BioDEX/raw_dataset · Datasets at Hugging Face

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{ "abstract": "OBJECTIVE\nThe aim of this study was to explore the effects of early oral ibuprofen administration on the incidence of hemodynamically significant patent ductus arteriosus (hsPDA) and define the association between serum ibuprofen levels and ductal closure.\n\n\nMETHODS\nPreterm infants with a gestational age of <28 weeks and/or birth weight of <1,000 g were randomized either to the intervention (ibuprofen prophylaxis) or control group. The intervention group received oral ibuprofen 10 mg/kg within 12-24 h after birth followed by 5 mg/kg at 24 and 48 h. Serum ibuprofen levels after the treatment were analyzed in the intervention group, and the incidence of hsPDA and complication rates were compared between two groups.\n\n\nRESULTS\nNineteen infants who received one course (three doses) of prophylactic ibuprofen in the intervention group and 17 infants in the control group who underwent an echocardiographic examination on the fourth day of life were analyzed. hsPDA was observed in five (26 %) infants in the intervention group and ten (58 %) infants in the control group (p = 0.09). In the intervention group two infants experienced gastrointestinal bleeding two infants had spontaneous intestinal perforation, and two infants developed acute kidney failure. Mean serum ibuprofen level was 28.7 ± 16.9 mg/L in the intervention group, and there was no correlation between ibuprofen level obtained on the fourth day and ductal closure.\n\n\nCONCLUSIONS\nOral ibuprofen prophylaxis reduces the rates of hsPDA even it is not statistically significant. The ductal closure rate did not correlate with serum ibuprofen levels. Due to high prevalence of adverse events observed, our data do not support the use of oral ibuprofen for prophylaxis of hsPDA.", "affiliations": "Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey. [email protected]", "authors": "Kanmaz\|Gozde\|G\|;Erdeve\|Omer\|O\|;Canpolat\|Fuat Emre\|FE\|;Oğuz\|Serife Suna\|SS\|;Uras\|Nurdan\|N\|;Altug\|Nahide\|N\|;Greijdanus\|Ben\|B\|;Dilmen\|Uğur\|U\|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen", "country": "Germany", "delete": false, "doi": "10.1007/s00228-012-1438-8", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-6970", "issue": "69(5)", "journal": "European journal of clinical pharmacology", "keywords": null, "medline_ta": "Eur J Clin Pharmacol", "mesh_terms": "D000284:Administration, Oral; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004374:Ductus Arteriosus, Patent; D005260:Female; D006801:Humans; D007052:Ibuprofen; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D008297:Male", "nlm_unique_id": "1256165", "other_id": null, "pages": "1075-81", "pmc": null, "pmid": "23128963", "pubdate": "2013-05", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial", "references": "22147286;2007940;11673749;9099319;1972434;21840880;12774141;22794156;413500;8397375;15001951;17564958;18307541;17768157;21089127;16696414;10974138;10693094;20876595;16322158;6909683;21094951;12971028;19620202;3516077;19255990", "title": "Serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus.", "title_normalized": "serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus" }	[ { "companynumb": "US-JNJFOC-20150219051", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017463", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PATENT DUCTUS ARTERIOSUS", "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": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KANMAZ G, ERDEVE O, CEANPOLAT FE, DGUZ SS, URAS, N, ALTUG N, ET AL. SERUM IBUPROFEN LEVELS OF EXTREMELY PRETERM INFANTS TREATED PROPHYLACTICALLY WITH ORAL IBUPROFEN TO PREVENT PATENT DUCTUS ARTERIOSUS. EUR.J CUN PHARMACAL 2013;69(5):1075-81.", "literaturereference_normalized": "serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150226", "receivedate": "20150226", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10870885, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "Cystic fibrosis (CF) patients receive many antibiotic treatments for recurrent respiratory infections and frequently report antibiotic hypersensitivity reactions (HSRs). In this retrospective study, medical records of CF patients were reviewed to clarify the clinical features, the culprit antibiotics, and the prevalence of antibiotic HSRs in the CF population. From 601 CF patients, 95 suspected antibiotic HSRs occurred in 60 patients (prevalence of 10.0%). β-Lactams were the most common inducers, but cotrimoxazole was also frequently involved. Seventy-six of 95 suspected HSRs were assessed by allergy workup including skin tests (43/76 reactions) and/or drug reintroduction as a full course of the culprit antibiotic (73 of 76 reactions). From the 43 suspected HSRs that were skin-tested, only three had positive skin tests and were not subjected to drug readministration. All the other 73 suspected HSRs received a full course of the culprit antibiotic: HSR symptoms recurred in 10 of 73 cases and therefore were considered as confirmed antibiotic HSRs; for the remaining 63 suspected HSRs that did not relapse after drug readministration, the diagnosis of antibiotic HSRs was excluded. In summary, 13 of 76 suspected HSRs were confirmed as antibiotic HSRs. The prevalence of suspected and confirmed antibiotic HSRs in CF patients appears similar to that reported in the general population. Of note, most of the antibiotic suspected HSRs are not confirmed after allergology workup. A complete allergy workup appears therefore crucial to make a correct diagnosis and to avoid unnecessary contraindication of major antibiotics.", "affiliations": "University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;Internal Medicine and Vascular Pathology Department, Adult Cystic Fibrosis Center, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Internal Medicine and Vascular Pathology Department, Adult Cystic Fibrosis Center, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Pediatric Pulmonology and Allergology Department, Pediatric Cystic Fibrosis Center, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;Pediatric Pulmonology and Allergology Department, Pediatric Cystic Fibrosis Center, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.", "authors": "Braun\|Camille\|C\|0000-0001-9260-8977;Reix\|Philippe\|P\|;Durieu\|Isabelle\|I\|;Nove-Josserand\|Raphaele\|R\|;Durupt\|Stéphane\|S\|;Ohlmann\|Camille\|C\|;Mainguy\|Catherine\|C\|;Nicolas\|Jean-François\|JF\|;Nosbaum\|Audrey\|A\|;Jubin\|Virginie\|V\|", "chemical_list": "D000900:Anti-Bacterial Agents; D047090:beta-Lactams", "country": "England", "delete": false, "doi": "10.1111/pai.13206", "fulltext": null, "fulltext_license": null, "issn_linking": "0905-6157", "issue": "31(4)", "journal": "Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology", "keywords": "allergy workup; antibiotic; cystic fibrosis; hypersensitivity", "medline_ta": "Pediatr Allergy Immunol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D002648:Child; D003550:Cystic Fibrosis; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D012882:Skin Tests; D055815:Young Adult; D047090:beta-Lactams", "nlm_unique_id": "9106718", "other_id": null, "pages": "396-404", "pmc": null, "pmid": "31880334", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": null, "title": "The diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work-up in cystic fibrosis patients.", "title_normalized": "the diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work up in cystic fibrosis patients" }	[ { "companynumb": "FR-TEVA-2020-FR-1503934", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "73303", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIVE PULMONARY EXACERBATION OF CYSTIC FIBROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Type I hypersensitivity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRAUN C, REIX P, DURIEU I, NOVE?JOSSERAND R, DURUPT S, OHLMANN C, ET AL. THE DIAGNOSIS OF HYPERSENSITIVITY TO ANTIBIOTICS IS RARELY CONFIRMED BY ALLERGY WORK?UP IN CYSTIC FIBROSIS PATIENTS. PEDIATR?ALLERGY?IMMUNOL 2020?31(4):396?404.", "literaturereference_normalized": "the diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work up in cystic fibrosis patients", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210628", "receivedate": "20200617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17906264, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "FR-TEVA-2020-FR-1503959", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "73303", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIVE PULMONARY EXACERBATION OF CYSTIC FIBROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Type I hypersensitivity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRAUN C, REIX P, DURIEU I, NOVE?JOSSERAND R, DURUPT S, OHLMANN C, ET AL. THE DIAGNOSIS OF HYPERSENSITIVITY TO ANTIBIOTICS IS RARELY CONFIRMED BY ALLERGY WORK?UP IN CYSTIC FIBROSIS PATIENTS. PEDIATR?ALLERGY?IMMUNOL 2020?31(4):396?404.", "literaturereference_normalized": "the diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work up in cystic fibrosis patients", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210628", "receivedate": "20200617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17906265, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20210717" } ]
