on logistic regression analysis, patients in the T80/A5/H12.5 group were estimated to be 2.1 times more likely to achieve a DBP/SBP of <90/140 mm Hg than were patients in the T80/A5 group (95% CI: 1.2 to 3.4). In addition, more patients achieved trough-seated DBP control (DBP <90 mm Hg) in the T80/A5/H12.5 group than in the T80/A5 group (Table 2). The probability of achieving DBP control at week 8 was estimated to be 1.9 times higher in the T80/A5/H12.5 group than in the T80/A5 group (95% CI: 1.2 to 3.2) on the basis of a logistic regression analysis.Table 2 DBP and SBP control rates and response rates in the full analysis set\n\n\t\tT80/A5/H12.5\tT80/A5\t\t\t\nEndpoint\tWeek\tN\tn\t(%)\tN\tn\t(%)\tORa\t95% CI\t\nDBP control\t4\t147\t70\t47.6\t160\t47\t29.4\t2.4\t(1.5–4.1)\t\n\t8\t\t83\t56.5\t\t68\t42.5\t1.9\t(1.2–3.2)\t\nSBP control\t4\t76\t37\t48.7\t89\t27\t30.3\t2.3\t(1.2–4.8)\t\n\t8\t\t48\t63.2\t\t40\t44.9\t2.5\t(1.2–5.3)\t\nDBP <90 mm Hg or decrease by 10 mm Hg\t4\t147\t80\t54.4\t160\t49\t30.6\t3.0\t(1.8–5.0)\t\n8\t\t98\t66.7\t\t72\t45.0\t2.8\t(1.7–4.8)\t\t\nSBP <140 mm Hg or decrease by 20 mm Hg\t4\t76\t41\t53.9\t89\t30\t33.7\t2.4\t(1.2–4.8)\t\n8\t\t54\t71.1\t\t40\t44.9\t4.1\t(1.9–9.1)\t\t\nDBP/SBP <90/140 mm Hg\t4\t147\t66\t44.9\t160\t39\t24.4\t2.9\t(1.7–5.1)\t\n8\t\t76\t51.7\t\t59\t36.9\t2.1\t(1.2–3.4)\t\t\nAbbreviations: CI, confidence interval; DBP, diastolic blood pressure; OR, odds ratio; SBP, systolic blood pressure; T80/A5, telmisartan 80 mg/amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg/amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\nOnly patients in the full analysis set with a trough-seated DSB of ⩾90 mm Hg or a SBP of ⩾140 mm Hg at reference baseline were included in the analysis.\n\naFor T80/A5/H12.5 vs. T80/A5.\n\n\n\nOf the patients within the FAS who had SBP ⩾140 mm Hg at reference baseline, a greater portion achieved trough-seated SBP control (SBP <140 mm Hg) by week 8 in the T80/A5/H12.5 group compared with patients in the T80/A5 group (Table 2). The probability of achieving SBP control at week 8 was estimated to be 2.5 times higher in the T80/A5/H12.5 group than in the T80/A5 group (95% CI: 1.2 to 5.3) on the basis of a logistic regression analysis. Furthermore, the proportion of patients who had an adequate response in trough-seated DBP (DBP <90 mm Hg or a reduction in DBP of ⩾10 mm Hg) at week 8 was larger in the T80/A5/H12.5 group than in the T80/A5 group. Of the patients within the FAS who had SBP ⩾140 mm Hg at reference baseline, more had an adequate response in trough-seated SBP (SBP <140 mm Hg or a reduction in SBP of ⩾20 mm Hg) at week 8 in the T80/A5/H12.5 group than in the T80/A5 group.\n\nSubgroup analysis\nWithin the treatment groups, patients were divided into subgroups based on patient characteristics, including age (<65, ⩾65 years), sex, body mass index (<25, 25–<30 and ⩾30 kg m−2), hypertension severity, hypertension duration (⩽1, >1–5, >5–10 and >10 years) and the number of previous antihypertension drugs used (two or three). The reductions in both DBP and SBP in each subgroup tended to be greater in patients treated with T80/A5/H12.5 than in patients treated with T80/A5 (Supplementary Tables 1 and 2).\n\nSafety\nAdverse events and laboratory findings\nThe number of patients who experienced adverse events during the double-blind 8-week period was higher in the T80/A5/H12.5 group (41.6%) than in the T80/A5 group (28.1%) (Table 3). The most common adverse events were increased blood uric acid levels, nasopharyngitis and hyperuricemia. Higher incidences in the T80/A5/H12.5 group compared with the T80/A5 group were seen for increased blood uric acid levels and hyperuricemia.Table 3 Summary of AEs and frequency of drug-related AEs experienced by ⩾1% of the patients in any one of the treatment groups in the treated set\n\n\tT80/A5/H12.5\tT80/A5\t\nVariable\tN\t%\tN\t%\t\nNumber of patients\t149\t100\t160\t100\t\nPatients with an AE\t62\t41.6\t45\t28.1\t\nPatients with investigator-defined drug-related AEs\t35\t23.5\t6\t3.8\t\nPatients with other significant AEs\t2\t1.3\t1\t0.6\t\nPatients with AEs leading to discontinuation\t2\t1.3\t1\t0.6\t\nSystem organ class and preferred term\t\n Metabolic and nutrition disorders\t10\t6.7\t1\t0.6\t\n Hyperuricemia\t8\t5.4\t1\t0.6\t\n Dyslipidemia\t2\t1.3\t0\t0.0\t\n Investigations (laboratory data abnormalities)\t21\t14.1\t4\t2.5\t\n Blood uric acid increased\t20\t13.4\t3\t1.9\t\n Blood creatinine increased\t2\t1.3\t0\t0.0\t\n Blood urea increased\t2\t1.3\t0\t0.0\t\nAbbreviations: AE, adverse event; T80/A5, telmisartan 80 mg+amlodipine 5 mg; T80/A5/H12.5, telmisartan 80 mg+amlodipine 5 mg+hydrochlorothiazide 12.5 mg.\n\n\n\nThe frequencies of drug-related adverse events are shown in Table 3. The incidences of drug-related adverse events were higher in the T80/A5/H12.5 group (23.5%) compared with the T80/A5 group (3.8%). This difference in the number of drug-related adverse events was largely because of the higher incidence of increased uric acid levels in the T80/A5/H12.5 group compared with the T80/A5 group (13.4% vs. 1.9%).\n\nIndeed, regarding laboratory parameters (Supplementary Table 3), noteworthy differences between groups were observed for the mean change from reference baseline in uric acid (1.0 mg dl−1 in the T80/A5/H12.5 group vs. 0.2 mg dl−1 in the T80/A5 group). In patients who had no abnormalities at reference baseline, possible clinically relevant abnormalities included the development of high triglycerides and high total cholesterol that were detected in 11.2% and 4.3% of patients in the T80/A5/H12.5 group, respectively, and 7.3% and 5.9% of the patients in the T80/A5 group, respectively.\n\nThe adverse events experienced by patients were mild or moderate in severity and no severe adverse events or deaths were reported in either treatment group. Two patients in the T80/A5/H12.5 group discontinued the study because of adverse events: atrial fibrillation and tachycardia (one patient) and hypotension (one patient). In the T80/A5 group, one patient discontinued because of ventricular extrasystoles. For all three patients, the adverse events were mild in intensity.\n\nAdherence\nThe overall compliance during the double-blind period was >80% in both treatment groups; 2 (1.3%) of the 149 patients in the T80/A5/H12.5 group and none of the 160 patients in the T80/A5 group had a compliance rate of <80%.\n\nVital signs and other safety parameters\nFollowing the 8-week treatment period, no clinically relevant changes in DBP, SBP or pulse rate following a position change were detected in either group compared with reference baseline. Furthermore, the seated pulse rate and pulse rate after a position change remained relatively unchanged at week 8 (Supplementary Table 4). Overall, both T80/A5/H12.5 and T80/A5 were well tolerated.\n\nDiscussion\nHypertension is a disease with a high incidence in Japan. The currently used monotherapies, including ARBs, CCBs and diuretics, are effective only in a limited proportion of patients. For those who remain resistant to therapy, a combination of antihypertensive agents is required.1 The aim of this study was to investigate the efficacy and safety of a combination of T80/A5/H12.5 for the treatment of hypertension in patients with an inadequate response to telmisartan 80 mg and amlodipine 5 mg. The results indicate that the T80/A5/H12.5 group achieved significantly greater reductions in seated DBP and SBP relative to those achieved in the T80/A5 group. In addition, significantly more patients achieved DBP and SBP control in the T80/A5/H12.5 group compared with patients treated with T80/A5.\n\nThe adverse events reported in this study were mild or moderate in severity, and those events were already observed in those receiving monotherapy or two-agent combination therapy. The incidence of drug-related adverse events was higher in the T80/A5/H12.5 group than in the T80/A5 group. The frequent drug-related adverse events in the T80/A5/H12.5 group were elevated uric acid levels and hyperuricemia. The cause of the increase in uric acid can likely be explained by the addition of hydrochlorothiazide, because elevated uric acid is a common side effect of diuretics.4 These adverse events were manageable and did not pose a health risk.\n\nIn this study, each patient received two tablets: T80/A5 fixed-dose combination and H12.5 or T80/A5 fixed-dose combination and placebo. It is possible that a single tablet T80/A5/H12.5 combination treatment would improve patient adherence. Previous studies reported that the fixed combination of valsartan/amlodipine/hydrochlorothiazide or olmesartan/amlodipine/hydrochlorothiazide improved adherence and persistence compared with administration of each drug as individual tablets.5, 6, 7 This suggests that the fixed combination of T80/A5/H12.5 may increase the adherence relative to a combination of three individual treatments.\n\nA similarly designed study of a combination of losartan 50 mg, hydrochlorothiazide 12.5 mg and amlodipine 5 mg compared with coadministration of losartan 50 mg plus amlodipine 5 mg in Japanese patients with essential hypertension did not demonstrate a significant difference in DBP reduction with hydrochlorothiazide 12.5 mg at week 8 (additional effect of −1.1 mm Hg; 95% CI: −2.7 to 0.6; P=0.205).8 However, there was a significant additional effect of hydrochlorothiazide 12.5 mg on SBP reduction at week 8 (−3.2 mm Hg; −5.7 to −0.8; P=0.011).8 The difference between the results of the losartan study and ours is possibly because of the profile of ARBs, that is, usual dosage range, terminal half-life and volume of distribution.9 The high-dose ARB with a large volume of distribution is suitable to completely inhibit the renin–angiotensin system activated by CCBs and diuretics.10 Among ARBs, telmisartan is a long-acting antihypertensive drug that may provide sustained reductions in blood pressure throughout a 24-h dosing period.9, 11\n\nThe results of this study should be considered in light of its limitations. The main limitation of this study was that the mean age of the patients was 54.7 years and only 14.6% of patients were ⩾65 years old. Therefore, the efficacy and safety profiles of T80/A5/H12.5 in older patients could not be determined. The study was also only conducted in institutions within Japan, and hence the results are not generalizable to populations of other ethnicities. Another limitation was the short duration of the study, as 8 weeks may not have been sufficient to observe the full benefit provided by the combination therapy, or the benefits may have been reduced over a longer period. Finally, we did not include patients with severe impaired kidney function (estimated glomerular filtration rate <30 ml min−1 1.73 m−2) who may also require combination therapies to manage hypertension.\n\nConclusions\nThe results from this phase III study indicate that the combination of telmisartan, amlodipine and hydrochlorothiazide is more effective than that of only telmisartan and amlodipine at reducing blood pressure in hypertensive patients. The addition of hydrochlorothiazide to a ARB/CCB combination therapy provides clinicians with a suitable treatment option for patients unresponsive to ARB/CCB combinations. This triple combination therapy is effective and well tolerated.\n\nSupplementary information\n\nSupplementary Information (DOC 268 kb)\n\n \n\n\nSupplementary Information accompanies the paper on Hypertension Research website\n\nAcknowledgements\nWe thank all investigators involved in this study: Shinichi Higashiue, MD (Kishiwada Tokushukai Hospital, Cardiovascular Surgery, Osaka, Japan); Kousuke Mabuchi, MD (Kanda Clinic, Internal Medicine, Tokyo, Japan); Shigeo Sawai, MD (Sawai Medical Clinic, Internal Medicine, Tokyo, Japan); Fumiki Oh, MD (Shinden Higashi Clinic, Internal Medicine, Miyagi, Japan); Isao Uchimura, MD (Chiyodahoujin Clinic, Internal Medicine, Tokyo, Japan); Masafumi Sugawara, MD (Dynamedical Nezu Clinic, Internal Medicine, Tokyo, Japan); Yoshihiro Tokeshi, MD (Chubu Tokushukai Hospital, Internal Medicine, Okinawa, Japan); Satoshi Inoue, MD (OCROM Clinic, Osaka, Japan); Katsuji Hashimoto, MD (AMC Nishiumeda Clinic, Internal Medicine, Osaka, Japan); Yoji Takatsuka, MD (Motomachi Takatsuka Naika Clinic, Internal Medicine, Kanagawa, Japan); Hiroshi Shimomura, MD (Musashino Polyclinic, Internal Medicine, Tokyo, Japan); Kazuko Takahashi, MD (Takahashi Clinic, Internal Medicine, Hokkaido, Japan); Fumihiko Takeda, MD (Riverside clinic, Internal Medicine, Hokkaido, Japan); Sohji Nagase, MD (Nagase Medical Clinic, Internal Medicine, Ibaraki, Japan); Toru Kihara, MD (Fukuoka Rehabilitation Hospital, Internal Medicine, Fukuoka, Japan); Toshiki Fukui, MD (NTT West Takamatsu Hospital, Internal Medicine, Kagawa, Japan); Takafumi Kondo, MD (Kaisei Hospital, Internal Medicine, Kagawa, Japan); Arihiro Kiyosue, MD (Tokyo-Eki Center-building Clinic, Internal Medicine, Tokyo, Japan); Takahiko Tokuyama, MD (Tokuyama Clinic, Internal Medicine, Chiba, Japan); Akira Numata, MD (Ikebukuro Metropolitan Clinic, Internal Medicine, Tokyo, Japan); Atsushi Hirayama, MD (Nihon University Itabashi Hospital, Division of Cardiovascular Medicine, Tokyo, Japan); Hideki Takizawa, MD (Teine Keijinkai Clinic, Kidney Internal Medicine, Hokkaido, Japan); Teruaki Mita, MD (Mita Internal Medicine Cardiology Clinic, Internal Medicine, Hokkaido, Japan); Chiaki Noguchi, MD (Shinkoiwa Ekimae Clinic, Internal Medicine, Tokyo, Japan); Yuichiro Nakamura, MD (Nakamura Cardiovascular Clinic, Cardiovascular Medicine, Fukuoka, Japan); Norimasa Sato, MD (Umeda Oak Clinic, Internal Medicine, Osaka, Japan); Takayuki Azuma, MD (Yaesu Sakura-dori Clinic, Internal Medicine, Tokyo, Japan); Nobuaki Onizawa, MD (Kaijo Bill Clinic, Internal Medicine, Tokyo, Japan); Koichi Yamamoto, MD (Osaka University Hospital, Presbyo-hypertension, Osaka, Japan); Yoshinori Seko, MD (The Institute for Adult Diseases, Asahi Life Foundation, Cardiovascular Internal Medicine, Tokyo, Japan). Treatments were developed by Nippon Boehringer Ingelheim. This study was funded by Nippon Boehringer Ingelheim. We thank Mami Mori of Nippon Boehringer Ingelheim for publication management and editorial support, and John Gibbins of Edanz Group for providing medical writing support. This medical writing assistance was funded by Nippon Boehringer Ingelheim.\n\nCompeting interests\nJH received consulting and lecture fees and/or research funding from Astellas Pharmaceutical, Nippon Boehringer Ingelheim, Mochida Pharmaceutical, Daiichi Sankyo, Sumitomo Dainippon Pharmaceutical, MSD, Novartis Pharmaceutical, Teijin Pharmaceutical and Takeda Pharmaceutical. IK has received lecture fees, research funding and/or scholarship grants from Daiichi Sankyo, Sumitomo Dainippon Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Astellas Pharmaceutical, Teijin Pharmaceutical, Sanofi, Kowa Company, Bayel Yakuhin and TOA EIYO. TO declares no conflict of interest. JH and IK were the Medical Experts and TO was the Coordinating Investigator of this study. KS, GL, AT, HI, DK and SN are employees of Nippon Boehringer Ingelheim.\n==== Refs\nReferences\n1 Shimamoto K Ando K Fujita T Hasebe N Higaki J Horiuchi M Imai Y Imaizumi T Ishimitsu T Ito M Ito S Itoh H Iwao H Kai H Kario K Kashihara N Kawano Y Kim-Mitsuyama S Kimura G Kohara K Komuro I Kumagai H Matsuura H Miura K Morishita R Naruse M Node K Ohya Y Rakugi H Saito I Saitoh S Shimada K Shimosawa T Suzuki H Tamura K Tanahashi N Tsuchihashi T Uchiyama M Ueda S Umemura S Japanese Society of Hypertension Committee for Guidelines for the Management of Hypertension The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014) Hypertens Res 2014 37 253 390 10.1038/hr.2013.80 24705419 \n2 Teramoto T Toshiro F Japan guideline assessment panel-2 (J-GAP2) Prog Med (Tokyo) 2010 30 1437 1449 \n3 Nakagawa M Masuda A Ura N Tanaka S Transition of achievement rate for lowering blood pressure target level and situation of prescription for antihypertensive drug J Blood Press 2011 18 73 77 \n4 Moore MJ Gong Y Hou W Hall K Schmidt SOF Curry RW Beitelshees AL Chapman A Turner ST Schwartz GL Bailey K Boerwinkle E Gums JG Cooper-DeHoff RM Johnson JA Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide Pharmacotherapy 2014 34 1132 1140 10.1002/phar.1483 25202885 \n5 Oparil S Melino M Lee J Fernandez V Heyrman R Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: the TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study Clin Ther 2010 32 1252 1269 10.1016/j.clinthera.2010.07.008 20678674 \n6 Mohan JC Jain R Chamle V Bhargava A Short term safety and tolerability of a fixed dose combination of olmesartan, amlodipine and hydrochlorothiazide J Clin Diagn Res 2015 9 OC10 OC13 26435982 \n7 Machnicki G Ong SH Chen W Wei ZJ Kahler KH Comparison of amlodipine/valsartan/hydrochlorothiazide single pill combination and free combination: adherence, persistence, health care utilization and costs Curr Med Res Opin 2015 31 2287 2296 10.1185/03007995.2015.1098598 26397178 \n8 Rakugi H Tsuchihashi T Shimada K Numaguchi H Nishida C Yamaguchi H Shirakawa M Azuma K Fujita KP Add-on effect of hydrochlorothiazide 12.5 mg in Japanese subjects with essential hypertension uncontrolled with losartan 50 mg and amlodipine 5 mg Hypertens Res 2015 38 329 335 10.1038/hr.2015.3 25716649 \n9 Chrysant SG Chrysant GS Desai A Current status of angiotensin receptor blockers for the treatment of cardiovascular diseases: focus on telmisartan J Hum Hypertens 2005 18 172 183 \n10 Konoshita TM Makino Y Kimura T Fuji M Wakahara S Arakawa K Inoki I Nakamura H Miyamori I Genomic Disease Outcome Consortium (G-DOC) Study Investigators A new-generation N/L-type calcium channel blocker leads to activation of the renin-angiotensin system compared with conventional L type calcium channel blocker J Hypertens 2010 28 2156 2160 10.1097/HJH.0b013e32833d01dd 20625317 \n11 Neutel J Smith DH Evaluation of angiotensin II receptor blockers for 24-hour blood pressure control: meta-analysis of a clinical database J Clin Hypertens 2003 5 58 63 10.1111/j.1524-6175.2003.01612.x\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0916-9636", "issue": "40(3)", "journal": "Hypertension research : official journal of the Japanese Society of Hypertension", "keywords": null, "medline_ta": "Hypertens Res", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017311:Amlodipine; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006973:Hypertension; D008297:Male; D008875:Middle Aged; D000077333:Telmisartan; D016896:Treatment Outcome", "nlm_unique_id": "9307690", "other_id": null, "pages": "251-258", "pmc": null, "pmid": "27761000", "pubdate": "2017-03", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": "26397178;12556655;20625317;26435982;25716649;25202885;24705419;20678674;15660122", "title": "Effect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study.", "title_normalized": "effect of hydrochlorothiazide in addition to telmisartan amlodipine combination for treating hypertensive patients uncontrolled with telmisartan amlodipine a randomized double blind study" }