{ "abstract": "The long-term efficacy of infliximab in patients with Crohn's disease is suboptimal.\n\n\n\nTo study prognostic factors for real-life long-term effcacy of infliximab in Crohn's disease.\n\n\n\nAll consecutive Crohn's disease patients treated with infliximab at a tertiary centre were retrospectively analysed. Only patients who received scheduled infliximab maintenance treatment were considered. Patient- and disease-related factors were used to identify independent predictors of infliximab failure-free survival using Cox proportional hazards regression.\n\n\n\nOf 1031 patients with Crohn's disease, 261 were eligible for inclusion. Median time on infliximab was 2.4 [IQR 1.4-4.7] years, and 65 (24.9%) patients experienced infliximab failure. Estimated 5-year infliximab failure-free survival was 65.9% (95% CI 58.3-73.5). Multivariate Cox regression identified disease duration ≥1 year (HR 2.5 (95% CI 1.2-5.2), P = 0.02), L1 disease location [HR 2.0 (1.1-3.5), P = 0.02], prior anti-TNF use [HR 2.3 (1.1-4.8), P = 0.03], haemoglobin <13.5 g/dL [HR 2.3 (1.2-4.4), P = 0.02], not using therapeutic drug monitoring [HR 8.0 (4.1-15.6), P = 1 × 10(-9) ], and first dose optimisation within first year [HR 3.7 (2.1-6.6), P = 5 × 10(-6) ] as independent predictors of infliximab failure-free survival. Stratifying patients into risk groups resulted in estimated 3-year infliximab failure-free survival rates ranging from 95.3% (94.2-96.4) to 26.3% (8.6-44.0) depending on the number of risk factors (P = 8 × 10(-13) ).\n\n\n\nThis study identified several easy to obtain predictors of infliximab failure in patients with Crohn's disease, and these are in line with previous reports. Those with a high-risk profile for infliximab failure in whom infliximab initiation is considered, should be treated as early as possible making use of therapeutic drug monitoring.", "affiliations": "Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.", "authors": "Billiet\|T\|T\|;Cleynen\|I\|I\|;Ballet\|V\|V\|;Ferrante\|M\|M\|;Van Assche\|G\|G\|;Gils\|A\|A\|;Vermeire\|S\|S\|", "chemical_list": "D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab", "country": "England", "delete": false, "doi": "10.1111/apt.13754", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "44(7)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000328:Adult; D003424:Crohn Disease; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult", "nlm_unique_id": "8707234", "other_id": null, "pages": "673-83", "pmc": null, "pmid": "27502581", "pubdate": "2016-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Prognostic factors for long-term infliximab treatment in Crohn's disease patients: a 20-year single centre experience.", "title_normalized": "prognostic factors for long term infliximab treatment in crohn s disease patients a 20 year single centre experience" }	[ { "companynumb": "BE-JNJFOC-20160913574", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "WEEK 0, 2 AND 6 FOLLOWED BY AT LEAST TWO??ADDITIONAL INFUSIONS AT WEEK 14 AND WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthropathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin reaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug specific antibody present", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm malignant", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug level decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILLIET T, CLEYNEN I, BALLET V, FERRANTE M, ASSCHE GV, GILS A, ET AL. PROGNOSTIC FACTORS FOR LONG-TERM INFLIXIMAB TREATMENT IN CROHN^S DISEASE PATIENTS: A 20-YEAR SINGLE CENTRE EXPERIENCE. ALIMENT PHARMACOL THER 09-AUG-2016;44:673-683.", "literaturereference_normalized": "prognostic factors for long term infliximab treatment in crohn s disease patients a 20 year single centre experience", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160927", "receivedate": "20160921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12767175, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]
{ "abstract": "In 2003, van Grotel and colleagues reported an infant suffering a chemotherapy-resistant eRMS of the tongue, that was treated with subtotal tumor resection and brachytherapy after major medical ethical discussions. As no long-term sequelae of such a procedure have been described, perspectives were uncertain at that time. Now, after 15 years, we describe hypoplasia of the mandibula, compromised dentation, osteopenia, neuropsychological deficits, and moderate speech impairment as the most prominent late effects. Also, mandibular cysts and basal cell carcinomas in the irradiated area, eventually led to the diagnosis Gorlin syndrome.", "affiliations": "*Princess Máxima Center for Pediatric Oncology §Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands †Department of Pediatrics, Erasmus MC-Sophia Children's Hospital ‡Department of Radiotherapy, Erasmus MC ∥Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital ¶Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.", "authors": "van Rijswijk\|Petra M\|PM\|;van den Heuvel-Eibrink\|Marry M\|MM\|;van den Akker\|Erica L T\|ELT\|;Slagter\|Cleo\|C\|;Lequin\|Maarten H\|MH\|;Aarsen\|Femke K\|FK\|;van Atteveld\|Jenneke E\|JE\|;Wagner\|Anja\|A\|;van Grotel\|Martine\|M\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000935", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "39(7)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000293:Adolescent; D001478:Basal Cell Nevus Syndrome; D001918:Brachytherapy; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007223:Infant; D008297:Male; D012208:Rhabdomyosarcoma; D018233:Rhabdomyosarcoma, Embryonal; D014062:Tongue Neoplasms", "nlm_unique_id": "9505928", "other_id": null, "pages": "566-569", "pmc": null, "pmid": "28859029", "pubdate": "2017-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Very Long-term Sequelae After Nonradical Surgery Combined With Brachytherapy in an Infant With a Chemotherapy-resistant Rhabdomyosarcoma of the Tongue.", "title_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue" }	[ { "companynumb": "NL-ACCORD-061501", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Basal cell naevus syndrome", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RIJSWIJK V. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. JOURNAL OF PEDIATRIC HEMATOLOGY/ONCOLOGY. 2017?39(7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180313", "receivedate": "20180313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14628649, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "NL-MYLANLABS-2017M1073516", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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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": "EMBRYONAL RHABDOMYOSARCOMA", "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": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL CUMULATIVE DOSE 34MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM, VAN DEN HEUVEL-EIBRINK MM, VAN DEN AKKER ELT, SLAGTER C, LEQUIN MH, AARSEN FK, ET AL. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J-PEDIATR-HEMATOL-ONCOL 2017;39(7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171121", "receivedate": "20171121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14208529, "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": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-156448", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77926", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CYCLICAL", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VICRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 CYCLES", "drugenddate": null, 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"reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tooth disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM, VAN DEN HEUVEL-EIBRINK MM, VAN DEN AKKER ELT, SLAGTER C, LEQUIN MH, AARSEN FK, ET AL. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J-PEDIATR-HEMATOL-ONCOL. 2017;39(7):566-569", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171207", "receivedate": "20171207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14258019, "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": "NL-PFIZER INC-2017543145", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE.. J-PEDIATR-HEMATOL-ONCOL. 2017?39(7):566-569", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180309", "receivedate": "20171228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14332812, "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" }, { "companynumb": "NL-FRESENIUS KABI-FK201710111", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065411", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074983", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK P,VAN DEN HEUVEL-EIBRINK M,VAN DEN AKKER E,SLAGTER C,LEQUIN M,AARSEN F. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J PEDIATR HEMATOL ONCOL 2017;39 (7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171127", "receivedate": "20171127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14226680, "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 17-year-old male subject with a history of deep venous thrombosis presented with acute unilateral severe chest pain. His examination was nonspecific, and vital signs were normal. His initial laboratory evaluation revealed mild thrombocytopenia, elevated troponin levels, and critically elevated activated partial thromboplastin time. A computed tomography angiogram of the chest revealed a pulmonary embolus, and anticoagulation therapy was initiated. His course was complicated by the development of multiple thrombi and respiratory failure. Extensive evaluation revealed a rare, underlying diagnosis in time for life-saving treatment to be initiated.", "affiliations": "Children's National Health System, Washington, District of Columbia; and [email protected].;Department of Dermatology, Georgetown University-Washington Hospital Center, Washington, District of Columbia.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.", "authors": "Shah\|Ankoor Y\|AY\|;Jamison\|Megan\|M\|;Otero\|Hansel J\|HJ\|;Jung\|Lawrence\|L\|;Frank\|Lowell H\|LH\|;Guerrera\|Michael F\|MF\|;Kirkorian\|A Yasmine\|AY\|", "chemical_list": "D016682:Lupus Coagulation Inhibitor; D014336:Troponin", "country": "United States", "delete": false, "doi": "10.1542/peds.2016-0794", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "139(3)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000293:Adolescent; D000307:Adrenal Gland Diseases; D016736:Antiphospholipid Syndrome; D002637:Chest Pain; D006470:Hemorrhage; D006801:Humans; D016682:Lupus Coagulation Inhibitor; D008297:Male; D010314:Partial Thromboplastin Time; D011655:Pulmonary Embolism; D013921:Thrombocytopenia; D014336:Troponin; D020246:Venous Thrombosis", "nlm_unique_id": "0376422", "other_id": null, "pages": null, "pmc": null, "pmid": "28159870", "pubdate": "2017-03", "publication_types": "D016429:Clinical Conference; D016428:Journal Article", "references": null, "title": "A 17-Year-Old With Chest Pain.", "title_normalized": "a 17 year old with chest pain" }	[ { "companynumb": "US-JNJFOC-20170526155", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEEP VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "4", "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH A, JAMISON M, OTERO H, JUNG L, FRANK L, GUERRERA M, ET AL. A 17-YEAR-OLD WITH CHEST PAIN. PEDIATRICS 2017;139:3.", "literaturereference_normalized": "a 17 year old with chest pain", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170530", "receivedate": "20170530", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13592297, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" } ]
{ "abstract": "An increase in amoxicillin-induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [interquartile range {IQR}, 43 to 110] mg/kg of body weight/day) in all patients, either for treating infection (n = 15) or as surgical prophylaxis (n = 30). Delay between AMX administration and AICN onset was 1 (IQR, 1 to 3) day; 30, 4, and 11 patients developed KDIGO stage 1, 2, and 3 acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 (IQR, 2 to 6) days. Precipitating factors were identified in only one-third of cases. Twelve patients required intensive care unit admission, and 8 needed renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN in the Paris RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers.", "affiliations": "Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France [email protected].;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Unité Transversale de Traitement des Infections, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France.;Département de Pharmacie Clinique, Institut Gustave Roussy, Villejuif, France.;Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.;Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.", "authors": "Vodovar\|Dominique\|D\|;Thomas\|Laure\|L\|;Mongardon\|Nicolas\|N\|;Lepeule\|Raphaël\|R\|;Lebrun-Vignes\|Bénédicte\|B\|;Biour\|Michel\|M\|;Netzer\|Florence\|F\|;Haouache\|Hakim\|H\|;Le Beller\|Christine\|C\|;Dhonneur\|Gilles\|G\|", "chemical_list": "D000658:Amoxicillin", "country": "United States", "delete": false, "doi": "10.1128/AAC.01630-17", "fulltext": null, "fulltext_license": null, "issn_linking": "0066-4804", "issue": "62(3)", "journal": "Antimicrobial agents and chemotherapy", "keywords": "acute kidney injury; adverse drug reaction; amoxicillin; amoxicillin-induced crystal nephropathy; crystals", "medline_ta": "Antimicrob Agents Chemother", "mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000658:Amoxicillin; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D012189:Retrospective Studies", "nlm_unique_id": "0315061", "other_id": null, "pages": null, "pmc": null, "pmid": "29263078", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": "16863455;22418755;26926627;22257367;20067334;3712526;22903046;4025964;2750161;18042305;17162145;23603656;19414839;5114750;27330071;12350188;12897111;8275607;10405561;20610357;25680270;25360508;10082069;12480988;3986077;12834178;19555813;16011448;21143023;8584329;4688560;5913575;5047606;11072960", "title": "Dramatic Increase of Amoxicillin-Induced Crystal Nephropathy Found in a Cohort Study of French Pharmacovigilance Centers.", "title_normalized": "dramatic increase of amoxicillin induced crystal nephropathy found in a cohort study of french pharmacovigilance centers" }	[ { "companynumb": "FR-MICRO LABS LIMITED-ML2019-01275", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205707", "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": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN/CLAVULANIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMOXICILLIN" }, "drugadditional": "3", "drugadministrationroute": null, "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": "AMOXICILLIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Crystal nephropathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VODOVAR D, THOMAS L, MONGARDON N, LEPEULE R, LEBRUN-VIGNES B, BIOUR M, NETZER F, HAOUACHE H, BELLER C, DHONNEUR G. DRAMATIC INCREASE OF AMOXICILLIN-INDUCED CRYSTAL NEPHROPATHY FOUND IN A COHORT STUDY OF FRENCH PHARMACOVIGILANCE CENTERS.. ANTIMICROB-AGENTS-CHEMOTHER. 2018?62:.", "literaturereference_normalized": "dramatic increase of amoxicillin induced crystal nephropathy found in a cohort study of french pharmacovigilance centers", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20190527", "receivedate": "20190527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16357130, "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": "BACKGROUND\nThe aim of this paper is to report maternal and neonatal outcomes in pregnant women treated with escitalopram during pregnancy and breastfeeding.\n\n\nMETHODS\nWomen enrolled in the DEGRA Database at the Clinic of Affective Disorders in Pregnancy and Postpartum in Italy, treated during pregnancy with escitalopram and followed up throughout pregnancy, were included in this study. All patients provided written informed consent and the study was approved by the local ethics committee. Psychiatric diagnoses were assessed using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition) Axis I Disorders and symptoms were assessed using the Hamilton Rating Scale for Depression (17 items) and Hamilton Rating Scale for Anxiety (14 items). Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded.\n\n\nRESULTS\nThe case histories of seven pregnant women treated for depression and/or anxiety disorders with escitalopram were reported. Four women were also treated with benzodiazepines. All pregnancies were full-term and all newborns had normal Apgar scores. There were no major malformations or miscarriages following exposure to escitalopram. Mild withdrawal syndrome was reported only in a newborn who was also exposed to a benzodiazepine. Two infants exposed to escitalopram during breastfeeding did not show any health problems.\n\n\nCONCLUSIONS\nOur experience with use of escitalopram in pregnant women did not reveal any maternal or neonatal concerns. However, considering the few cases analyzed and the paucity of published literature, no conclusions can be drawn on its safety profile in pregnancy and breastfeeding.", "affiliations": "Psychiatric Unit and DEGRA Center, United Hospital and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.", "authors": "Bellantuono\|Cesario\|C\|;Bozzi\|Francesca\|F\|;Orsolini\|Laura\|L\|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/NDT.S45951", "fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S45951ndt-9-1333Case SeriesSafety of escitalopram in pregnancy: a case series Bellantuono Cesario Bozzi Francesca Orsolini Laura Psychiatric Unit and DEGRA Center, United Hospital and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, ItalyCorrespondence: Laura Orsolini, Psychiatric Unit and DEGRA Center, United Hospital and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Via Conca 71, 60020 Ancona, Italy, Tel +39 07 1596 3308, Fax +39 07 1596 3313, Email [email protected] 2013 09 9 2013 9 1333 1337 © 2013 Bellantuono et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2013The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.Background\nThe aim of this paper is to report maternal and neonatal outcomes in pregnant women treated with escitalopram during pregnancy and breastfeeding.\n\nMethods\nWomen enrolled in the DEGRA Database at the Clinic of Affective Disorders in Pregnancy and Postpartum in Italy, treated during pregnancy with escitalopram and followed up throughout pregnancy, were included in this study. All patients provided written informed consent and the study was approved by the local ethics committee. Psychiatric diagnoses were assessed using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition) Axis I Disorders and symptoms were assessed using the Hamilton Rating Scale for Depression (17 items) and Hamilton Rating Scale for Anxiety (14 items). Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded.\n\nResults\nThe case histories of seven pregnant women treated for depression and/or anxiety disorders with escitalopram were reported. Four women were also treated with benzodiazepines. All pregnancies were full-term and all newborns had normal Apgar scores. There were no major malformations or miscarriages following exposure to escitalopram. Mild withdrawal syndrome was reported only in a newborn who was also exposed to a benzodiazepine. Two infants exposed to escitalopram during breastfeeding did not show any health problems.\n\nConclusion\nOur experience with use of escitalopram in pregnant women did not reveal any maternal or neonatal concerns. However, considering the few cases analyzed and the paucity of published literature, no conclusions can be drawn on its safety profile in pregnancy and breastfeeding.\n\nKeywords\nescitaloprampregnancybreastfeedingmajor malformationsperinatal complications\n==== Body\nIntroduction\nMajor depressive disorder, in many cases in comorbidity with anxiety disorders, frequently occurs during pregnancy. Approximately 10%–15% of pregnant women experience these disorders,1,2 with clinically relevant consequences for the outcome of pregnancy. In fact, depressed women do not seek early prenatal care and are more likely to adopt other unsafe behaviors, such as inadequate diet and use of tobacco, alcohol, and other harmful substances. Further, women with untreated major depressive disorder can be at risk of self-harm or suicide.3 High rates of relapse were reported by women with depression who discontinued antidepressant therapy at the time of conception, compared with women who continued therapy throughout the pregnancy, in a study conducted by Cohen et al.4 There is an unwillingness among physicians and patients to use antidepressant drugs during the gestational period, because there are conflicting results about the use of such drugs, and the risk of major congenital malformations.5–8 The Canadian Paediatric Society recommends that satisfactory treatment of depression in pregnancy is important for the well-being of both the mother and infant, and that individual risk-benefit assessment must be made when a selective serotonin reuptake inhibitor needs to be prescribed during pregnancy.9\n\nNowadays, the selective serotonin reuptake inhibitor, escitalopram, is considered to be one of the most effective and well tolerated agents for the treatment of moderate and severe major depressive disorder,10 as well as for the treatment of anxiety disorders. Overall, the data available on its use during pregnancy and breastfeeding suggest a good safety profile.5 The aim of this paper is to report the maternal and neonatal outcomes of seven pregnant women treated with escitalopram during their pregnancy.\n\nMaterials and methods\nCases of women who were treated during pregnancy with escitalopram were drawn from a recently implemented database (www.degradatabase.it, September 2009). The DEGRA Database now includes 110 pregnant women who have been followed during their pregnancy at the Clinic of Affective Disorders in Pregnancy and Postpartum (DEGRA Center), Academic Psychiatric Unit, United Hospitals of Ancona, Italy. The psychiatric diagnosis of patients at their first visit was made using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual - Fourth Edition) Axis I Disorders,11 while severity was assessed using the Hamilton Rating Scale for Depression (HAM-D-17 items) and Hamilton Rating Scale for Anxiety (HAM-A-14 items). All patients were fully informed about the benefits, risks, and potential adverse effects of treatment with the drug during pregnancy and breastfeeding, as well as on the risks of untreated depression/anxiety disorder in pregnancy, by a senior psychiatrist (CB) before initiating treatment. Pregnant women were also asked to sign a consent form approved by the ethics committee.\n\nOnly pregnant women treated with escitalopram and followed up by our team throughout pregnancy and, in some cases, also during postpartum, were included in this study. Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded during the study period. Neonatal outcomes were assessed in terms of mean birth weight, routine pediatric examination, Apgar scores, and examination for major congenital malformations or other minor anomalies.\n\nResults\nWe report seven cases of women treated with escitalopram during their pregnancy drawn from the DEGRA Database. Clinical and sociodemographic characteristics and neonatal outcomes of these seven cases are summarized in Table 1. Mean age (± standard deviation) at the time of presentation was 34.14 ± 3.76 (range 29–38) years. All women were of Caucasian ancestry, living with their partners, and currently working. For four women, this was their first pregnancy; three women had previously given birth to healthy babies after full-term pregnancies. Two patients were diagnosed with panic disorder, one with generalized anxiety disorder, and four with major depressive disorder (one of these also had panic disorder). Four patients were moderate smokers (5–10 cigarettes/day).\n\nSix women were exposed to escitalopram (10–20 mg/day) at conception; of these, two received escitalopram throughout their pregnancy, one discontinued treatment at week 8 and restarted at week 24 (up to delivery) due to a new severe episode of anxiety, and one was switched to paroxetine because of lack of efficacy of escitalopram at week 16. Two women decided to discontinue treatment at week 8 and 13, respectively. Only one patient was treated with escitalopram from week 21 to delivery. All cases but one showed a good clinical response to escitalopram.