[ { "companynumb": "JP-ALLERGAN-1819281US", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "020504", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12.5 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE UNK" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE\\TELMISARTAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "5+80 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ESSENTIAL HYPERTENSION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE W/TELMISARTAN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIGAKI J, KOMURO I, SHIKI K, LEE G, TANIGUCHI A, IKEDA H, KUROKI D, NISHIMURA S, OGIHARA T.. EFFECT OF HYDROCHLOROTHIAZIDE IN ADDITION TO TELMISARTAN/AMLODIPINE COMBINATION FOR TREATING HYPERTENSIVE PATIENTS UNCONTROLLED WITH TELMISARTAN/AMLODIPINE: A RANDOMIZED, DOUBLE-BLIND STUDY. HYPERTENSION RESEARCH. 2017?40:251-58", "literaturereference_normalized": "effect of hydrochlorothiazide in addition to telmisartan amlodipine combination for treating hypertensive patients uncontrolled with telmisartan amlodipine a randomized double blind study", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180406", "receivedate": "20180406", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14730016, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "JP-IPCA LABORATORIES LIMITED-IPC201703-000349", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "040807", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TELMISARTAN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TELMISARTAN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESILATE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HIGAKI J,KOMURO I,SHIKI K,LEE G,ATSUSHI T,HIROSHI I. EFFECT OF HYDROCHLOROTHIAZIDE IN ADDITION TO TELMISARTAN/AMLODIPINE COMBINATION FOR TREATING HYPERTENSIVE PATIENTS UNCONTROLLED WITH TELMISARTAN/AMLODIPINE: A RANDOMIZED, DOUBLE-BLIND STUDY. HYPERTENSION RESEARCH 2017;40:251-8.", "literaturereference_normalized": "effect of hydrochlorothiazide in addition to telmisartan amlodipine combination for treating hypertensive patients uncontrolled with telmisartan amlodipine a randomized double blind study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170403", "receivedate": "20170403", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13398761, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" } ]

{ "abstract": "Steroid-refractory chronic graft-versus-host disease (cGVHD) is associated with high morbidity. To date, there is no standard therapy for patients who fail to respond to steroids. In this nonrandomized, open-label, single-arm, multicenter prospective phase II study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF) to treat sclerotic/fibrotic type cGVHD. The primary endpoint was the overall response rate (ORR) to imatinib mesylate plus MMF in 1 year, and the secondary endpoints included safety, quality of life, discontinuation of steroids, and overall survival (OS) rate. A total of 13 patients were enrolled, with a median age of 10.4 years (range, 5.0 to 20.1 years). All patients received a myeloablative conditioning regimen. Specifically, 6 of these patients had previously experienced acute GVHD. The most frequently affected organs were the eyes, lungs, skin, and liver. There were 2 premature deaths. One patient died of pulmonary infection and progression of cGVHD, and the other patient died from neuroblastoma progression and septic shock. The ORR was 76.9% (10 of 13 patients), and the median steroid dose was decreased from 1.0 mg/kg/day to 0.21 mg/kg/day. One-year OS was 84.6% (n = 13), and common adverse events included elevated liver enzyme and serum creatinine levels and fever. Although our sample size was limited, treatment of cGVHD with imatinib mesylate plus MMF shows promising results with acceptable toxicity.", "affiliations": "Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, Seoul, Republic of Korea.;Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea.;Department of Pediatrics, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea.;Department of Pediatrics, College of Medicine, Yeungnam University, Daegu, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Electronic address: [email protected].", "authors": "Choi|Jung Yoon|JY|;Kim|Hyery|H|;Baek|Hee Jo|HJ|;Kook|Hoon|H|;Lee|Jae Min|JM|;Kim|Bo Kyung|BK|;An|Hong Yul|HY|;Hong|Kyung Taek|KT|;Shin|Hee Young|HY|;Kang|Hyoung Jin|HJ|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jtct.2021.07.019", "fulltext": null, "fulltext_license": null, "issn_linking": "2666-6367", "issue": "27(11)", "journal": "Transplantation and cellular therapy", "keywords": "Children; Chronic graft-versus-host disease; Imatinib mesylate; Mycophenolate mofetil", "medline_ta": "Transplant Cell Ther", "mesh_terms": null, "nlm_unique_id": "101774629", "other_id": null, "pages": "925.e1-925.e7", "pmc": null, "pmid": "34314892", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Open-Label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Pediatric Patients with Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-Host Disease.", "title_normalized": "open label multicenter phase ii study of combination therapy of imatinib mesylate and mycophenolate mofetil in pediatric patients with steroid refractory sclerotic fibrotic type chronic graft versus host disease" }

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Open-label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in pediatric patients with Steroid-Refractory Sclerotic/fibrotic Type Chronic Graft-versus-host disease. Transplantation and Cellular Therapy. 2021;Unk:Unk", "literaturereference_normalized": "open label multicenter phase ii study of combination therapy of imatinib mesylate and mycophenolate mofetil in pediatric patients with steroid refractory sclerotic fibrotic type chronic graft versus host disease", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20211223", "receivedate": "20211223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20220659, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" }, { "companynumb": "KR-ALKEM LABORATORIES LIMITED-KR-ALKEM-2021-05028", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB MESYLATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Chronic graft versus host disease", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "Choi JY, Kim H, Baek HJ, Kook H, et al. Open-label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in pediatric patients with Steroid-Refractory Sclerotic/fibrotic Type Chronic Graft-versus-host disease. Transplantation and Cellular Therapy. 2021;Unk:Unk", "literaturereference_normalized": "open label multicenter phase ii study of combination therapy of imatinib mesylate and mycophenolate mofetil in pediatric patients with steroid refractory sclerotic fibrotic type chronic graft versus host disease", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20211223", "receivedate": "20211223", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20220660, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 1, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220303" } ]

{ "abstract": "A case of spontaneous fetal bladder rupture occurring in a woman with SARS-CoV-2 pneumonia receiving invasive ventilatory support is reported.\nA 33-year-old woman was admitted at 30.6 weeks' gestation with the diagnosis of severe pneumonia due to COVID-19. The patient required invasive mechanical ventilation on day 2. Propofol, fentanyl, midazolam, and dexmedetomidine were administered for sedation, pain relief, and to improve patient-ventilator interaction. A bedside ultrasound on day 3 revealed fetal megacystis. Follow-up scan two days later showed urinary ascites and a collapsed bladder. The diagnosis of fetal bladder rupture was confirmed postpartum. Bladder repair was performed on day 5, with an uneventful recovery.\nTransplacental transfer of opioids during invasive ventilatory support in pregnancy may cause acute fetal bladder atony leading to severe urine retention and, potentially, bladder rupture. This can be a serious complication of adjunctive therapy in women with severe SARS-CoV-2 pneumonia.", "affiliations": "Department of Obstetrics and Gynecology, Clinica Indisa, Santiago, Chile.;FETALMED-Maternal-Fetal Diagnostic Center, Santiago, Chile.;Department of Pediatric Urology, Clinica Indisa, Santiago, Chile.;Department of Obstetrics and Gynecology, Clinica Indisa, Santiago, Chile.;Neonatal Intensive Care Unit, Clinica Indisa, Santiago, Chile.", "authors": "Gutierrez|Jorge|J|;Sepulveda|Waldo|W|https://orcid.org/0000-0002-3856-574X;Ramirez|Raul|R|;Acosta|Gina|G|;Ambiado|Sergio|S|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1080/15513815.2021.1963359", "fulltext": null, "fulltext_license": null, "issn_linking": "1551-3815", "issue": null, "journal": "Fetal and pediatric pathology", "keywords": "COVID-19; SARS-CoV-2 pneumonia; fetal bladder rupture; prenatal diagnosis", "medline_ta": "Fetal Pediatr Pathol", "mesh_terms": null, "nlm_unique_id": "101230972", "other_id": null, "pages": "1-5", "pmc": null, "pmid": "34369260", "pubdate": "2021-08-09", "publication_types": "D016428:Journal Article", "references": null, "title": "Fetal Bladder Rupture as a Complication of Adjunctive Therapy in Severe Maternal SARS-CoV-2 Pneumonia.", "title_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia" }

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"PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021 AUG 09?.", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210908", "receivedate": "20210908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19809497, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-ALVOGEN-2021-ALVOGEN-117446", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": 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"drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "202097", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TRANSDERMAL SYSTEM", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", 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"reactionmeddrapt": "Drug withdrawal syndrome", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021. DOI: 10.1080/15513815.2021.1963359.", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210909", "receivedate": "20210909", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19812927, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-HQ SPECIALTY-CL-2021INT000152", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": "3", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 UG/KG,1 HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATIVE THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, 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null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206628", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE HYDROCHLORIDE." } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Apgar score low", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W.. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021?1?5", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210831", "receivedate": "20210831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19768830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-PFIZER INC-202101062933", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL CITRATE" }, "drugadditional": "3", "drugadministrationroute": "064", "drugauthorizationnumb": "019115", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 UG/KG PER HOUR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL CITRATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FENTANYL CITRATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "019115", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL CITRATE." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Urinary ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SEPULVEDA, W.. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL AND PEDIATRIC PATHOLOGY. 2021?10.1080/15513815.2021.1963359", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210909", "receivedate": "20210831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19769380, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "CL-TEVA-2021-CL-1955184", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "020747", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, 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"drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "3.5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANALGESIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Atonic urinary bladder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ascites", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal megacystis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL?PEDIATR?PATHOL 2021?:NO PAGINATION.", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210917", "receivedate": "20210917", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19846440, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "CL-WEST THERAPEUTIC DEVELOPMENT-2021WTD00015", "fulfillexpeditecriteria": "1", "occurcountry": "CL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MIDAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE OF 0.3 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE 3.5 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXMEDETOMIDINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXMEDETOMIDINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FENTANYL" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "022569", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "MATERNAL DOSE WAS 2 MCG/KG/H", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FENTANYL." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Urinary bladder rupture", "reactionmeddraversionpt": "24.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "GUTIERREZ J, SEPULVEDA W, RAMIREZ R, ACOSTA G, AMBIADO S. FETAL BLADDER RUPTURE AS A COMPLICATION OF ADJUNCTIVE THERAPY IN SEVERE MATERNAL SARS?COV?2 PNEUMONIA. FETAL PEDIATR PATHOL. 2021", "literaturereference_normalized": "fetal bladder rupture as a complication of adjunctive therapy in severe maternal sars cov 2 pneumonia", "qualification": "3", "reportercountry": "CL" }, "primarysourcecountry": "CL", "receiptdate": "20210831", "receivedate": "20210831", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19771183, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" } ]