\n\nFour patients were also taking low doses of alprazolam, lorazepam, and clonazepam at bedtime. One patient, affected by thyroid disease, was exposed throughout pregnancy to L-thyroxine.\n\nAll pregnancies were full-term. The mean birth weight of the newborns was 2,870 ± 269.01 g (range 2,400–3,100 g), which is considered to be in the normal range (2,500–4,500 g); only one infant showed a low birth weight of 2,400 g. All newborns had normal Apgar scores at 1 and 5 minutes. We did not detect any major congenital malformations or other minor anomalies in the newborns.\n\nOne newborn also exposed to paroxetine (20–40 mg/day) and a benzodiazepine during late pregnancy developed a withdrawal reaction characterized by hypoglycemia (controlled with dextrose administration), lethargy, hypotonia, decreased primitive reflexes, and poor responsiveness to noxious stimuli. Symptoms improved within 48 hours and the newborn did not require any other medical intervention.\n\nDuring the postpartum period, all women and newborns were followed up for 6 months. Only two patients decided to continue drug treatment with escitalopram (10 mg/day) until 1 and 5 months after delivery, respectively, in order to prevent postpartum depression. All infants exposed to escitalopram showed no health problems during the follow-up period.\n\nDiscussion\nThe safety profile of escitalopram during the gestational period is an important topic for the health care community because the prescription of such drugs during pregnancy and in women of childbearing age affected by psychiatric illnesses is still up for debate. There is still some uncertainty about the relative risk concerning the use of escitalopram in pregnancy, as data on its safety are available only after the drug has been prescribed for many years. On the other hand, it is well documented that untreated maternal major depressive disorder and/or anxiety disorders, as well as other severe psychiatric illnesses, can have disruptive consequences on the outcome of pregnancy and on the safety of the newborn.3,4,9 In our case series, no major malformations were detected after exposure to escitalopram during early pregnancy. This is consistent with the available literature suggesting that escitalopram is not associated with an increased risk of major or minor abnormalities.5,7,12 We reported only one underweight newborn, a finding which is consistent with other evidence showing an increased risk of low birth weight of newborns exposed in utero to escitalopram.7 We also observed a case of withdrawal syndrome, even though the event occurred in a newborn whose exposure to escitalopram was stopped at 16 weeks but who was also exposed to paroxetine and clonazepam later during the pregnancy. Therefore, it is unlikely that escitalopram was responsible for this adverse effect, as this drug is not frequently associated with withdrawal reactions at therapeutic doses.13\n\nThis case series demonstrates the need for antidepressant therapy during pregnancy and provides valuable information on the use of escitalopram in pregnancy in a real-life clinical setting, with a range of depression-related diagnoses and exposure to escitalopram, concomitant use of other drugs, and in the presence of other risk factors. However, results from this case series should be interpreted with caution due to the low number of cases reported and the lack of controls. Due to these limitations, the causation, association, strength of association, and effect of confounders on the findings, eg, depression, maternal smoking, and socioeconomic status, are uncertain.\n\nOur findings are in agreement with evidence from large population-base studies reported in the literature, and provide data to support the safety of escitalopram in pregnancy in terms of no increased risk of major malformations.6,7,12 However, randomized controlled studies with a larger sample size are required in order to establish the safety profile of escitalopram in pregnancy and in breastfeeding women.\n\nA range of depression rating scales are available for assessment of symptom severity. We used the HAM-D-17 and HAM-A-14 scales to assess symptoms of depression and anxiety during the follow-up period. However, although beyond the scope of this study, other scales, such as the Montgomery-Åsberg Depression Rating Scale, may better differentiate biological and somatic symptoms of depression from symptoms commonly experienced during pregnancy.\n\nConclusion\nThe data from this small preliminary case series, together with the existing evidence, suggest that escitalopram does not appear to be associated with a higher risk of adverse maternal and neonatal outcomes when used by women during the gestational period, despite the fact that perinatal complications with other selective serotonin reuptake inhibitors have been reported in the literature. Given the paucity of data on the safety of escitalopram in pregnancy and the risk involved with nontreatment of major depressive disorder during pregnancy, any additional data are welcomed. However, considering the low number of cases and lack of controls in this series, it is prudent not to draw definitive conclusions on its safety during pregnancy and breastfeeding. These preliminary data are from a recently implemented database; therefore, future findings with larger patient numbers will add to the literature on the treatment of depression during pregnancy and the safety of escitalopram in the newborn.\n\nAuthor contributions\n\nCB, the senior psychiatrist responsible for treatment of patients afferent to the Clinic of Affective Disorders in Pregnancy and Postpartum, designed and planned the research. FB and LO performed the literature search and database analysis. All authors participated in drafting the manuscript and approving the final version for submission. The authors thank David Bellantuono for developing the online DEGRA Database used in this study.\n\nDisclosure\n\nEditorial assistance was provided by Raelene Simpson on behalf of inScience Communications, Springer Healthcare. This assistance was supported by Lundbeck. Otherwise, there are no potential conflicts of interest to disclose and no commercial support or funding was received for the study.\n\nTable 1 Maternal sociodemographic characteristics, drugs prescribed, and neonatal outcomes\n\nCase\tAge and demographic characteristics of women\tPrevious pregnancy\tDiagnosis\tHabits\tPsychotropic drug dosage in mg/day (weeks of exposure)\n\tDelivery\tBirth weight (g)\tApgar score (1/5 minutes)\tNeonatal outcomes\t\nAD\tBDZ\t\n1\t38, Caucasian, with partner, office worker\tOne miscarriage One healthy full-term pregnancy\tPD\tModerate alcohol use Smoker\tESC 10 (0–40)\tALP 0.25 (0–3)\tFull-term Natural\tLow (2,400)\t9/10\tHealthy\t\n2\t31, Caucasian, with partner, craftsman\tOne healthy full-term pregnancy\tComorbid PD and MDD\tModerate alcohol use Nonsmoker\tESC 10–20 (0–39)\tNone\tFull-term Cesarean\tNormal (3,100)\t9/10\tHealthy\t\n3\t29, caucasian, with partner, craftsman\tNonparous\tMDD\tNo alcohol use Nonsmoker\tESC 10 (0–13)\tNone\tFull-term Natural\tNormal (2,900)\t9/10\tHealthy\t\n4\t31, caucasian, with partner, craftsman\tNonparous\tMDD\tModerate alcohol use Nonsmoker\tESC 10–20 (21–38)\tNone\tFull-term Natural\tNormal (3,030)\t9/10\tHealthy\t\n5\t37, caucasian, with partner, office worker\tNonparous\tGAD\tNo alcohol use Smoker\tESC 20 (0–8 and 24–40)\tALP 1.25 (0–8 and 24–40)\tPost-term Natural\tNormal (3,100)\t9/10\tHealthy\t\n6\t38, caucasian, with partner, office worker\tTwo healthy full-term pregnancies\tPD\tNo alcohol use Smoker\tESC 10 (0–8)\tALP 1.25 (29–38)\tFull-term Natural\tNormal (2,600)\t10/10\tHealthy\t\n7\t35, caucasian, with partner, housewife\tNonparous\tMDD\tOccasional alcohol abuse Smoker\tESC 10 (0–16) PAR 20–40 (16–38)\tCLO 0.5 (0–11) LOR 1 (12–38)\tFull-term Natural\tNormal (2,960)\t8/10\tWithdrawal symptoms\t\nAbbreviations: PD, panic disorder; MDD, major depressive disorder; GAD, generalized anxiety disorder; AD, antidepressant; BDZ, benzodiazepine; ESC, escitalopram; ALP, alprazolam; PAR, paroxetine; CLO, clonazepam; LOR, lorazepam.