{ "abstract": "A 69-year-old man was admitted to our hospital with a 1-year history of progressive easy fatigability while walking. He presented with proximal muscle weakness dominant in the lower extremities, hoarseness, and mild dysphagia. Muscle pseudo-hypertrophy was observed in the gastrocnemius. A biopsy specimen from the left deltoid muscle revealed amyloid deposition in the blood vessels and ring-like fibers. These findings suggested amyloid myopathy. The serum and urine immunofixation electrophoresis detected κ type Bence-Jones proteins, and bone marrow examination showed an increase in atypical plasma cells; thus, we established a diagnosis of multiple myeloma. Thereafter, he experienced frequent diarrhea, and the gastrointestinal endoscopy revealed extensive amyloid deposition in the upper and lower digestive tract. We started treatment with lenalidomide and dexamethasone; however, his condition worsened, and he died of aspiration pneumonia. Amyloid myopathy indicated systemic AL amyloidosis; therefore, muscle biopsy was necessary in this case.", "affiliations": "Department of Neurology, Toyonaka Municipal Hospital.;Department of Neurology, Toyonaka Municipal Hospital.;Department of Neurology, Toyonaka Municipal Hospital.;Department of Internal Medicine (Hematology), Toyonaka Municipal Hospital.;Department of Neurology, Osaka Toneyama Medical Center.;Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP).;Department of Neurology, Toyonaka Municipal Hospital.", "authors": "Yata|Tomohiro|T|;Miwa|Takashi|T|;Araki|Katsuya|K|;Kida|Toru|T|;Toyooka|Keiko|K|;Nishino|Ichizo|I|;Tatsumi|Chikao|C|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.5692/clinicalneurol.cn-001339", "fulltext": null, "fulltext_license": null, "issn_linking": "0009-918X", "issue": "60(1)", "journal": "Rinsho shinkeigaku = Clinical neurology", "keywords": "AL amyloidosis; amyloid myopathy; multiple myeloma; muscle biopsy", "medline_ta": "Rinsho Shinkeigaku", "mesh_terms": "D000368:Aged; D001706:Biopsy; D017809:Fatal Outcome; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D008297:Male; D009101:Multiple Myeloma; D009132:Muscles", "nlm_unique_id": "0417466", "other_id": null, "pages": "60-63", "pmc": null, "pmid": "31852873", "pubdate": "2020-01-30", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A case of systemic AL amyloidosis diagnosed on muscle biopsy.", "title_normalized": "a case of systemic al amyloidosis diagnosed on muscle biopsy" }

[ { "companynumb": "JP-CELGENEUS-JPN-20200101172", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLETS", "drugdosagetext": null, "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULES", "drugdosagetext": null, "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "PLASMA CELL MYELOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "REVLIMID" } ], "patientagegroup": null, "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "66", "reaction": [ { "reactionmeddrapt": "Pneumonia aspiration", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Dysphagia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2018" } }, "primarysource": { "literaturereference": "MIWA T, YATA T, ARAKI K, KIDA T, TOYOOKA K, NISHINO I. A CASE OF SYSTEMIC AL AMYLOIDOSIS DIAGNOSED ON MUSCLE BIOPSY. CLINICAL NEUROLOGY. 2020?60(1):1?4.", "literaturereference_normalized": "a case of systemic al amyloidosis diagnosed on muscle biopsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210722", "receivedate": "20200106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17236438, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20211014" }, { "companynumb": "JP-CELGENE-JPN-20200101172", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021880", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Capsule", "drugdosagetext": "UNKNOWN", "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": "1", "drugtreatmentdurationunit": "802", "medicinalproduct": "REVLIMID" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "DEXAMETHASONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Tablet", "drugdosagetext": "UNKNOWN", "drugenddate": "201807", "drugenddateformat": "610", "drugindication": "Plasma cell myeloma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201806", "drugstartdateformat": "610", "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": "1", "drugtreatmentdurationunit": "802", "medicinalproduct": "LENADEX" } ], "patientagegroup": "6", "patientonsetage": "69", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "66", "reaction": [ { "reactionmeddrapt": "No adverse event", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Yata T, Miwa T, Araki K, Kida T, Toyooka K, Nishino I. et al. A case of systemic AL amyloidosis diagnosed on muscle biopsy. Clinical neurology. 2020; 60(1): 1-4.", "literaturereference_normalized": "a case of systemic al amyloidosis diagnosed on muscle biopsy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220501", "receivedate": "20220501", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20772052, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "Combination therapy using a BRAF and MEK inhibitor significantly improves both progression-free and overall survival in patients with BRAF V600-mutated stage IV melanoma. Dual MAPK inhibition achieves an objective response in the majority of patients. We present a case of a woman with BRAF V600E-mutated malignant melanoma and rapidly progressing liver, bone, and lymph node metastases. The patient commenced dabrafenib and trametinib with clinical and biochemical signs of response after 2 days. On day 3 she developed grade 3 liver hemorrhage, which was successfully embolized. Her anemia responded appropriately to transfusions and stabilized after interventional resolution of the hemorrhagic event. Subsequently she developed a pathological fracture of the right proximal humerus. MRI showed cystic bone metastases with stigmata of bleeding. To our knowledge, this is the first case report of a patient with hemorrhage of both liver and bone metastases of a melanoma. As the patient responded rapidly to dabrafenib and trametinib we hypothesize that the hemorrhage may be due to rapid tumor necrosis and bleeding of affected tumor supplying blood vessels. Our case demonstrates the importance of considering tumoral bleeding as a side effect of BRAF and MEK inhibition in responding melanoma patients. Mechanical intervention can be effective in resolving this treatment-related adverse event.", "affiliations": "Department of Medical Oncology, General Hospital Sint-Jozef Malle, Malle.;Department of General Medical Oncology, Leuven Cancer Institute.;Department of General Medical Oncology, Leuven Cancer Institute.;Department of Radiology, University Hospitals Leuven.;Department of Radiology, University Hospitals Leuven.;Department of General Medical Oncology, Leuven Cancer Institute.", "authors": "Loyson|Tine|T|;Werbrouck|Emilie|E|;Punie|Kevin|K|;Bonne|Lawrence|L|;Vandecaveye|Vincent|V|;Bechter|Oliver|O|", "chemical_list": "D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; C561627:dabrafenib", "country": "England", "delete": false, "doi": "10.1097/CMR.0000000000000419", "fulltext": null, "fulltext_license": null, "issn_linking": "0960-8931", "issue": "28(2)", "journal": "Melanoma research", "keywords": null, "medline_ta": "Melanoma Res", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D005260:Female; D006470:Hemorrhage; D006801:Humans; D007093:Imidazoles; D008113:Liver Neoplasms; D020930:MAP Kinase Kinase Kinases; D008545:Melanoma; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D012878:Skin Neoplasms", "nlm_unique_id": "9109623", "other_id": null, "pages": "147-150", "pmc": null, "pmid": "29215399", "pubdate": "2018-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Hemorrhage of liver and bone metastases as a result of rapid response to dual BRAF/MEK inhibition in metastatic melanoma: a case report.", "title_normalized": "hemorrhage of liver and bone metastases as a result of rapid response to dual braf mek inhibition in metastatic melanoma a case report" }

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{ "abstract": "A 19-year-old male with therapy-related myelodysplastic syndrome underwent allogeneic bone marrow transplantation with reduced-intensity conditioning from his HLA-identical sibling whose ABO blood type exhibited major incompatibility with the patient. After post-transplantation 1 month, chimerism analysis of the bone marrow revealed mixed chimerism with 30% of recipient cells, and after post-transplantation 3 months, complete remission was maintained; however, recipient granulocytes were elevated up to 50% per the chimerism analysis. Next, pancytopenia developed following the rapid discontinuation of the immunosuppressive agent. Although neutrophils and platelets spontaneously recovered, anemia progressed. Based on severe erythroid hypoplasia in the bone marrow and the elevation of anti-ABO isohemagglutinin against donor-derived red blood cells, the patient was diagnosed with pure red cell aplasia (PRCA) following hematopoietic cell transplantation. Because complete chimerism was attained at the PRCA onset even for B cells, we decided to conservatively manage PRCA with only red blood cell transfusion. Notably, after 2 months of the PRCA onset, anemia improved. This case suggests that the therapeutic strategy for PRCA following hematopoietic cell transplantation should be determined by considering the status of each patient, including chimerism.", "affiliations": "Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.;Department of Pediatrics, Kyoto Prefectural University of Medicine.", "authors": "Okamoto|Kenji|K|;Osone|Shinya|S|;Saito|Taeko|T|;Imamura|Toshihiko|T|;Hosoi|Hajime|H|", "chemical_list": "D000017:ABO Blood-Group System; D016572:Cyclosporine", "country": "Japan", "delete": false, "doi": "10.11406/rinketsu.59.2408", "fulltext": null, "fulltext_license": null, "issn_linking": "0485-1439", "issue": "59(11)", "journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology", "keywords": "Chimerism; Cyclosporine; Hematopoietic cell transplantation; Pure red cell aplasia", "medline_ta": "Rinsho Ketsueki", "mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D001787:Blood Group Incompatibility; D016026:Bone Marrow Transplantation; D046528:Chimerism; D016572:Cyclosporine; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D012010:Red-Cell Aplasia, Pure; D014184:Transplantation, Homologous; D055815:Young Adult", "nlm_unique_id": "2984782R", "other_id": null, "pages": "2408-2412", "pmc": null, "pmid": "30531134", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation.", "title_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation" }

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"reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dysplasia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO K, OSONE S, SAITO T, IMAMURA T, HOSOI H. 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null, "drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77269", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOSPORINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "74656", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G/M2 ON DAYS -8 TO -5", "drugenddate": null, "drugenddateformat": null, "drugindication": "BONE MARROW CONDITIONING REGIMEN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO K, OSONE S, SAITO T, IMAMURA T, HOSOI H. [PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION]. RINSHO-KETSUEKI 2018?59(11):2408-2412.", "literaturereference_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190723", "receivedate": "20190711", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16558762, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "JP-PFIZER INC-2018531012", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINBLASTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXAL [VINBLASTINE SULFATE]" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAMPTO" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "GERM CELL CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONCOVIN" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Second primary malignancy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO, K.. PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION. THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2018?59(11):2408-2412", "literaturereference_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190723", "receivedate": "20181228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15772291, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" }, { "companynumb": "JP-MYLANLABS-2019M1061183", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", 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"drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MEDIASTINUM NEOPLASM", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Myelodysplastic syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Withdrawal syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aplasia pure red cell", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OKAMOTO K, OSONE S, SAITO T, IMAMURA T, HOSOI H. [PURE RED CELL APLASIA FOLLOWING THE RAPID REDUCTION AND DISCONTINUATION OF CYCLOSPORINE FOR MIXED CHIMERISM AFTER ALLOGENEIC BONE MARROW TRANSPLANTATION]. RINSHO-KETSUEKI 2018?59(11):2408-2412.. 2018?59(11):2408-2412", "literaturereference_normalized": "pure red cell aplasia following the rapid reduction and discontinuation of cyclosporine for mixed chimerism after allogeneic bone marrow transplantation", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190703", "receivedate": "20190703", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16526413, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191004" } ]

{ "abstract": "We report the case of a 59-year-old patient with Heartware (Framingham, MA, USA) biventricular assist device (BIVAD) implantation who had long-term sustained ventricular fibrillation and was managed on low-molecular-weight heparin for up to two years without any adverse events. The successful outcome in this case provides a clue that the long-term management of Heartware BIVADs with low-molecular-weight heparins could be a viable option even in patients with underlying malignant arrhythmias. <Learning objective: Long-term management of Heartware biventricular assist devices (BIVADs) using low-molecular-weight heparin is possible. This treatment strategy can serve as an alternative to oral anticoagulants in a select group of patients. This case report also suggests that BIVADs can potentially serve as a useful alternative to total artificial heart.>.", "affiliations": "Division of Cardiovascular Surgery, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.;Division of Cardiovascular Surgery, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.;Division of Cardiovascular Surgery, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.", "authors": "Chandola|Rahul|R|;Buchholz|Holger|H|;Macarthur|Roderick|R|", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1016/j.jccase.2016.08.002", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-5409", "issue": "14(6)", "journal": "Journal of cardiology cases", "keywords": "Heartware; Low-molecular-weight heparin; Unfractionated heparin", "medline_ta": "J Cardiol Cases", "mesh_terms": null, "nlm_unique_id": "101549579", "other_id": null, "pages": "171-173", "pmc": null, "pmid": "30546687", "pubdate": "2016-12", "publication_types": "D016428:Journal Article", "references": "17670627;2680160;17470211;16156320;14967716;17670482;11213859;20958827;17437746;10715251;8236105;24239003", "title": "Long-term use of low-molecular-weight heparin in a patient with Heartware BIVAD (HVAD) with underlying sustained ventricular fibrillation.", "title_normalized": "long term use of low molecular weight heparin in a patient with heartware bivad hvad with underlying sustained ventricular fibrillation" }

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{ "abstract": "Diffuse alveolar hemorrhage (DAH) is a life-threatening condition requiring urgent treatment. There are many different treatment-relevant causes of DAH, making the diagnostic approach to these patients complex and necessitating a multidisciplinary team. We report the case of a kidney transplant recipient in whom all diagnostic efforts did not reveal the cause of DAH, and only autopsy was able to establish an unexpected diagnosis.", "affiliations": "Institute for Pathology, University Hospital Basel, Basel, Switzerland.", "authors": "Schlageter|Manuel|M|;Jahn|Kathleen D|KD|;Tzankov|Alexandar|A|;Wiese|Mark|M|;Bubendorf|Lukas|L|;Tamm|Michael|M|;Savic|Spasenija|S|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000358566", "fulltext": null, "fulltext_license": null, "issn_linking": "0025-7931", "issue": "87(6)", "journal": "Respiration; international review of thoracic diseases", "keywords": null, "medline_ta": "Respiration", "mesh_terms": "D001163:Arteriovenous Anastomosis; D017809:Fatal Outcome; D006394:Hemangiosarcoma; D006469:Hemoptysis; D006470:Hemorrhage; D006801:Humans; D007165:Immunosuppression Therapy; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008168:Lung; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0137356", "other_id": null, "pages": "504-7", "pmc": null, "pmid": "24732422", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "An unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient.", "title_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient" }

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AN UNEXPECTED CAUSE OF DIFFUSE ALVEOLAR HEMORRHAGE IN A KIDNEY TRANSPLANT PATIENT. RESPIRATION. 2014;87 (6):504-7", "literaturereference_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20140723", "receivedate": "20140723", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10335867, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20150326" }, { "companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-105814", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "089247", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HIGH-DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ALVEOLAR HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY ALVEOLAR HAEMORRHAGE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary alveolar haemorrhage", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchopulmonary aspergillosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Angiosarcoma metastatic", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SCHLAGETER M, JAHN KD, TZANKOV A, WIESE M, BUBENDORF L, TAMM M, ET AL. AN UNEXPECTED CAUSE OF DIFFUSE ALVEOLAR HEMORRHAGE IN A KIDNEY TRANSPLANT PATIENT. RESPIRATION. 2014?87 (6):504-7", "literaturereference_normalized": "an unexpected cause of diffuse alveolar hemorrhage in a kidney transplant patient", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20151110", "receivedate": "20151110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11717947, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]

{ "abstract": "Gorham-Stout disease (GSD) is a rare disorder characterised by massive painless osteolysis due to lymphangiomatous tissue progression. GSD's pathogenesis is still unclear, but osteoclasts' activation may play a role in its pathogenesis. There are multiple complications associated with GSD. One of the most severe and life-threatening complications is a chylothorax. Herein we discuss a case of a patient with a history of GSD who presented to the hospital with progressive dyspnoea secondary to a large left-sided pleural effusion, which was later confirmed to be a chylothorax. We will further discuss the current literature and treatment of chylothorax associated with GSD.", "affiliations": "Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA [email protected].;Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA.;Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA.;Internal Medicine, Cooper University Health Care, Camden, New Jersey, USA.", "authors": "Olea-Mendoza|Daniel|D|;Terrigno|Vittorio Romeo|VR|;Balogun|Ayobamidele|A|;Caprio|Colleen|C|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1136/bcr-2020-239891", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(3)", "journal": "BMJ case reports", "keywords": "bronchopulmonary dysplasia; haematology (incl blood transfusion); oncology; respiratory medicine; vascular surgery", "medline_ta": "BMJ Case Rep", "mesh_terms": "D002916:Chylothorax; D006801:Humans; D010015:Osteolysis, Essential; D010996:Pleural Effusion", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33692056", "pubdate": "2021-03-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Gorham-Stout disease: interesting cause of pleural effusion.", "title_normalized": "gorham stout disease interesting cause of pleural effusion" }

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DOI: 10.1136/BCR?2020?239891.", "literaturereference_normalized": "gorham stout disease interesting cause of pleural effusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210417", "receivedate": "20210417", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19149846, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0134166", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091186", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOLEDRONIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SIROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201578", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USE IN UNAPPROVED INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIROLIMUS." } ], "patientagegroup": "5", "patientonsetage": "21", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pain in jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteonecrosis of jaw", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "OLEA?MENDOZA D, TERRIGNO VR, BALOGUN A, CAPRIO C. GORHAM?STOUT DISEASE: INTERESTING CAUSE OF PLEURAL EFFUSION. BMJ CASE REPORTS. 2021?14(3):ARTICLE NUMBER E239891. DOI: 10.1136/BCR?2020?239891.", "literaturereference_normalized": "gorham stout disease interesting cause of pleural effusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210414", "receivedate": "20210414", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19131892, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "BACKGROUND\nAtrial fibrillation (AF) patients eligible for cardioversion tend to be younger and are at lower risk than 'general' AF clinic populations. We evaluated the incidence of major bleeding and death, as well as the predictive value of the HAS-BLED score in non-valvular AF patients who underwent electrical cardioversion (ECV).\n\n\nMETHODS\nConsecutive non-valvular AF patients who underwent ECV were recruited. Major bleeding episodes and mortality were recorded. Factors associated with both endpoints and the predictive value of the HAS-BLED score were analysed.\n\n\nRESULTS\n406 patients (281 males; age 66.9±10.9years) undergoing 571 ECV were included. After a follow-up of nearly 3years, 20 patients presented with major bleeding (1.9%/year;) and 26 patients died (2.4%/year). The HAS-BLED score predicted both major bleeding [c-statistics: 0.77; 95%CI: 0.71-0.83; p<0.001] and mortality [c-statistics: 0.83; 95%CI: 0.79-0.87; p<0.001]. Variables associated with bleeding were: renal impairment (HR: 4.35; 95%CI: 1.22-15.52; p=0.02), poor quality anticoagulation (HR: 3.21; 95%CI: 1.11-9.32; p=0.03), previous bleeding-predisposition (HR: 5.43; 95%CI: 1.76-16.75; p=0.003) and the HAS-BLED score (HR: 1.88; 95%CI: 1.34-2.64; p<0.001). Factors associated with mortality were: age (HR: 1.08; 95%CI: 1.03-1.14; p=0.004), poor quality anticoagulation (HR: 3.11; 95%CI: 1.15-8.36; p=0.02), previous bleeding-predisposition (HR: 5.90; 95%CI: 1.41-24.65; p=0.01), liver impairment (HR: 9.27; 95%CI:1.64-52.34; p=0.01), the CHA2DS2-VASc score (HR: 1.63; 95%CI: 1.18-2.26; p=0.003) and the HAS-BLED score (HR: 2.74; 95%CI: 1.86-4.04); p<0.001).\n\n\nCONCLUSIONS\nIn AF patients undergoing ECV, major bleeding episodes and mortality were independently associated with poor quality anticoagulation control and previous bleeding-predisposition. The HAS-BLED score successfully predicted major bleeding and mortality.", "affiliations": "Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;Department of Cardiology, Virgen de la Arrixaca University Hospital, University of Murcia, Spain. Electronic address: [email protected].;Hematology and Medical Oncology Unit, Morales Meseguer University Hospital, University of Murcia, Spain.;Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;Department of Cardiology, Virgen de la Arrixaca University Hospital, University of Murcia, Spain.;Arrhythmia Unit, Cardiology Department, General University Hospital of Alicante, Spain.;University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom.", "authors": "García-Fernández|Amaya|A|;Marín|Francisco|F|;Roldán|Vanessa|V|;Galcerá-Jornet|Emilio|E|;Martínez-Martínez|Juan Gabriel|JG|;Valdés|Mariano|M|;Sogorb|Francisco|F|;Lip|Gregory Y H|GY|", "chemical_list": "D000925:Anticoagulants", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0167-5273", "issue": "217()", "journal": "International journal of cardiology", "keywords": "Atrial fibrillation; Electrical cardioversion; HAS-BLED; Haemorrhage; Mortality; Risk factors", "medline_ta": "Int J Cardiol", "mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D004554:Electric Countershock; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D015996:Survival Rate", "nlm_unique_id": "8200291", "other_id": null, "pages": "42-8", "pmc": null, "pmid": "27179207", "pubdate": "2016-08-15", "publication_types": "D016428:Journal Article", "references": null, "title": "The HAS-BLED score predicts long-term major bleeding and death in anticoagulated non-valvular atrial fibrillation patients undergoing electrical cardioversion.", "title_normalized": "the has bled score predicts long term major bleeding and death in anticoagulated non valvular atrial fibrillation patients undergoing electrical cardioversion" }