\n==== Refs\nReferences\n1 Birndorf CA Madden A Portera L Leon AC Psychiatric symptoms, functional impairment, and receptivity toward mental health treatment among obstetrical patients Int J Psychiatry Med 2001 31 4 355 365 11949734 \n2 Grant BF Goldstein RB Chou SP Sociodemographic and psychopathologic predictors of first incidence of DSM-IV substance use, mood and anxiety disorders: results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions Mol Psychiatry 2009 14 11 1051 1066 18427559 \n3 Yonkers KA Wisner KL Stewart DE The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists Gen Hosp Psychiatry 2009 31 5 403 413 19703633 \n4 Cohen LS Altshuler LL Harlow BL Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment JAMA 2006 295 5 499 507 16449615 \n5 Bellantuono C Bozzi F Orsolini L Catena-Dell’Osso M The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review Hum Psychopharmacol 2012 27 6 534 539 23044635 \n6 Einarson A Choi J Einarson TR Koren G Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study Can J Psychiatry 2009 54 4 242 246 19321030 \n7 Klieger-Grossmann C Weitzner B Panchaud A Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study J Clin Pharmacol 2012 52 5 766 770 22075232 \n8 Diav-Citrin O Ornoy A Selective serotonin reuptake inhibitors in human pregnancy: to treat or not to treat? Obstet Gynecol Int 2012 2012 698947 22190957 \n9 Jefferies AL Canadian Paediatric Society, and Fetus and Newborn Committee Selective serotonin reuptake inhibitors in pregnancy and infant outcomes Paediatric Child Health 2011 16 9 562 563 \n10 Cipriani A Furukawa TA Salanti G Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis Lancet 2009 373 9665 746 758 19185342 \n11 First MB Spitzer RL Gibbon M Williams JBW Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-1-CV) New York, NY Biometrics Research Department, New York State Psychiatric Institute, Department of Psychiatry, Columbia University 1995 \n12 Kallen BA Otterblad OP Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infact congenital malformations Birth Defects Res A Clin Mol Teratol 2007 79 4 301 308 17216624 \n13 Tixier H Feyeux C Girod S Acute voluntary intoxication with selective serotonin reuptake inhibitors during the third trimester of pregnancy: therapeutic management of mother and fetus Am J Obstet Gynecol 2008 199 5 e9 e12 18984074\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6328", "issue": "9()", "journal": "Neuropsychiatric disease and treatment", "keywords": "breastfeeding; 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"reactionmeddrapt": "Drug withdrawal syndrome neonatal", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ORSOLINI L, BOZZI F, BELLANTUONO C. SAFETY OF ESCITALOPRAM IN PREGNANCY: A CASE SERIES. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2013 SEP 07;9:1333-1337.", "literaturereference_normalized": "safety of escitalopram in pregnancy a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20140731", "receivedate": "20140731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10353827, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" }, { "companynumb": "IT-LUPIN PHARMACEUTICALS INC.-2014-01390", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078169", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MAJOR DEPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Major depression", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ORSOLINI L, BOZZI F, BELLANTUONO C. SAFETY OF ESCITALOPRAM IN PREGNANCY: A CASE SERIES. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2013 SEP 07;9:1333-1337.", "literaturereference_normalized": "safety of escitalopram in pregnancy a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141007", "receivedate": "20141007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10501502, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150528" }, { "companynumb": "IT-LUPIN PHARMACEUTICALS INC.-2014-01389", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "078169", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": "2.4", "reaction": [ { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ORSOLINI L, BOZZI F, BELLANTUONO C. SAFETY OF ESCITALOPRAM IN PREGNANCY: A CASE SERIES. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2013 SEP 07;9:1333-1337.", "literaturereference_normalized": "safety of escitalopram in pregnancy a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20140731", "receivedate": "20140731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10353830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]
{ "abstract": "To illustrate that patients with diabetic retinopathy who are treated exclusively with anti-vascular endothelial growth factor (VEGF) therapy and have an interruption in treatment may experience marked progression of disease with potentially devastating visual consequences.\n\n\n\nRetrospective, multicenter, case series.\n\n\n\nRetrospective review of patients treated exclusively with anti-VEGF therapy for proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy (NPDR), with or without diabetic macular edema (DME), and temporarily lost to follow-up. Baseline disease characteristics, cause and duration of the treatment interruption, and resulting disease progression, complications, and outcomes were assessed.\n\n\n\nThirteen eyes of 12 patients with type 2 diabetes were identified. The mean age was 57 ± 10 years, and 50% were women. Anti-VEGF therapy was indicated for PDR with DME in 7 (54%) eyes, PDR without DME in 3 (23%) eyes, and moderate to severe NPDR with DME in 3 (23%) eyes. Eight eyes had visual acuity (VA) of 20/80 or better before treatment interruption. The median duration of treatment hiatus was 12 months. Reasons for treatment interruption included intercurrent illness (31%), noncompliance (31%), and financial issues (15%). Complications upon follow-up included vitreous hemorrhage (9 eyes), neovascular glaucoma (5 eyes), and traction retinal detachment (4 eyes). Despite treatment of these complications, 77% of eyes lost ≥3 lines of VA, with 46% of eyes having a final VA of hand motion or worse.\n\n\n\nDiabetic patients are subject to significant lapses in follow-up because of illness, financial hardship, or noncompliance. In patients with diabetic retinopathy, especially PDR, who are managed with anti-VEGF therapy alone, unintentional treatment interruptions can result in irreversible blindness.", "affiliations": "Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.;Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: [email protected].;Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.", "authors": "Wubben\|Thomas J\|TJ\|;Johnson\|Mark W\|MW\|;\|\|\|", "chemical_list": "D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab", "country": "United States", "delete": false, "doi": "10.1016/j.ajo.2019.03.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9394", "issue": "204()", "journal": "American journal of ophthalmology", "keywords": null, "medline_ta": "Am J Ophthalmol", "mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D003930:Diabetic Retinopathy; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D012160:Retina; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity", "nlm_unique_id": "0370500", "other_id": null, "pages": "13-18", "pmc": null, "pmid": "30878488", "pubdate": "2019-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Retinopathy: Consequences of Inadvertent Treatment Interruptions.", "title_normalized": "anti vascular endothelial growth factor therapy for diabetic retinopathy consequences of inadvertent treatment interruptions" }	[ { "companynumb": "US-ROCHE-2414348", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFLIBERCEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC RETINOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AFLIBERCEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125156", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC RETINOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125085", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC RETINOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glaucoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tractional retinal detachment", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitreous haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WUBBEN T, JOHNSON M, SOHN E, PEAIRS J, KAY C, KIM S ET AL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR DIABETIC RETINOPATHY: CONSEQUENCES OF INADVERTENT TREATMENT INTERRUPTIONS.. AMERICAN JOURNAL OF OPHTHALMOLOGY. 