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{ "abstract": "Thyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. First line treatment of thyroid storm is directed towards decreasing thyroid hormone production and peripheral conversion of T4 to T3, and treating adrenergic symptoms. When medical therapy fails, plasmapheresis is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis.\nA 50-year-old male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to another hospital with fever and altered mentation. He was found to have pneumonia on imaging and was started on antibiotics. He developed shock complicated by atrial fibrillation with rapid ventricular rate which was treated with amiodarone. He was transferred to our hospital for further management. On arrival, TSH was <0.01 mIU/L, free T4 was >7 ng/dL and total T3 was 358 ng/dL. The endocrinology team determined he was in thyroid storm. His medical treatment of thyroid storm was aggressively titrated to maximal therapy. His hospital course was complicated by transaminitis, respiratory failure requiring intubation, shock requiring vasopressor support, kidney failure requiring continuous renal replacement therapy, and heart failure. Despite maximal anti-thyroid therapy, he had not improved clinically and T4 and T3 remained markedly elevated. A 4-day course of plasmapheresis was initiated resulting in marked lowering of T4 and T3 and clinical stability.\nWhile current guidelines for plasmapheresis for thyroid storm recommend individualized decision making, no further clarification is provided on who would be a good candidate for the procedure. We present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis after failing maximal medical therapy. Given the significant improvement seen with plasmapheresis, endocrinologists should consider this mode of treatment earlier in the course of thyroid storm when patients are not improving with medical therapy alone.", "affiliations": "Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.;Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.", "authors": "Miller|Ann|A|https://orcid.org/0000-0002-2098-3193;Silver|Kristi D|KD|https://orcid.org/0000-0002-8320-517X", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2019/2475843", "fulltext": "\n==== Front\nCase Rep EndocrinolCase Rep EndocrinolCRIECase Reports in Endocrinology2090-65012090-651XHindawi 10.1155/2019/2475843Case ReportThyroid Storm with Multiorgan Failure Treated with Plasmapheresis https://orcid.org/0000-0002-2098-3193Miller Ann https://orcid.org/0000-0002-8320-517XSilver Kristi D. [email protected] of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USAAcademic Editor: Osamu Isozaki\n\n2019 9 10 2019 2019 24758439 5 2019 15 7 2019 29 7 2019 Copyright © 2019 Ann Miller and Kristi D. Silver.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n Thyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. First line treatment of thyroid storm is directed towards decreasing thyroid hormone production and peripheral conversion of T4 to T3, and treating adrenergic symptoms. When medical therapy fails, plasmapheresis is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis. \n\nCase\nA 50-year-old male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to another hospital with fever and altered mentation. He was found to have pneumonia on imaging and was started on antibiotics. He developed shock complicated by atrial fibrillation with rapid ventricular rate which was treated with amiodarone. He was transferred to our hospital for further management. On arrival, TSH was <0.01 mIU/L, free T4 was >7 ng/dL and total T3 was 358 ng/dL. The endocrinology team determined he was in thyroid storm. His medical treatment of thyroid storm was aggressively titrated to maximal therapy. His hospital course was complicated by transaminitis, respiratory failure requiring intubation, shock requiring vasopressor support, kidney failure requiring continuous renal replacement therapy, and heart failure. Despite maximal anti-thyroid therapy, he had not improved clinically and T4 and T3 remained markedly elevated. A 4-day course of plasmapheresis was initiated resulting in marked lowering of T4 and T3 and clinical stability. \n\nConclusion\nWhile current guidelines for plasmapheresis for thyroid storm recommend individualized decision making, no further clarification is provided on who would be a good candidate for the procedure. We present a patient with thyroid storm and multiorgan failure who was treated with plasmapheresis after failing maximal medical therapy. Given the significant improvement seen with plasmapheresis, endocrinologists should consider this mode of treatment earlier in the course of thyroid storm when patients are not improving with medical therapy alone.\n==== Body\n1. Background\nThyroid storm is a severe manifestation of thyrotoxicosis and can present with multiorgan failure. Thyroid storm has an estimated mortality rate of 20%–30% [1]. First line treatment of thyroid storm is directed at decreasing thyroid hormone production and peripheral conversion of thyroxine (T4) to triiodothyronine (T3), and treating adrenergic symptoms. When medical therapy fails, therapeutic plasma exchange (TPE), also called therapeutic plasmapheresis, is an alternative treatment option. Here we present a patient with thyroid storm and multiorgan failure who was successfully treated with TPE.\n\n2. Case\nA 50-year-old African American male with a history of hyperthyroidism, hypertension, and congestive heart failure presented to an outside hospital with fever and an altered mental status. He was diagnosed with hyperthyroidism about three months prior to hospitalization. He was started on methimazole (MMI), but compliance taking the medication was low. His primary care provider had recommended thyroidectomy; however, he was unable to have the procedure due to lack of health insurance. On presentation to the outside hospital, imaging revealed right lower lobe pneumonia with an effusion and he was started on antibiotics. His clinical status deteriorated, and he developed shock complicated by atrial fibrillation with rapid ventricular rate with documented rates in the 140–190 beats per minute. His arrhythmia was refractory to digoxin, diltiazem, and two attempts at cardioversion with 200 Joules. He was initiated on an amiodarone infusion which stabilized his arrhythmia. His TSH documented at the outside hospital was 0.01 mIU/L and free T4 was 8 ng/dL.\n\nHe was transferred to our hospital for further management. Prior to transfer, he was started on hydrocortisone 50 mg every 6 hours and MMI 10 mg three times daily. MMI was used instead of propylthiouracil (PTU) due to elevated liver function tests. On the day of arrival to our hospital, the inpatient endocrinology team was consulted for assistance with thyroid management. He was intubated for respiratory distress at the time of the endocrinology team's initial assessment. His blood pressure, supported by two pressors, was 90/63 mmHg. His temperature was 36.9˚C and his pulse ranged from 88 to 134 beats per minute on the amiodarone infusion. Physical examination was significant for scleral icterus and left neck fullness. No thyroid bruit or discrete nodules were identified; however, the neck exam was limited due to multiple central lines. His heart beat was irregular consistent with atrial fibrillation and a cardiac murmur was also detected. Lower extremities were notable for edema and hyperreflexia. The endocrinology team was unable to assess his mental status due to the patient being sedated. Thyroid labs on admission to our hospital included TSH <0.01 mIU/L (0.47–4.68 mIU/L), total T3 358 ng/dL (97–169 ng/dL), free T4 > 7 ng/dL (0.6–2.5 ng/dL) and thyroid stimulating antibodies >500% (normal ≤122%). Additional laboratory studies (Table 1) showed acute kidney injury and elevated liver function tests, troponin, and white blood cell count. Thyroid ultrasound with doppler showed an enlarged, heterogeneous thyroid gland, more pronounced on the right than the left without any nodules, although the view of the left side was limited due to the endotracheal tube and central line.\n\nHis Burch–Wartofsky score [2] for hyperthyroid storm was 100 which was highly concerning for thyroid storm. As the Burch–Wartofsky score can sometimes be misleading with elevated scores in critically ill patients without thyroidal illness, the Japan Thyroid Association thyroid storm criteria, a diagnostic criterion less likely to incorrectly diagnose thyroid storm in critically ill patients, was also utilized to assess for thyroid storm in our patient [3]. Employing this second diagnostic criterion, our patient again met criteria for thyroid storm based on the family report of altered mental status, tachycardia with documented rates of 140–190 per minute, heart failure with an estimated ejection fraction of 30%, and thyrotoxicosis with suppressed TSH and elevated free T4 and total T3 levels.\n\nThe endocrine consult team recommended increasing MMI to 20 mg three times daily and starting cholestyramine 4 g three times daily. Over the ensuing days, his renal function worsened such that he required continuous renal replacement therapy. On day 2, saturated potassium iodide solution (SSKI) 250 mg three times daily was initiated and cholestyramine was increased to 4 g four times daily. Liver function tests improved by day 3; therefore, he was switched from MMI to PTU 200 mg three times daily to take advantage of the decreased conversion of T4 to T3 seen with PTU. On day 4, TSH remained undetectable and free T4 was unchanged at >7 ng/dL. Total T3 began to decrease, but remained >200 ng/dL. Despite maximal medical therapy for thyroid storm, his clinical status continued to worsen with evidence of multiorgan failure. The endocrinology team consulted the hematology physicians for initiation of TPE.\n\nHe was started on daily TPE on hospital day 4. Replacement fluid contained half fresh frozen plasma (FFP) and half 5% albumin and was equal in volume to his total plasma volume (about 4L). His TPE treatment lasted about two hours each day and he received plasmapheresis daily for four days. After the first day of TPE, his free T4 and total T3 decreased to 5.3 ng/dL and 139 ng/dL, respectively. After 4 sessions of daily TPE, his free T4 was 1.9 ng/dL and total T3 was 77 ng/dL (Figure 1). With TPE, his clinical course significantly improved to the point where he was weaned off of pressors and extubated. Over the following 2 weeks, he was safely titrated off of SSKI and hydrocortisone, and switched from PTU to MMI. For definitive treatment of hyperthyroidism, the endocrine surgery team was consulted to evaluate the patient for total thyroidectomy. At the time of their evaluation, the patient was clinically euthyroid. Given his recent critical illness, the surgeons considered him to be a high-risk surgical candidate. Therefore, they recommended performing an elective thyroidectomy once the patient was further out from his critical illness and had undergone outpatient cardiac optimization. He was discharged home three weeks later on MMI 30 mg twice daily and cholestyramine 4 g twice daily. At time of discharge, he did not require any supplemental oxygen and his left ventricular ejection fraction improved to 48% as measured on positron emission tomography myocardial perfusion scan. He was no longer in atrial fibrillation as he had converted back to sinus rhythm and amiodarone had been discontinued. With the exception of total bilirubin, his liver function tests had normalized before discharge. By 2 months post discharge, his total bilirubin had also normalized. He was discharged with intermittent dialysis needs, though two weeks after leaving the hospital, dialysis was discontinued because his kidney function recovered.\n\n3. Discussion\nPlasmapheresis is an extracorporeal blood purification technique that helps remove larger molecular weight substances from blood. Plasmapheresis is a general term that refers to removing plasma from blood. TPE is a type of plasmapheresis that involves removal of patient plasma and replacing it with something else (either donor plasma, colloid, or crystalloid). TPE is most often used to treat conditions, where a pathogenic substance or component is in the blood and needs to be rapidly removed. Examples of pathogenic substances include auto-antibodies, immunocomplexes, cryoglobulins, myeloma light chains, endotoxins, cholesterol containing lipoproteins, and as with our patient, plasma protein-bound thyroid hormones. The necessary tools for TPE include vascular access, either using large-bore needles in the limb veins or an implanted catheter in the large veins of the neck, chest, or groin, and a plasmapheresis machine. The machine separates the patient's plasma from the rest of the blood components and exchanges plasma with a replacement fluid. TPE is effective for treatment of thyroid storm as thyroid hormone is almost entirely bound to plasma proteins (99.97% of total serum T4 and 99.7% of total serum T3). The three main plasma proteins that bind T4 and T3 are thyroxine binding globulin (TBG), transthyretin, and albumin. TBG binds 75% of T4 and T3. Transthyretin binds 20% of T4 and <5% of T3. Albumin binds 5% of T4 and 20% of T3. TBG and transthyretin are relatively similar in size, 54 kDa and 55 kDa, respectively. Albumin is larger with a molecular mass of 66.5 kDa [4]. Because of the size of thyroid binding proteins, conventional dialysis cannot remove these proteins from blood. In contrast, TPE removes larger proteins, and thus can be used to reduce circulating thyroid hormone and treat refractory thyroid storm. TPE can also remove TSH receptor autoantibody (also referred to as thyroid stimulating immunoglobulin) and its removal has been predicted mathematically to result in rapid lowering of the free thyroxine levels [5].\n\nRandomized placebo-controlled studies of TPE with medical management resistant thyroid storm have not been performed due to the rarity of the disorder. Therefore, guidelines for the use of TPE for thyroid storm are based on case reports, retrospective studies, and expert opinion. According to The American Society for Apheresis 2016 clinical practice guidelines, treatment of thyroid storm with plasmapheresis is a category III indication [6] meaning that the optimal role of TPE in thyroid storm is not established and the decision to use TPE for this indication should be individualized. Per these guidelines, when plasmapheresis is used to treat thyroid storm, FFP or albumin should be used as the replacement fluid. FFP has the benefit of increasing the concentration of TBG, which binds specifically to thyroxine and triiodothyronine, while albumin provides greater capacity for binding thyroid hormone. The recommended volume of replacement fluid is 1–1.5 times the total plasma volume. TPE treatment should be daily to every 3 days until clinical improvement is noted. TPE should be reserved for patients with severe symptoms of thyroid storm in whom first line medical therapies have failed or have had detrimental side effects that outweigh the benefits of treatment. These guidelines are similar to the guidelines set forth by The Japan Thyroid Association and Japan Endocrine Society in 2016 [7]. The Japanese guidelines recommend the use of TPE for treatment of thyroid storm if there is acute liver failure or no clinical improvement after 24–48 hours on optimized medical management. The Japanese guidelines recommend FFP over albumin as the replacement fluid due to its higher levels of TBG and specificity to bind thyroid hormone.\n\nThe effectiveness of TPE is dependent on multiple variables and is not a procedure without risk. The successful removal of pathogenic substances from blood through plasmapheresis depends on the volume of blood processed and plasma exchanged in each procedure, number of procedures performed, frequency of exchange, and rate of mobilization, stabilization, and re-synthesis of the cells or plasma components. Complications of plasmapheresis include bleeding, infection, disseminated intravascular coagulation (DIC), coagulation factor depletion leading to hypocoagulability, hypocalcemia, hypotension, and transfusion reactions such as transfusion associated infections, pulmonary edema, and pulmonary embolism. Despite these potential complications, the mortality rate of plasmapheresis is <1% [8].\n\nAshkar et al. first described thyrotoxicosis treated with plasmapheresis in 1970 in a case report of three thyrotoxic patients [9]. All three patients had deteriorating clinical status despite maximal medical treatment of thyrotoxicosis. The first patient underwent true TPE as his plasma was replaced with his red blood cells and lactate ringers. The other two patients were treated with plasmapheresis with removal of plasma with only their red blood cells returned to them. All three patients had significant clinical improvement. Since this initial description, case reports have described successful treatment with TPE in a variety of hyperthyroid scenarios ranging from post-operative thyroid storm complicated by pneumonia and septic shock [10] to MMI induced agranulocytosis [11] to amiodarone induced thyrotoxicosis [12]. While patients previously described as receiving plasmapheresis for thyroid storm were often critically ill, few have had multisystem organ failure similar to our patient. Of the few with multiorgan failure, one with a history of Graves' and medication noncompliance developed symptomatic thyrotoxicosis including palpitations, nausea, and vomiting. He was treated with medical therapy, but had to be switched from PTU to MMI due to liver dysfunction. He clinically decompensated despite medical therapy and developed DIC. He was treated with plasmapheresis and after two treatments, his free T4 and free T3 normalized. The same paper discusses a male with Graves' disease who also presented with thyrotoxicosis symptoms and medication noncompliance. This patient was started on oral medical therapy with MMI 20 mg daily and propranolol 40 mg twice daily. Shortly after admission, he became febrile with a temperature of 38.1°C and was found unresponsive and pulseless. He underwent cardiopulmonary resuscitation. He developed ventricular fibrillation and required electrical cardioversion. His clinical status further worsened with development of transaminitis and acute kidney injury with continued tachyarrhythmia. Neurologically, he was unresponsive off of sedation. After one day of plasmapheresis, his free T4 declined from 10.9 ng/dL to 8.57 ng/dL. He received two more treatments of plasmapheresis daily over the next two days. His free T4 continued to trend downwards as he continued to receive methimazole, SSKI, and steroids. While the paper does not talk about his neurological status after TPE, it did say that he became clinically and biochemically euthyroid and underwent definitive treatment with a total thyroidectomy [13]. Similarly, in a case reported by Baena et al., a 36-year-old woman with Graves' disease and multiorgan failure including acute liver and heart failure, acute kidney injury, cytopenia, rhabdomyolysis and coagulopathy improved with the use of medical management plus plasmapheresis [14].\n\nBecause of the infrequent use of TPE for treatment of thyroid storm/thyrotoxicosis, randomized controlled studies on its efficacy versus continuing with only maximal medical therapy have not yet been performed. Few retrospective reviews on TPE with thyroid storm involving more than one or two patients have been published. In a review by Ezer et al., 11 thyrotoxicosis patients successfully responded to pre-operative plasmapheresis treatment [15]. The etiologies of thyrotoxicosis (7-Graves' Disease, 3-toxic multinodular goiters, 1-iodine induced thyrotoxicosis) and the indications for plasmapheresis varied (7-poor response to medical therapy, 2-agranulocytosis, 1-iodine induced thyrotoxicosis and 1-urgent need for operation). All patients underwent plasmapheresis prior to surgery (10 patients underwent total thyroidectomy and 1 patient underwent an open reduction and internal fixation for femur fracture). The majority of patients required 1 to 3 plasmapheresis sessions to see clinical improvement and reductions in free T4 levels. Only one patient experienced a complication from plasmapheresis, a non-life threatening allergic reaction. Another patient had intraoperative bleeding from operative sites assumed to be secondary to the coagulopathy that can develop from TPE. Additionally, 50% of patients who underwent total thyroidectomy developed transient postoperative hypocalcemia. Hypocalcemia was presumed to be the result of long-term exposure to thyroid hormones with severe untreated hyperthyroidism, though postoperative hypocalcemia may have been due to parathyroid injury during surgery. Hyperthyroidism increases bone turnover which over time can lead to thyrotoxic osteodystrophy. After total thyroidectomy for hyperthyroidism, hypocalcemia can result from rapid recalcification of bones after loss of thyroid hormone stimulation [16].\n\nIn the largest retrospective study to date, 46 patients with thyrotoxicosis who were either unable to use anti-thyroid medications due to side effects, did not improve with standard thyrotoxicosis treatment or needed rapid improvement in thyroid function due to thyroid storm were treated with TPE [17]. Plasmapheresis was performed daily with sessions lasting 2.5–3 hours. The replacement fluid was FFP and the volume of replacement fluid was 1–1.5 times the calculated total plasma volume of the patient. The underlying etiology for the majority of the patients' thyrotoxicosis was Graves' disease with smaller numbers having amiodarone induced thyrotoxicosis or toxic nodular goiter. A significant improvement in free T4 levels from before to after plasmapheresis (free T4 2.9 ng/dL vs. 1.6 ng/dL, P ≤ 0.001) was found in all patients. When stratified by hyperthyroid diagnosis, only the patients with Graves' disease had a statistically significant reduction in free T4 levels with TPE (free T4 2.9 ng/dL vs. 1.6 ng/dL, P ≤ 0.001). While not statistically significant, possibly due to smaller numbers of subjects, the median free T4 did decrease after TPE in the patients with non-Graves' hyperthyroidism (free T4 3.1 ng/dL vs. 1.8 ng/dL, P = NS). In this study, complications related to TPE comprised of a deep vein thrombosis in a pregnant female and 2 catheter infections.\n\n4. Conclusion\nWhile current recommendations regarding TPE for treatment of thyroid storm recommend individualized decision making, little clarification regarding who would be a good candidate is available. In our case report, we present a patient with thyroid storm and multiorgan failure who was ineffectively treated with maximal medical anti-thyroid therapy alone, but was rapidly and successfully treated once plasmapheresis was added to medical anti-thyroid therapy. Our case is one of the first to show that a patient with severe critical multiorgan failure can benefit from TPE. Given our patient's extraordinary recovery and the remarkable improvements in other patients with thyroid storm treated with TPE, endocrinologists should have a lower threshold to pursue treatment of thyroid storm with plasmapheresis if patients are not improving with medical antithyroid therapy alone. Future research is needed to answer questions regarding optimal replacement fluid and volume, frequency, and duration at which TPE should proceed for thyroid storm.\n\nAbbreviations\nMMI:Methimazole\n\nPTU:Propylthiouracil\n\nSSKI:Saturated potassium iodide solution\n\nTPE:Therapeutic plasma exchange\n\nT4:Thyroxine\n\nTBG:Thyroxine binding globulin\n\nT3:Triiodothyronine.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Free T4 and total T3 Levels during hospitalization. ∗Values were >7 ng/dL, → first day of plasmapheresis.\n\nTable 1 Admission laboratory studies.\n\nLab\tResult\tReference range\t\nWBC\t29.7\t4.5–11.0 K/µL\t\nHemoglobin\t10.3\t12.6–17.4 g/dL\t\nPlatelets\t149\t153–367 K/µL\t\nCreatinine\t1.43\t0.66–1.25 mg/dL\t\nAST\t177\t17–59 units/L\t\nALT\t44\t21–72 units/L\t\nTotal bilirubin\t3.8\t0.3–1.2 mg/dL\t\nLactate\t2.8\t0.5–1.6 mmol/L\t\nTroponin\t7.05\t≤0.06 ng/mL\n==== Refs\n1 Tietgens S. T. Leinung M. C. Thyroid storm Medical Clinics of North America 1995 79 1 169 184 10.1016/S0025-7125(16)30090-6 2-s2.0-0028861298 7808090 \n2 Burch H. B. Wartofsky L. Life-threatening thyrotoxicosis. thyroid storm Endocrinology and Metabolism Clinics of North America 1993 22 2 263 277 10.1016/S0889-8529(18)30165-8 8325286 \n3 Akamizu T. Satoh T. Isozaki O. Diagnostic criteria, clinical features, and incidence of thyroid storm based on nationwide surveys Thyroid 2012 22 7 661 679 10.1089/thy.2011.0334 2-s2.0-84863428154 22690898 \n4 Pappa T. Ferrara A. M. Refetoff S. Inherited defects of thyroxine-binding proteins Best Practice & Research Clinical Endocrinology & Metabolism 2015 29 5 735 747 10.1016/j.beem.2015.09.002 2-s2.0-84945974045 26522458 \n5 Leow M. K.-S. A mathematical model of pituitary–thyroid interaction to provide an insight into the nature of the thyrotropin–thyroid hormone relationship Journal of Theoretical Biology 2007 248 2 275 287 10.1016/j.jtbi.2007.05.016 2-s2.0-34548039279 17602707 \n6 Schwartz J. Padmanabhan A. Aqui N. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the american society for apheresis: the seventh special issue Journal of Clinical Apheresis 2016 31 3 149 162 10.1002/jca.21470 2-s2.0-84975795988 27322218 \n7 Satoh T. Isozaki O. Suzuki A. Guidelines for the management of thyroid storm from the Japan thyroid association and Japan endocrine society (first edition) Endocrine Journal 2016 63 12 1025 1064 10.1507/endocrj.EJ16-0336 2-s2.0-85007618830 27746415 \n8 Huestis D. W. Mortality in therapeutic haemapheresis The Lancet 1983 321 8332 p. 1043 10.1016/S0140-6736(83)92664-8 2-s2.0-0021096795 \n9 Ashkar F. S. Katims R. B. Smoak W. M. Thyroid storm treatment with blood exchange and plasmapheresis JAMA: The Journal of the American Medical Association 1970 214 7 1275 1279 10.1001/jama.214.7.1275 5536311 \n10 Petry J. Van Schil P. E. Y. Abrams P. Jorens P. G. Plasmapheresis as effective treatment for thyrotoxic storm after sleeve pneumonectomy The Annals of Thoracic Surgery 2004 77 5 1839 1841 10.1016/S0003-4975(03)01246-3 2-s2.0-1942532740 15111206 \n11 Vyas A. A. Vyas P. Fillipon N. L. Vijayakrishnan R. Trivedi N. Successful treatment of thyroid storm with plasmapheresis in a patient with methimazole-induced agranulocytosis Endocrine Practice 2010 16 4 673 676 10.4158/EP09265.CR 2-s2.0-79952020460 20439250 \n12 Diamond T. H. Rajagopal R. Ganda K. Manoharan A. Luk A. Plasmapheresis as a potential treatment option for amiodarone-induced thyrotoxicosis Internal Medicine Journal 2004 34 6 369 370 10.1111/j.1444-0903.2004.00600.x 2-s2.0-3242812001 15228405 \n13 Carhill A. Gutierrez A. Lakhia R. Nalini R. Surviving the storm: two cases of thyroid storm successfully treated with plasmapheresis BMJ Case Reports 2012 2012 10.1136/bcr2012-006696 \n14 Baena J. C. Padilla J. Guzman G. Thyroid storm associated with multiorganic dysfunction Medicina (B Aires) 2017 77 4 337 440 28825582 \n15 Ezer A. Caliskan K. Parlakgumus A. Belli S. Kozanoglu I. Yildirim S. Preoperative therapeutic plasma exchange in patients with thyrotoxicosis Journal of Clinical Apheresis 2009 24 3 111 114 10.1002/jca.20200 2-s2.0-67449168623 19484727 \n16 Karunakaran P. Maharajan C. Ramalingam S. Rachmadugu S. V. Is hungry bone syndrome a cause of postoperative hypocalcemia after total thyroidectomy in thyrotoxicosis? a prospective study with bone mineral density correlation Surgery 2018 163 2 367 372 10.1016/j.surg.2017.09.008 2-s2.0-85035103440 29146231 \n17 Simsir I. Y. Ozdemir M. Duman S. Erdogan M. Donmez A. Ozgen A. G. Therapeutic plasmapheresis in thyrotoxic patients Endocrine 2018 62 1 144 148 10.1007/s12020-018-1661-x 2-s2.0-85049573906 29968224\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-651X", "issue": "2019()", "journal": "Case reports in endocrinology", "keywords": null, "medline_ta": "Case Rep Endocrinol", "mesh_terms": null, "nlm_unique_id": "101576457", "other_id": null, "pages": "2475843", "pmc": null, "pmid": "31687222", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "20439250;15228405;5536311;15111206;27322218;26522458;7808090;23087271;6133078;28825582;8325286;22690898;19484727;17602707;29146231;27746415;29968224", "title": "Thyroid Storm with Multiorgan Failure Treated with Plasmapheresis.", "title_normalized": "thyroid storm with multiorgan failure treated with plasmapheresis" }