2019?204:13-8.", "literaturereference_normalized": "anti vascular endothelial growth factor therapy for diabetic retinopathy consequences of inadvertent treatment interruptions", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191007", "receivedate": "20191007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16889586, "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": "A 67-year-old gentleman developed persistent Staphylococcus epidermidis bacteraemia following transjugular intrahepatic portal shunting. 'Endotipsitis' was diagnosed. Conventional therapy with a vancomycin infusion, amikacin and rifampicin failed after 17 days. He was cured with a 6-week course of high-dose (8 mg/kg) daptomycin monotherapy.", "affiliations": "Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Trust, Oxford, UK. [email protected]", "authors": "Colston\|Julia Marie\|JM\|;Scarborough\|Matthew\|M\|;Collier\|Jane\|J\|;Bowler\|Ian C J W\|IC\|", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D000583:Amikacin; D017576:Daptomycin; D012293:Rifampin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2013()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000583:Amikacin; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002405:Catheterization, Central Venous; D057785:Catheters; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D008297:Male; D012293:Rifampin; D013203:Staphylococcal Infections; D013212:Staphylococcus epidermidis; D017211:Treatment Failure; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "23595199", "pubdate": "2013-04-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22100575;16353112;22160888;21731907;21923436;22908167;19929905;16914701;12567297;22985884;15183855;18591272;22931050", "title": "High-dose daptomycin monotherapy cures Staphylococcus epidermidis 'endotipsitis' after failure of conventional therapy.", "title_normalized": "high dose daptomycin monotherapy cures staphylococcus epidermidis endotipsitis after failure of conventional therapy" }	[ { "companynumb": "GB-MYLANLABS-2015M1010598", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "050", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pathogen resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "COLSTON JM, SCARBOROUGH M, COLLIER J, BOWLER IC. HIGH-DOSE DAPTOMYCIN MONOTHERAPY CURES STAPHYLOCOCCUS EPIDERMIDIS ^ENDOTIPSITIS^ AFTER FAILURE OF CONVENTIONAL THERAPY. BMJ-CASE-REP 2013; :.", "literaturereference_normalized": "high dose daptomycin monotherapy cures staphylococcus epidermidis endotipsitis after failure of conventional therapy", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150401", "receivedate": "20150401", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10975996, "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": "Wilkie's syndrome or superior mesenteric artery syndrome is an unusual cause of proximal intestinal obstruction, primarily attributed to recent weight loss. We report the case of a 19-year-old woman comes to our clinic and reports weight loss, abdominal pain, nausea, and vomiting. Laboratory tests revealed anemia, hypoalbuminemia, hypomagnesemia, and a suppressed thyroid stimulating hormone secondary to levothyroxine. A barium swallow test showed gastric dilatation, delayed gastric emptying and an axial computed tomography revealed an aortomesenteric angle of 11.7°. Conservative management with total parenteral and enteral nutrition was initiated, being the first-line treatment. In refractory cases surgery is a safe and effective option.", "affiliations": "Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México; Departamento de Bienestar y Desarrollo Sustentable, Centro Universitario del Norte, Universidad de Guadalajara. Colotlán, Jalisco, México.;Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México.;Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México.;Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México.", "authors": "Cervantes Pérez\|Enrique\|E\|;Martínez-Soto Holguín\|Martha C\|MC\|;Diaz Juárez\|Juan Pedro\|JP\|;Reyes Ramírez\|Ana Luz Del C\|ALDC\|", "chemical_list": null, "country": "Peru", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1022-5129", "issue": "40(3)", "journal": "Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru", "keywords": null, "medline_ta": "Rev Gastroenterol Peru", "mesh_terms": "D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D013478:Superior Mesenteric Artery Syndrome; D055815:Young Adult", "nlm_unique_id": "9108294", "other_id": null, "pages": "274-277", "pmc": null, "pmid": "33181816", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Wilkie's syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism: a case report and literature review.", "title_normalized": "wilkie s syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism a case report and literature review" }	[ { "companynumb": "MX-LUPIN PHARMACEUTICALS INC.-2021-26755", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209713", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Autoimmune hypothyroidism", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209713", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Superior mesenteric artery syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Perez EC, Martinez-Soto Holguin MC, Juarez JPD, Del C Reyes Ramirez AL. Wilkie^s syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism: A case report and literature review. Revista de Gastroenterolog?i del Peru. 2020;40 (3):274-277", "literaturereference_normalized": "wilkie s syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism a case report and literature review", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20220324", "receivedate": "20220111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20323863, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" } ]
{ "abstract": "Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy.", "affiliations": "Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan.;Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Japan.;Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.", "authors": "Suzuki\|Soichiro\|S\|;Naito\|Shotaro\|S\|;Numasawa\|Yoshiyuki\|Y\|;Asada\|Mizuho\|M\|;Shoji\|Norikazu\|N\|;Zeniya\|Moko\|M\|;Takahashi\|Daiei\|D\|;Sato\|Hidehiko\|H\|;Iimori\|Soichiro\|S\|;Nomura\|Naohiro\|N\|;Sohara\|Eisei\|E\|;Okado\|Tomokazu\|T\|;Ishiwata\|Yasuyoshi\|Y\|;Nagata\|Masashi\|M\|;Rai\|Tatemitsu\|T\|;Yokota\|Takanori\|T\|;Uchida\|Shinichi\|S\|", "chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.1785-18", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3079933910.2169/internalmedicine.1785-18Case ReportEncephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient Suzuki Soichiro 1Naito Shotaro 1Numasawa Yoshiyuki 2Asada Mizuho 3Shoji Norikazu 1Zeniya Moko 1Takahashi Daiei 1Sato Hidehiko 1Iimori Soichiro 1Nomura Naohiro 1Sohara Eisei 1Okado Tomokazu 1Ishiwata Yasuyoshi 3Nagata Masashi 3Rai Tatemitsu 1Yokota Takanori 2Uchida Shinichi 1\n1 Department of Nephrology, Tokyo Medical and Dental University, Japan\n2 Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan\n3 Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, JapanCorrespondence to Dr.　Shotaro Naito, [email protected]\n\n25 2 2019 15 6 2019 58 12 1775 1779 4 7 2018 4 12 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal 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/).Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy. \n\nceftriaxoneend-stage kidney diseaseencephalopathytriphasic waves\n==== Body\nIntroduction\nEncephalopathy is a rare side effect of cephalosporin treatment. Although encephalopathy caused by ceftriaxone, a third-generation cephalosporin, is particularly rare, several studies have reported this complication in patients with end-stage kidney disease (ESKD) (1, 2). Renal insufficiency is considered to be a predisposing factor for ceftriaxone neurotoxicity (1, 2); however, to date, no studies have evaluated the plasma and cerebral spinal fluid (CSF) concentrations of ceftriaxone in relation to encephalopathy. We herein present a case of encephalopathy in a hemodialysis patient who received intravenous ceftriaxone for Helicobacter cinaedi bacteremia. Our analysis revealed that the plasma and CSF concentrations of ceftriaxone were higher than the optimal range.