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{ "abstract": "The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is life-threatening. It associates a skin condition with hematological and visceral disorders. The DRESS syndrome diagnosis in the intensive care unit (ICU) is difficult as clinical features are nonspecific. Furthermore, the need to treat patients with multiple drugs usually prevents the identification of the causative drug. We report the case of a patient who developed two bouts of DRESS caused by piperacillin-tazobactam, the first being complicated with a distributive shock. Cases of DRESS occurring inside ICU are seldom reported. However, any intensivist may encounter this situation during his career and should be aware of its diagnostic and management specific aspects.", "affiliations": "Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département de Néonatologie et de Réanimation Néonatale, Hôpital Femme Mère Enfant, 32 Avenue Doyen Jean Lépine, 69500 Bron, France.;Département d'Allergologie et d'Immunologie Clinique, Centre Hospitalier de Lyon-Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France.;Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France; Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France.", "authors": "Moriceau|Florent|F|0000-0003-1699-6757;Prothet|Johanne|J|;Blaise|Benjamin J|BJ|;Ben Said|Benoit|B|;Page|Mathieu|M|;Ber|Charles-Eric|CE|;Crozon|Jullien|J|;Rimmelé|Thomas|T|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/9453286", "fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2016/9453286Case ReportDRESS Syndrome in the ICU: When a Patient Is Treated with Multiple Drugs http://orcid.org/0000-0003-1699-6757Moriceau Florent \n1\n\n*\nProthet Johanne \n1\nBlaise Benjamin J. \n2\nBen Said Benoit \n3\nPage Mathieu \n1\nBer Charles-Eric \n1\nCrozon Jullien \n1\nRimmelé Thomas \n1\n\n4\n1Département d'Anesthésie-Réanimation, Hôpital Edouard Herriot, 5 place d'Arsonval, 69003 Lyon, France2Département de Néonatologie et de Réanimation Néonatale, Hôpital Femme Mère Enfant, 32 Avenue Doyen Jean Lépine, 69500 Bron, France3Département d'Allergologie et d'Immunologie Clinique, Centre Hospitalier de Lyon-Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Bénite, France4Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France*Florent Moriceau: [email protected] Editor: Caterina Mammina\n\n2016 24 1 2016 2016 945328622 11 2015 4 1 2016 Copyright © 2016 Florent Moriceau et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is life-threatening. It associates a skin condition with hematological and visceral disorders. The DRESS syndrome diagnosis in the intensive care unit (ICU) is difficult as clinical features are nonspecific. Furthermore, the need to treat patients with multiple drugs usually prevents the identification of the causative drug. We report the case of a patient who developed two bouts of DRESS caused by piperacillin-tazobactam, the first being complicated with a distributive shock. Cases of DRESS occurring inside ICU are seldom reported. However, any intensivist may encounter this situation during his career and should be aware of its diagnostic and management specific aspects.\n==== Body\n1. Introduction\nThe DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome is a severe drug hypersensitivity reaction. Although it is less known than Lyell or Stevens-Johnson syndromes and less striking than anaphylactic shock, it can result in a dreadful prognosis, with a mortality rate of 2 to 45% [1–3]. DRESS occurring in an intensive care unit (ICU) is a complex situation. It can mimic more usual causes of shock and organ failure, such as sepsis. Furthermore, identifying the responsible treatment may not be straightforward due to the multiple drugs use in the intensive care unit. Finally, the necessity to remove any suspected treatment will make the patient's management more complicated. We report the case of DRESS induced by piperacillin-tazobactam initially identified as a septic shock and reoccurring after the inappropriate reintroduction of a suspected treatment. The patient's family gave a written consent to report this case.\n\n2. Case Report\nA 53-year-old woman was admitted to the ICU due to angiocholitis complicated by a septic shock. She had a medical history of high blood pressure and, despite two episodes of kidney transplantation, she had recently reached end-stage renal disease. She was under antihypertensive therapy and immunosuppressant drugs (prednisolone, mycophenolate, and cyclosporine).\n\nThe early evolution was positive with a probabilistic antibiotherapy associating piperacillin-tazobactam and amikacin. It was decreased to ceftriaxone alone on the fifth day, after the identification of a biliary Klebsiella pneumoniæ pneumoniæ (Figure 1). On the 21st day after the ICU admission, the patient developed another septic shock due to angiocholitis, forcing the reintroduction of the initial probabilistic antibiotherapy. On the 23rd day, the antibiotherapy was modified again to ceftriaxone and vancomycin, after the bloodstream identification of a Pantoea agglomerans and a coagulase-negative Staphylococcus. A third round of septic shock occurred on the 26th day leading us to widen the antibiotherapy, associating piperacillin-tazobactam and amikacin to the already administered vancomycin (Figure 1).\n\nFollowing this last modification, a benign-looking rash appeared on the patient's chest on the 29th day. After 48 h of hemodynamic stability, a high fever and a distributive shock requiring consequent norepinephrine infusion (1 μg/kg/min) emerged. The procalcitonin measurement reached a high level (2.98 μg/L), which was compatible with sepsis. However, the rash evolved into erythrodermia (Figure 2), associated with enlarged cervical and inguinal lymph nodes, eosinophilia (absolute eosinophil count of 1.0 × 109/L), agranulocytosis (absolute neutrophil count of 0.4 × 109/L), and activated circulating T-lymphocytes. These elements led to the diagnosis of DRESS syndrome.\n\nAll drugs introduced at least ten days before the rash were interrupted, except for vasopressors. Vancomycin was replaced by linezolid. A systemic corticotherapy with methylprednisolone (1 mg/kg/d) was initiated, along with the use of granulocyte colony-stimulating factors (G-CSF).\n\nEosinophilia reached a maximum of 4.2 × 109/L on the 32nd day, associated with a thrombocytopenia and a nonregenerative anemia. A myelogram revealed a hypoplastic bone marrow, mostly composed of eosinophils (30%) without hemophagocytic lymphohistiocytosis. A skin biopsy showed basal membrane vacuoles, spongiosis, and an inflammatory infiltration of dermis, described as activated lymphocytes and eosinophils. The Epstein-Barr Virus (EBV) load was found elevated at 700 copies/mL. No differential diagnosis was identified.\n\nThe cutaneous condition improved within 10 days, from the chest to the limbs, with a reepithelialization following a desquamation and blisters. Eosinophilia and agranulocytosis normalized within five days. However, the nonregenerative anemia and the thrombocytopenia remained.\n\nVancomycin was initially suspected. Therefore, piperacillin-tazobactam was used again during another bout of sepsis, after the identification of a sensitive Klebsiella pneumoniæ pneumoniæ (Figure 1). Erythrodermia reoccurred immediately following this reintroduction, with early eosinophilia (absolute eosinophil count of 1.0 × 109/L), deep agranulocytosis (undetectable neutrophils), and hyperlactatemia (3.2 mmol/L), but without hemodynamic instability. This new DRESS was associated with EBV reactivation (viral load of 5,200 copies/mL). A new myelogram reported a highly hypoplastic bone marrow, with more eosinophils (40%) than previously counted, and the noticeable absence of neutrophilic cells. We thus interrupted the piperacillin-tazobactam administration and increased methylprednisolone up to 2 mg/kg/d. Cutaneous and hematological conditions improved within two weeks. This recurrence clearly incriminated piperacillin-tazobactam.\n\nLater evolution was unfortunately negative, with numerous ICU-associated adverse events (ventilator-associated pneumonia, neuromyopathy, and severe malnutrition). The patient died of septic shock complications triggered by pneumonia, on day 102 after ICU admission.\n\n3. Discussion\nAn occurrence of DRESS inside the ICU is difficult to diagnose, and its management is not obvious. In addition, the intensive care specific aspects are seldom mentioned in the literature.\n\nThe DRESS syndrome is a delayed hypersensitivity reaction. Its clinical features include a cutaneous reaction (almost 100% of cases, usually maculopapular, often itchy and extensive to the whole body), a facial edema (76%), a polyadenopathy (54%), a fever (90%), and an organ involvement (91%, either liver, lung, brain, kidney, or heart) [2, 4, 5]. Mortality ranges from 2 to 45% depending on the severity of the organ involvement [1–3, 6]. Few cases of shock have recently been reported, highlighting the need to mention the DRESS syndrome in the diagnosis algorithm of a distributive shock [6]. Hematological abnormalities include a possible eosinophilia (95%) which can be delayed, with either lymphopenia (5%) or lymphocytosis, and often circulating activated T-lymphocytes (67%), as observed in infectious mononucleosis [2]. A hemophagocytic lymphohistiocytosis is not uncommon. It is associated with a worse prognosis and sometimes preceded by biological marker raises (hyperferritinemia, hypertriglyceridemia, and elevated lactate dehydrogenase levels). Procalcitonin can rise regardless of any sepsis [5].\n\nThe pathophysiology of the organ involvement is multifactorial and still not fully understood. Human herpes-virus family reactivations, their local proliferation, and the cytotoxic immune response they induce may be involved. Indeed, viral DNAs have been identified in affected organs, but no causal link has yet been established [3, 7, 8]. The viral load is a diagnosis criterion in some countries [9]. Descamps and Ranger-Rogez also reported a genetic predisposition that influences cytotoxic T-lymphocytes response [5].\n\nThe list of medications that may potentially induce DRESS keeps growing and includes more than 40 drugs. The most frequent triggers are (in descending order) anticonvulsants (carbamazepine, lamotrigine, phenobarbital, phenytoin, and sodium valproate), allopurinol, psychotropic drugs, sulfonamides (dapsone, sulfasalazine, and sulfamethoxazole), antiviral therapies, and antibiotics (mostly vancomycin and beta-lactam antibiotics) [2, 4, 10, 11]. The DRESS syndrome is a relatively rare drug reaction with an incidence of 1/5000 for anticonvulsants [12]. It occurs with a median delay of 22 days after the administration of the causal treatment [2]. Any drug initiated one to four weeks before the rash must be suspected. In the intensive care unit, the use of multiple medications may prevent the identification of the responsible drug. This is usually achieved after full recovery, through further allergological investigations such as skin or immunobiological tests (lymphocytes proliferation and cytokine production assays). In this case, the antibiotic changes increased the number of potential causal drugs. Vancomycin was the initial main suspect as it is the most common trigger for DRESS among antibiotics [2], and as the 10-day delay between introduction and symptoms was compatible with the pathophysiology of the DRESS. Furthermore, piperacillin-tazobactam had seldom been related to DRESS at that time, with only three cases reported [13–15]. Since then, Cabañas et al. have added 8 more [16]. Interestingly, piperacillin-tazobactam had been used only 24 hours before the last onset of symptoms. The delay of the symptoms onset can indeed be dramatically shortened in the case of a previous exposure, as the sensitized antigen-specific T-lymphocytes can remain activated for years [17, 18]. Thus, we observed a shortened delay and an intensified reaction when DRESS reoccurred.\n\nRuling out the differential diagnoses is an additional difficulty in the ICU. DRESS can indeed complicate an underlying condition, such as sepsis with which it shares many clinical features. Kardaun et al. [4] suggested a score that classifies cases as definite, probable, possible, or no case. Relevant clinical features were fever, enlarged lymph nodes, a skin condition, and a late resolution (more than 15 days). Additional criteria were hematological abnormalities (eosinophilia, activated circulating lymphocytes), a compatible skin biopsy, and organ involvement. They also considered the unfruitful research of differential diagnoses, after ruling out autoimmune diseases (lupus, Kawasaki disease), infectious diseases (mononucleosis or other viral exanthems, toxic shock syndrome), and hematological diseases (angioimmunoblastic lymphoma, hypereosinophilic syndrome), to be relevant. In the present case, Kardaun's score reached 8 points, making the diagnosis of DRESS syndrome certain.\n\nThe key element in the management of a patient with DRESS is the early and permanent withdrawal of every suspected medication. The use of strong topical steroids is sufficient for mild cases. Severe cases will require the use of a systemic corticotherapy (methylprednisolone 1-2 mg/kg/d). In our case, the early corticotherapy initiated with 1 mg/kg/d of methylprednisolone allowed a general improvement but did not prevent the recurrence. Full recovery will generally be obtained after weeks, even with an early and optimal management [5]. Intravenous immunoglobulins are no longer recommended due to their frequent secondary effects and lack of benefit compared to corticotherapy [19]. A granulopoietic stimulant (G-CSF) can be discussed. On one hand, it may shorten the duration of agranulocytosis. On the other hand, it may redirect the immune response of T4 lymphocytes from the hyperactivated T helper 1 (Th-1) response to the Th-2 response [20, 21]. Viral reactivations may benefit from a specific treatment.\n\n4. Conclusion\nAny intensivist may encounter or may have to manage a patient with DRESS syndrome. In the ICU, clinical features and organ involvement have a poor specificity. The suspicious drugs are often numerous due to the many treatments used. The prognosis relies on organ failure and delay to the treatment initiation. The early and permanent withdrawal of every suspected causal agent is of primary importance. Any reintroduction of a drug exposes the patient to the risk of a more severe recurrence.\n\nDisclosure\nAll the authors have approved the final paper.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 The chronology of events and drugs use related to DRESS occurrences. D: day; TZP: piperacillin-tazobactam; AMK: amikacin; CTX: ceftriaxone; VA: vancomycin; IMP: imipenem; LIN: linezolid; MP: methylprednisolone. Day 1: admission to the ICU.\n\nFigure 2 Erythrodermia in ICU ventilated patient. Focus on the chest showing a maculopapular rash.\n==== Refs\n1 Bocquet H. Bagot M. Roujeau J. C. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS) Seminars in Cutaneous Medicine and Surgery 1996 15 4 250 257 10.1016/S1085-5629(96)80038-1 2-s2.0-0030441359 9069593 \n2 Kardaun S. H. Sekula P. Valeyrie-Allanore L. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study British Journal of Dermatology 2013 169 5 1071 1080 10.1111/bjd.12501 2-s2.0-84887102194 23855313 \n3 Eshki M. Allanore L. Musette P. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure Archives of Dermatology 2009 145 1 67 72 10.1001/archderm.145.1.67 2-s2.0-58849091724 19153346 \n4 Kardaun S. H. Sidoroff A. Valeyrie-Allanore L. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? British Journal of Dermatology 2007 156 3 609 611 10.1111/j.1365-2133.2006.07704.x 2-s2.0-33846997845 17300272 \n5 Descamps V. Ranger-Rogez S. DRESS syndrome Joint Bone Spine 2014 81 1 15 21 10.1016/j.jbspin.2013.05.002 2-s2.0-84893747138 23816504 \n6 Kimmoun A. Dubois E. Perez P. Barbaud A. Levy B. Shock state: an unrecognized and underestimated presentation of drug reaction with eosinophilia and systemic symptoms Shock 2013 40 5 387 391 10.1097/shk.0000000000000041 2-s2.0-84887101009 24088996 \n7 Mardivirin L. Descamps V. Lacroix A. Delebassée S. Ranger-Rogez S. Early effects of drugs responsible for DRESS on HHV-6 replication in vitro \n Journal of Clinical Virology 2009 46 3 300 302 10.1016/j.jcv.2009.08.006 2-s2.0-72149134631 19758840 \n8 Mardivirin L. Valeyrie-Allanore L. Branlant-Redon E. Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on human herpesvirus 6 replication in vitro European Journal of Dermatology 2010 20 1 68 73 10.1684/ejd.2010.0821 2-s2.0-76749119336 19822481 \n9 Shiohara T. Iijima M. Ikezawa Z. Hashimoto K. The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations British Journal of Dermatology 2007 156 5 1083 1084 10.1111/j.1365-2133.2007.07807.x 2-s2.0-34247329801 17381452 \n10 Cacoub P. Musette P. Descamps V. The DRESS syndrome: a literature review American Journal of Medicine 2011 124 7 588 597 10.1016/j.amjmed.2011.01.017 2-s2.0-79959337439 21592453 \n11 Um S. J. Lee S. K. Kim Y. H. Clinical features of drug-induced hypersensitivity syndrome in 38 patients Journal of Investigational Allergology and Clinical Immunology 2010 20 7 556 562 2-s2.0-79251486696 21313995 \n12 Tennis P. Stern R. S. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study Neurology 1997 49 2 542 546 10.1212/wnl.49.2.542 2-s2.0-0030749007 9270593 \n13 Jurado-Palomo J. Cabañas R. Prior N. Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillintazobactam: two case reports Journal of Investigational Allergology and Clinical Immunology 2010 20 5 433 436 2-s2.0-78649363676 20945612 \n14 Cabañas R. Muñoz L. López-Serrano C. Hypersensitivity to piperacillin Allergy 1998 53 8 819 820 2-s2.0-0031878164 9722239 \n15 Fahim S. Jain V. Victor G. Pierscianowski T. Piperacillin-tazobactam-induced drug hypersensitivity syndrome Cutis 2006 77 6 353 357 2-s2.0-33745844489 16838767 \n16 Cabañas R. Calderón O. Ramírez E. Piperacillin-induced DRESS: distinguishing features observed in a clinical and allergy study of 8 patients Journal of Investigational Allergology and Clinical Immunology 2014 24 6 425 430 2-s2.0-84918812712 25668894 \n17 Wu Y. Farrell J. Pirmohamed M. Park B. K. Naisbitt D. J. Generation and characterization of antigen-specific CD4+ , CD8+ , and CD4+ CD8+ T-cell clones from patients with carbamazepine hypersensitivity Journal of Allergy and Clinical Immunology 2007 119 4 973 981 10.1016/j.jaci.2006.12.617 2-s2.0-34047103842 17320939 \n18 Rozieres A. Vocanson M. Saïd B. B. Nosbaum A. Nicolas J.-F. Role of T cells in nonimmediate allergic drug reactions Current Opinion in Allergy and Clinical Immunology 2009 9 4 305 310 10.1097/ACI.0b013e32832d565c 2-s2.0-68649096857 19474707 \n19 Joly P. Janela B. Tetart F. Poor benefit/risk balance of intravenous immunoglobulins in DRESS Archives of Dermatology 2012 148 4 543 544 10.1001/archderm.148.4.dlt120002-c 2-s2.0-84859958072 22508885 \n20 Nishio D. Izu K. Kabashima K. Tokura Y. T cell populations propagating in the peripheral blood of patients with drug eruptions Journal of Dermatological Science 2007 48 1 25 33 10.1016/j.jdermsci.2007.05.013 2-s2.0-34548031382 17601705 \n21 Franzke A. Piao W. Lauber J. G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases Blood 2003 102 2 734 739 10.1182/blood-2002-04-1200 2-s2.0-0037818348 12676791\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6420", "issue": "2016()", "journal": "Case reports in critical care", "keywords": null, "medline_ta": "Case Rep Crit Care", "mesh_terms": null, "nlm_unique_id": "101598416", "other_id": null, "pages": "9453286", "pmc": null, "pmid": "26904309", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "19758840;19474707;17320939;17300272;25668894;21313995;17601705;22508885;9722239;12676791;23816504;20945612;21592453;19822481;17381452;16838767;23855313;9069593;9270593;24088996;19153346", "title": "DRESS Syndrome in the ICU: When a Patient Is Treated with Multiple Drugs.", "title_normalized": "dress syndrome in the icu when a patient is treated with multiple drugs" }

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"drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (26TH DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, (23RD DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEPTIC SHOCK", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LINEZOLID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIBIOTIC THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINEZOLID." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Cholangitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Pantoea agglomerans infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Hyperlactacidaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Pneumonia", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Neuromyopathy", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Distributive shock", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Klebsiella infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Staphylococcal infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null }, { "reactionmeddrapt": "Epstein-Barr virus infection", "reactionmeddraversionpt": "19.0", "reactionoutcome": null } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20120502" } }, "primarysource": { "literaturereference": "MORICEAU, F.. DRESS SYNDROME IN THE ICU: WHEN A PATIENT IS TREATED WITH MULTIPLE DRUGS. CASE REPORTS IN CRITICAL CARE (ONLINE). 2016;9453286", "literaturereference_normalized": "dress syndrome in the icu when a patient is treated with multiple drugs", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20160427", "receivedate": "20160325", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12211272, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "During the coronavirus disease 2019 (COVID-19) pandemic, a rapid screening method for COVID-19 detection is needed to decide the appropriate strategy to treat stroke patients. In acute ischemic stroke treatment, the efficacy and safety of emergent carotid artery stenting (eCAS) for hyperacute ischemic stroke (hAIS) due to internal carotid artery stenosis (ICS) have not been sufficiently established.\n\n\n\nA 71-year-old man with hAIS caused by severe ICS was treated via intravenous alteplase infusion. The patient underwent screening for COVID-19 by the loop-mediated isothermal amplification (LAMP) assay shortly after arrival at our institution. The LAMP result was obtained within 90 minutes, during intravenous alteplase infusion, and turned out to be negative. The symptom of hemiplegia worsened during alteplase infusion, and he, therefore, underwent eCAS after administration of aspirin (200 mg). Recanalization was achieved successfully by eCAS, and dual antiplatelet therapy and argatroban were administrated following eCAS. Hemorrhagic complications or restenosis/occlusion of the carotid artery were not observed. He was discharged without neurologic deficits 15 days following eCAS. Because of the rapid negative diagnosis for COVID-19 using the LAMP method, eCAS could be performed following standard procedures, along with infectious defense, without delay.\n\n\n\nThis case report suggests that eCAS for hAIS due to ICS following intravenous alteplase can be an effective treatment, along with appropriate antiplatelet medication and management in select patients. During the COVID-19 pandemic, the LAMP assay for COVID-19 detection might be a suitable diagnostic strategy preceding stroke treatment because of the rapid turnaround time.", "affiliations": "Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan. Electronic address: [email protected].;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.;Department of Neurosurgery, International University of Health and Welfare, School of Medicine, Narita Hospital, Narita City, Chiba, Japan.", "authors": "Michiwaki|Yuhei|Y|;Tanaka|Tatsuya|T|;Wakamiya|Tomihiro|T|;Tabei|Yusuke|Y|;Samura|Kazuhiro|K|;Suehiro|Eiichi|E|;Kawashima|Masatou|M|", "chemical_list": "D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban", "country": "United States", "delete": false, "doi": "10.1016/j.wneu.2020.09.166", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-8750", "issue": "145()", "journal": "World neurosurgery", "keywords": "Acute ischemic stroke; Alteplase; COVID-19; Carotid artery stenting; Emergency; LAMP assay", "medline_ta": "World Neurosurg", "mesh_terms": "D000368:Aged; D001120:Arginine; D000086382:COVID-19; D016893:Carotid Stenosis; D003131:Combined Modality Therapy; D005343:Fibrinolytic Agents; D006429:Hemiplegia; D006801:Humans; D000083242:Ischemic Stroke; D008279:Magnetic Resonance Imaging; D008297:Male; D025202:Molecular Diagnostic Techniques; D021141:Nucleic Acid Amplification Techniques; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D015607:Stents; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "101528275", "other_id": null, "pages": "356-359", "pmc": null, "pmid": "33045450", "pubdate": "2021-01", "publication_types": "D002363:Case Reports", "references": "32295835;31978945;32228369;32333644;25517348;25671798;25671797;18403765;22170821;25882510;27725550;32277754;26898852;32361529;25882376;22115640;32387786;15891193;7477192;32276116;32253352;32233980;18815396", "title": "Emergent Carotid Artery Stenting Following Intravenous Alteplase Infusion After Rapid Negative Diagnosis for COVID-19 by Loop-Mediated Isothermal Amplification Assay.", "title_normalized": "emergent carotid artery stenting following intravenous alteplase infusion after rapid negative diagnosis for covid 19 by loop mediated isothermal amplification assay" }

[ { "companynumb": "JP-ROCHE-2714241", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "103172", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ISCHAEMIC STROKE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2020", "drugstartdateformat": "602", "drugstructuredosagenumb": ".6", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTILYSE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "103172", "drugbatchnumb": "ASKED BUT UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CAROTID ARTERY STENOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTILYSE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DABIGATRAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DABIGATRAN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ASPIRIN." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hemiplegia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2020" } }, "primarysource": { "literaturereference": "MICHIWAKI Y, TANAKA T, WAKAMIYA T, TABEI Y, SAMURA K, SUEHIRO E, ET AL. EMERGENT CAROTID ARTERY STENTING FOLLOWING INTRAVENOUS ALTEPLASE INFUSION AFTER RAPID NEGATIVE DIAGNOSIS FOR COVID-19 BY LOOP-MEDIATED ISOTHERMAL AMPLIFICATION ASSAY.. WORLD NEUROSURGERY. ?145:356-359.", "literaturereference_normalized": "emergent carotid artery stenting following intravenous alteplase infusion after rapid negative diagnosis for covid 19 by loop mediated isothermal amplification assay", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20201117", "receivedate": "20201117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 18511451, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]

{ "abstract": "OBJECTIVE\nTricyclic antidepressants (TCAs) are still widely used and are available to purchase without prescription in some countries. Awareness of adverse cutaneous drug reactions is essential.\n\n\nMETHODS\nWe reported a case of photo-distributed hyperpigmentation due to imipramine and carried out a systematic search of the related articles using the search terms \"tricyclic antidepressants\" or \"tricyclic antidepressive agents\", and \"hyperpigmentation\" or \"photosensitivity disorder\". Fifty non-duplicate citations were identified of which 28 articles which were independently assessed in full. The review was registered in PROSPERO, CRD42018107338.\n\n\nRESULTS\nThe remaining 25 articles met our inclusion criteria. Photo-distributed hyperpigmentation tricyclic antidepressant-induced photosensitivity reactions (TIPs) was the most common presentation. In 21 cases, this presented as an asymptomatic discolouration of exposed sites. Imipramine (81%), amitriptyline (9.5%), desipramine hydrochloride (4.8%) and mirtazapine (4.8%) were reported to be the culprit drugs. Nineteen were female with a mean age at presentation of 55 years. Mean duration from commencing the culprit drug until the development of discolouration was 10.4 years. Mean daily dose was 222.7 mg for imipramine. Histology was characteristic with golden-brown or brownish granules deposited in dermis. Staining for Masson-Fontana and MEL-5 was positive in all cases. Phototesting had not been done in cases prior to ours (negative 3 months after discontinuation of imipramine). Three further reports of suspected TIP presented with non-specific and eczematous eruption. The two presentations were reported along with systemic problems (thrombocytopenia and hepatic injury).\n\n\nCONCLUSIONS\nThis systematic review highlights the characteristic features of exposed site hyperpigmentation of TCA-induced photosensitivity occurring after prolonged drug exposure in many cases.", "affiliations": "Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Dermatopathology Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.;Photobiology Unit, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK.", "authors": "Boontaveeyuwat|Einapak|E|;Steyn|Mia|M|;Rickaby|William|W|;Mcfadden|John P|JP|;Sarkany|Robert P E|RPE|;Fityan|Adam|A|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1111/phpp.12724", "fulltext": null, "fulltext_license": null, "issn_linking": "0905-4383", "issue": null, "journal": "Photodermatology, photoimmunology & photomedicine", "keywords": "hyperpigmentation; imipramine; photocontact allergy; phototoxicity; tricyclic antidepressants", "medline_ta": "Photodermatol Photoimmunol Photomed", "mesh_terms": null, "nlm_unique_id": "9013641", "other_id": null, "pages": null, "pmc": null, "pmid": "34358364", "pubdate": "2021-08-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Tricyclic antidepressant-induced photosensitivity; A case report and systematic review.", "title_normalized": "tricyclic antidepressant induced photosensitivity a case report and systematic review" }

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"activesubstance": { "activesubstancename": "ATORVASTATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATORVASTATIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DOCUSATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCUSATE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VITAMIN D3" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN", "drugenddate": null, "drugenddateformat": null, "drugindication": "Product used for unknown indication", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Photosensitivity reaction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Skin hyperpigmentation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Boontaveeyuwat E, Steyn M, Rickaby W, Mcfadden JP, Sarkany RPE, Fityan A. Tricyclic antidepressant-induced photosensitivity; a case report and systematic review. Photodermatology Photoimmunology and Photomedicine. 2022;38(2):112-122", "literaturereference_normalized": "tricyclic antidepressant induced photosensitivity a case report and systematic review", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20220430", "receivedate": "20220418", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20720100, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 2, "seriousnesslifethreatening": 2, "seriousnessother": 2, "transmissiondate": "20220721" } ]

{ "abstract": "The mortality associated with unresectable or metastatic melanoma remains high despite of the emergence of new anti-tumor agents. In this case report, we present two metastatic melanoma patients with copy number variations (CNVs) of cyclin dependent kinase 4 (CDK4) pathway-related genes, who had failed in previous chemotherapy or immunotherapy, were treated with CDK4/6 inhibitor palbociclib and achieved tumor control for over 6 months. The copy number of CDK4, CCND1 and P16INK4a of one patient was 3.6, 3, 2 copies, and for the other patient, the copy number was 3, 2, 1 respectively. It indicates that CDK4 may be a potential target for melanoma.", "affiliations": "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing 100142, China. [email protected].", "authors": "Tang|Bixia|B|;Sheng|Xinan|X|;Kong|Yan|Y|;Chi|Zhihong|Z|;Si|Lu|L|;Cui|Chuanliang|C|;Yan|Xieqiao|X|;Mao|Lili|L|;Lian|Bin|B|;Li|Siming|S|;Wang|Xuan|X|;Dai|Jie|J|;Bai|Xue|X|;Zhou|Li|L|;Guo|Jun|J|", "chemical_list": "D010879:Piperazines; D011725:Pyridines; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib", "country": "China", "delete": false, "doi": "10.21037/cco.2018.06.08", "fulltext": null, "fulltext_license": null, "issn_linking": "2304-3865", "issue": "7(6)", "journal": "Chinese clinical oncology", "keywords": "Metastatic; cyclin dependent kinase 4 (CDK4); melanoma; mutation; palbociclib", "medline_ta": "Chin Clin Oncol", "mesh_terms": "D000328:Adult; D051358:Cyclin-Dependent Kinase 4; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008545:Melanoma; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines; D011725:Pyridines", "nlm_unique_id": "101608375", "other_id": null, "pages": "62", "pmc": null, "pmid": "30180747", "pubdate": "2018-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Palbociclib for treatment of metastatic melanoma with copy number variations of CDK4 pathway: case report.", "title_normalized": "palbociclib for treatment of metastatic melanoma with copy number variations of cdk4 pathway case report" }

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{ "abstract": "BACKGROUND\nINI1-deficient undifferentiated rhabdoid carcinoma is a rare pancreatic carcinoma for which the optimal treatment is unknown. Pancreatic ductal adenocarcinoma, the most common histology of pancreas cancer, is treated with combination chemotherapy in the advanced setting, a strategy supported by strong evidence in well powered studies. In patients with excellent performance status, first-line treatment usually consists of the three-drug regimen FOLFIRINOX, with the combination of gemcitabine with nab-paclitaxel, typically less toxic than the three-drug regimen, reserved for second-line therapy. Given the lack of published reports describing treatment outcomes for patients with rare forms of pancreatic cancer, the same treatment approach used for pancreatic ductal adenocarcinoma is typically employed.\n\n\nMETHODS\nThis case describes a patient with metastatic pancreatic INI1-deficient undifferentiated rhabdoid carcinoma who was primarily resistant to FOLFIRINOX therapy but who then achieved an immediate, marked and sustained response to gemcitabine with nab-paclitaxel.\n\n\nCONCLUSIONS\nGiven the lack of data informing on optimal management of INI1-deficient pancreatic undifferentiated rhabdoid carcinoma, and the exceptional response achieved by gemcitabine with nab-paclitaxel, this case report highlights a surprising and potentially informative anecdote. Additional studies are needed to confirm responses observed in this report which when taken together may strongly influence first-line therapy choice for this rare malignancy. Given the difficult in acquiring sufficient numbers of these rare histologies in any one institution, multi-institution collaboration in studying outcomes of rare pancreatic malignancies is likely essential.", "affiliations": "Department of Medicine, Stanford University, Stanford, CA, USA.;Department of Medicine, Stanford University, Stanford, CA, USA.;Department of Pathology, Stanford University, Stanford, CA, USA.;Department of Medicine, Stanford University, Stanford, CA, USA.", "authors": "King|Daniel A|DA|;Rahalkar|Smruti|S|;Bingham|David B|DB|;Fisher|George A|GA|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/jgo-20-478", "fulltext": null, "fulltext_license": null, "issn_linking": "2078-6891", "issue": "12(2)", "journal": "Journal of gastrointestinal oncology", "keywords": "INI1-deficient undifferentiated rhabdoid carcinoma; case report; pancreatic cancer; sarcomatoid undifferentiated carcinoma", "medline_ta": "J Gastrointest Oncol", "mesh_terms": null, "nlm_unique_id": "101557751", "other_id": null, "pages": "874-879", "pmc": null, "pmid": "34012674", "pubdate": "2021-04", "publication_types": "D002363:Case Reports", "references": "20195681;31433515;26372701;22409864;26151040;21345145;30980040;31146420;25103069;27811314;11420713;21934399;20979179;27528705;26941181;21561347", "title": "Pancreatic INI1-deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab-paclitaxel following immediate progression on FOLFIRINOX: a case report.", "title_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report" }

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PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. 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PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. JOURNAL OF GASTROINTESTINAL ONCOLOGY. 2021?12(2):874?9", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210804", "receivedate": "20210804", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19657698, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20211014" }, { "companynumb": "US-DRREDDYS-USA/USA/21/0135960", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "091365", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201907" } }, "primarysource": { "literaturereference": "KING D, RAHALKAR S, BINGHAM B, FISHER A. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. J GASTROINTEST ONCOL. 2021?12(2):874?9. DOI:10.21037/JGO?20?478", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210529", "receivedate": "20210529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19331759, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-MYLANLABS-2021M1032244", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "850 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FREQUENCY WAS REDUCED TO EVERY OTHER WEEK AFTER 2 MONTHS OF THERAPY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202668", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUOROURACIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "FREQUENCY WAS REDUCED TO EVERY OTHER WEEK AFTER 2 MONTHS OF THERAPY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201906" } }, "primarysource": { "literaturereference": "KING DA, RAHALKAR S, BINGHAM DB, FISHER GA. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. J?GASTROINTEST?ONCOL 2021?12(2):874?879.", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210602", "receivedate": "20210602", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19367270, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "US-TEVA-2021-US-1920111", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "079160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078589", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "100", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAB?PACLITAXEL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "IRINOTECAN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "078589", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "5?FLUOROURACIL" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAB?PACLITAXEL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "RECEIVED THREE DOSES AS PART OF THE MFOLFIRINOX REGIMEN", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201906", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "OXALIPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "022160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHABDOID TUMOUR", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXALIPLATIN." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "079160", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANCREATIC CARCINOMA METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201907", "drugstartdateformat": "610", "drugstructuredosagenumb": "850", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." } ], "patientagegroup": "5", "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rash", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neuropathy peripheral", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201906" } }, "primarysource": { "literaturereference": "KING DA, RAHALKAR S, BINGHAM DB, FISHER GA. PANCREATIC INI1?DEFICIENT UNDIFFERENTIATED RHABDOID CARCINOMA ACHIEVES COMPLETE CLINICAL RESPONSE ON GEMCITABINE AND NAB?PACLITAXEL FOLLOWING IMMEDIATE PROGRESSION ON FOLFIRINOX: A CASE REPORT. J?GASTROINTEST?ONCOL 2021?12(2):874?879.", "literaturereference_normalized": "pancreatic ini1 deficient undifferentiated rhabdoid carcinoma achieves complete clinical response on gemcitabine and nab paclitaxel following immediate progression on folfirinox a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210621", "receivedate": "20210610", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19399945, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Hyponatraemia is the commonest electrolyte abnormality and has major clinical implications. However, few studies of hyponatraemia in the primary care setting has been published to date.\n\n\n\nTo determine the prevalence, potential causes and management of hyponatraemia and to identify factors associated with severity of hyponatraemia among older persons in a primary care setting.\n\n\n\nElectronic records were searched to identify all cases aged ≥60 years with a serum sodium <135mmol/l, attending outpatient clinic in 2014. Patients' medical records with the available blood test results of glucose, potassium, urea and creatinine were reviewed.\n\n\n\nOf the 21,544 elderly, 5873 patients (27.3%) had electrolyte profile tests. 403 (6.9%) had hyponatraemia in at least one blood test. Medical records were available for 253, mean age 72.9±7.3 years, 178 (70.4%) had mild hyponatraemia, 75 (29.6%) had moderate to severe hyponatraemia. Potential causes were documented in 101 (40%). Patients with moderate to severe hyponatraemia were five times more likely to have a cause of hyponatraemia documented (p<0.01). Medications were the commonest documented cause of hyponatraemia (31.7%). Hydrochlorothiazide use was attributed in 25 (78.1%) of 32 with medication-associated hyponatraemia. Repeat renal profile (89%) was the commonest management of hypotonic hyponatraemia.\n\n\n\nWhilst hyponatraemia was common in the clinic setting, many cases were not acknowledged and had no clear management strategies. In view of mild hyponatraemia has deleterious consequences, future studies should determine whether appropriate management of mild hyponatraemia will lead to clinical improvement.", "affiliations": "Simpang Health Clinic, Taiping, Perak, Malaysia. [email protected].;Institute of Applied Health Sciences, School of Medicine, Medical Sciences & Nutrition College of Life Sciences & Medicine, University of Aberdeen, United Kingdom.;University of Malaya Medical Centre, Department of Primary Care Medicine, Kuala Lumpur, Malaysia.;Aberdeen Royal Infirmary Foresterhill, Department of Geriatric Medicine, Aberdeen, United Kingdom.;University of Malaya Medical Centre, Department of Medicine, Geriatric Unit, Kuala Lumpur, Malaysia.", "authors": "Tay|C L|CL|;Myint|P K|PK|;Mohazmi|M|M|;Soiza|R L|RL|;Tan|M P|MP|", "chemical_list": null, "country": "Malaysia", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-5283", "issue": "74(2)", "journal": "The Medical journal of Malaysia", "keywords": null, "medline_ta": "Med J Malaysia", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006784:Hospitals, Teaching; D006801:Humans; D007010:Hyponatremia; D015994:Incidence; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011320:Primary Health Care; D012720:Severity of Illness Index", "nlm_unique_id": "0361547", "other_id": null, "pages": "121-127", "pmc": null, "pmid": "31079122", "pubdate": "2019-04", "publication_types": "D016428:Journal Article", "references": null, "title": "Prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic.", "title_normalized": "prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic" }

[ { "companynumb": "MY-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-251389", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FUROSEMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "070043", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FUROSEMIDE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAY CL, MYINT PK, MOHAMED M, SOIZA RL, TAN MP. PREVALENCE AND DOCUMENTED CAUSES OF HYPONATRAEMIA AMONG GERIATRIC PATIENTS ATTENDING A PRIMARY CARE CLINIC. MED J MALAYSIA. 2019?74(2):121?127", "literaturereference_normalized": "prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17982842, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "MY-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-214220", "fulfillexpeditecriteria": "1", "occurcountry": "MY", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "40810", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROCHLOROTHIAZIDE." } ], "patientagegroup": "6", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "TAY CL, MYINT PK, MOHAMED M, SOIZA RL, TAN MP. PREVALENCE AND DOCUMENTED CAUSES OF HYPONATRAEMIA AMONG GERIATRIC PATIENTS ATTENDING A PRIMARY CARE CLINIC. MED J MALAYSIA. 2019?74(2):121?127", "literaturereference_normalized": "prevalence and documented causes of hyponatraemia among geriatric patients attending a primary care clinic", "qualification": "3", "reportercountry": "MY" }, "primarysourcecountry": "MY", "receiptdate": "20200706", "receivedate": "20200706", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17982271, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Mycobacterium chelonae is a rapidly growing mycobacterium that has the potential to cause refractory infections in humans. Mycobacteremia resulting from the organism is extremely rare, and its clinical features are yet to be uncovered. We herein present a case of M. chelonae bloodstream infection involving an immunocompromised older patient. A 79-year-old woman, on a long-term treatment with prednisolone plus tacrolimus for rheumatoid arthritis, visited our outpatient department complaining of deteriorating pain and swelling at her right 1st toe. Laboratory parameters showed elevated C-reactive protein and leukocytosis, and magnetic resonance imaging indicated osteomyelitis at the proximal phalanx of her right 1st toe. Considering the refractory course, the infected toe was immediately amputated. M. chelonae was isolated from bacterial cultures of the resected tissue and blood (BD BACTEC™ FX blood culture system, Becton Dickinson, Sparks, MD, USA), leading to a diagnosis of disseminated M. chelonae infection. We treated the patient with an antibiotic combination of clarithromycin, minocycline, and imipenem (2 weeks), which was converted to oral therapy of clarithromycin, doxycycline, and levofloxacin. This case highlighted the potential pathogenesis of M. chelonae to cause mycobacteremia in an immunocompromised patient.", "affiliations": "Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address: [email protected].;Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, Japan.;Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.", "authors": "Ueda|Yayoi|Y|;Tokumasu|Kazuki|K|;Hagiya|Hideharu|H|;Iio|Koji|K|;Fujimori|Takumi|T|;Kakehi|Ayaka|A|;Okura|Mami|M|;Minabe|Hiroshi|H|;Otsuka|Fumio|F|", "chemical_list": "D000900:Anti-Bacterial Agents", "country": "Netherlands", "delete": false, "doi": "10.1016/j.jiac.2020.03.004", "fulltext": null, "fulltext_license": null, "issn_linking": "1341-321X", "issue": "26(8)", "journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy", "keywords": "Mycobacteremia; Mycobacterium chelonae; Non-tuberculous mycobacteria; Osteomyelitis; Rapidly growing mycobacteria; Rheumatoid arthritis", "medline_ta": "J Infect Chemother", "mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008279:Magnetic Resonance Imaging; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D010019:Osteomyelitis; D014034:Toes; D016896:Treatment Outcome", "nlm_unique_id": "9608375", "other_id": null, "pages": "843-846", "pmc": null, "pmid": "32402735", "pubdate": "2020-08", "publication_types": "D002363:Case Reports", "references": null, "title": "Mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe: A case report.", "title_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report" }

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MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. J INFECT CHEMOTHER. 2020 MAY 10:S1341-321X(20)30082-9. DOI: 10.1016/J.JIAC.2020.03.004.", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200601", "receivedate": "20200601", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17845745, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "JP-TEVA-2020-JP-1824693", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "080354", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM DAILY; LONG?TERM THERAPY, HAD BEEN RECEIVING FOR 3 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM DAILY; 250MG TWICE DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "CELLULITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN?CLAVULANATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM DAILY; LONG?TERM THERAPY, HAD BEEN RECEIVING FOR 2 YEARS", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": "6", "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "26.5", "reaction": [ { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteomyelitis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, IIO K, FUJIMORI T, KAKEHI A, ET AL. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. J?INFECT?CHEMOTHER 2020?26(8):843?846.", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200915", "receivedate": "20200908", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18239995, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20201103" }, { "companynumb": "JP-ACCORD-183152", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LONG-TERM TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "091195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "LONG-TERM TREATMENT", "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "26.5", "reaction": [ { "reactionmeddrapt": "Osteomyelitis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, IIO K, FUJIMORI T, KAKEHI A, ET AL. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. J INFECT CHEMOTHER. 2020 MAY 10:S1341-321X(20)30082-9.", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200604", "receivedate": "20200528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17833241, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" }, { "companynumb": "JP-BAUSCH-BL-2020-014862", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "75250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": "26.5", "reaction": [ { "reactionmeddrapt": "Mycobacterium chelonae infection", "reactionmeddraversionpt": "23.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "UEDA Y, TOKUMASU K, HAGIYA H, LIO K, FUJIMORI T, KAKEHI A, OKURA M, MINABE H, OTSUKA F. MYCOBACTERIUM CHELONAE BLOODSTREAM INFECTION INDUCED BY OSTEOMYELITIS OF TOE: A CASE REPORT. JOURNAL OF INFECTION AND CHEMOTHERAPY. 2020 MAY 10?1-4. DOI:10.1016/J.JIAC.2020.03.004", "literaturereference_normalized": "mycobacterium chelonae bloodstream infection induced by osteomyelitis of toe a case report", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200526", "receivedate": "20200526", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17826593, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200714" } ]