\n\nCase Report\nAn 86-year-old woman on maintenance hemodialysis for ESKD due to benign nephrosclerosis presented to the emergency department with complaints of vomiting, diarrhea, and mild alteration of consciousness. Her medical history included rheumatoid arthritis, hypothyroidism, and hypertension. Her medications included prednisolone (5 mg), levothyroxine, rabeprazole, mosapride, butyric acid bacteria, and amezinium metilsulfate. A physical examination revealed soft abdomen; however, the patient complained of pain in her right lower abdomen. Although laboratory data showed leukocytosis and an elevated C-reactive protein level, the patient was afebrile and hemodynamically stable when she presented to the emergency department. She was sent home without any medication. One day later, she developed high fever with persistent abdominal pain and was admitted to our hospital. Her altered consciousness had improved at the time of admission. Intravenous ceftriaxone (1 g daily) was administered as an empirical treatment for bacterial enteritis. On the third day of admission, the presence of gram-negative bacteria was confirmed by blood culture, and the ceftriaxone dosage was increased to 2 g daily. Eventually, Helicobacter cinaedi was identified as the causative agent by blood culture.\n\nOn the 13th day of ceftriaxone treatment, the patient showed an altered mental state and a decreased level of consciousness as well as myoclonic jerks involving the right shoulder and arm. A neurological examination revealed roving eye movement and preserved light reflex. Brain magnetic resonance imaging did not reveal acute stroke or other focal findings that would account for her symptoms. No obvious abnormalities in the liver function or serum electrolyte levels were observed (Table). Hypoglycemia was not detected by capillary glucose monitoring. A CSF analysis revealed no elevated cell counts, and CSF cultures were negative. Electroencephalography (EEG) was performed, which showed generalized triphasic waves (TWs), predominantly in the frontal area (Fig. 1). Because the patient's symptoms were suspected to have been caused by ceftriaxone-induced encephalopathy, ceftriaxone was discontinued on the day after the onset of neurological symptoms. Consequently, a progressive improvement in the patient's neurological state was noted, and her consciousness completely recovered at four days after the discontinuation of ceftriaxone. Accordingly, she was diagnosed with ceftriaxone-induced encephalopathy. EEG performed seven days after the discontinuation of ceftriaxone revealed normal wave patterns and the absence of TWs.\n\nTable. Laboratory Data at the Onset of Neurological Symptoms.\n\nAlb\t2.6\tg/dL\tTSH\t5.03\tμIU/mL\t\nBUN\t26\tmg/dL\tFT3\t1.14\tpg/mL\t\nCr\t3.52\tmg/dL\tFT4\t1.25\tng/dL\t\nNa\t145\tmEq/L\tTPO-Ab\t9\tIU/mL\t\nK\t4.6\tmEq/L\tVit B1\t54\tng/mL\t\nCl\t106\t/mEq/L\tVit B12\t193\tpg/mL\t\nCa\t8.4\tmg/dL\t\t\t\t\nMg\t2.0\tmg/dL\tWBC\t10,700\t/μL\t\nGlucose\t84\tmg/dL\tHb\t11.0\tg/dL\t\nCRP\t0.64\tmg/dL\tPlt\t19.0\t/μL\t\nNH3\t12\tμmol/L\t\t\t\t\nT-Bil\t0.2\tmg/dL\tCerebrospinal fluid\t\t\t\nγ-GTP\t19\tU/L\tCell count\t1\tcell/μL\t\nAST\t15\tU/L\tGlucose\t48\tmg/dL\t\nALT\t13\tU/L\tProtein\t64\tmg/dL\t\nAlb: Albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, Ca: calcium, Cl: chloride, Cr: creatinine, CRP: C-reactive protein, FT3: free triiodothyronine, FT4: Free Thyroxin, γ-GTP: gamma-glutamyltransferase, K: potassium, LDH: lactate dehydrogenase, Mg: magnesium, NH3: ammonia, Plt: platelet, RBC: red blood cell, T-Bil: total bilirubin, TPO-Ab: thyroid peroxidase antibody, TSH: thyroid-stimulating hormone, Vit B1: vitamin B1, Vit B12: vitamin B12\n\nFigure 1. Electroencephalogram shows periodic generalized triphasic waves predominantly in the frontal area. EMG: electromyogram, EOG: electrooculogram, ECG: electrocardiogram\n\nThe differential diagnoses included other potential causes of disturbed consciousness (e.g., electrolyte disorders, metabolic alterations, cerebral hypoxia, infection, stroke, and medication use). However, no other factors that could possibly explain her neurological symptoms were identified, and hemodialysis did not improve her mental state. Retrospective measurement of plasma and CSF ceftriaxone concentrations was performed by high-performance liquid chromatography using specimens collected at the onset of her consciousness disturbance (Fig. 2). The plasma and CSF concentrations of ceftriaxone were both found to be high (>100 μg/mL and 10.2 μg/mL, respectively), indicating that ceftriaxone neurotoxicity was causally related to the adverse events in this case.\n\nFigure 2. The time course of the ceftriaxone concentration and administered dose. The concentrations were measured approximately 20 h after an infusion of ceftriaxone (2 g). The CTRX concentration rapidly decreased after discontinuation. CTRX: ceftriaxone, HD: hemodialysis\n\nDiscussion\nEncephalopathy is known as an infrequent adverse effect of ceftriaxone (1-4). The exact mechanism that leads to ceftriaxone-induced encephalopathy as a side effect is not completely understood; however, it has been presumed to be caused by competitive antagonism of brain γ-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system (5), and increased excitatory amino acids (6).\n\nThe elimination half-life of ceftriaxone, which ranges from 6 to 9 hours in patients with a normal renal function, is longer than that of any other third-generation cephalosporin. Its elimination route is via kidney and biliary excretion; the half-life of ceftriaxone in hemodialysis patients was found to double from 8 to 16 hours in a previous study (7). Furthermore, unlike most cephalosporins that are highly dialyzable, ceftriaxone is not dialyzed during hemodialysis (8, 9). With renal failure, the accumulated toxic organic acids compete with cephalosporins for active transportation from the CSF to the blood, which increases the concentration of cephalosporin in the CSF (10).\n\nIn the present case, the patient presented with several risk factors for drug-induced neurotoxicity, including old age, renal impairment, and high-dose treatment (11). To clarify the association between ceftriaxone and encephalopathy, we measured the plasma and CSF concentrations of ceftriaxone. Although cefepime, a commonly used cephalosporin, is the only antibiotic mentioned in more than ten reports on the relationship between serum cephalosporin concentrations and neurotoxicity (12), no reports on ceftriaxone-induced encephalopathy have reported the drug concentrations associated with the condition. According to a previous report, after ceftriaxone (2 g, every 24 hours), the plasma trough levels ranged from 13 to 15 μg/mL in adults with a normal renal function (13). In the present case, the ceftriaxone plasma concentration before hemodialysis (approximately 20 hours after infusion of 2 g ceftriaxone) was >100 μg/mL. This value is far higher than that reported in a previous study (13), suggesting that a high plasma concentration of ceftriaxone was maintained ceftriaxone during administration. As already mentioned, the elimination half-life of ceftriaxone is longer in hemodialysis patients, which may lead to sustained high ceftriaxone concentrations in the plasma.\n\nIn the present case, the CSF ceftriaxone concentration was also high. Generally, the protein-unbound, free fraction of agents can freely penetrate the blood-brain/blood-CSF barrier (14). Approximately 90-95% of ceftriaxone is protein-bound and thus it can rarely penetrate the blood-CSF barrier (14). Nau et al. reported that the CSF concentrations of ceftriaxone after an infusion of ceftriaxone (2 g) in patients with uninflamed meninges ranged from 0.18 to 1.04 μg/mL (15), whereas the CSF ceftriaxone level in the current patient was 10.2 μg/mL even at more than 24 hours after the discontinuation of ceftriaxone. Furthermore, the free fraction of ceftriaxone is higher in patients with an abnormal renal function (4, 16). In the present case, the high proportion of unbound plasma ceftriaxone - due to the low albumin level and renal insufficiency - presumably made the CSF ceftriaxone concentration higher, resulting in neurotoxicity. The high proportion of unbound plasma ceftriaxone resulted in a relatively high rate of removal by dialysis; approximately 40% of ceftriaxone was dialyzed during hemodialysis.\n\nNeurological manifestations of ceftriaxone-associated encephalopathy, such as myoclonus, asterixis, seizures, and consciousness alteration, have been reported in patients with an impaired renal function (3, 17). Previous studies reported that EEG findings such as slow waves and TWs might be associated with cephalosporin neurotoxicity. TWs are defined by their typical morphology, characterized by a predominant surface positive wave, preceded and followed by smaller surface negative deflections, conferring them a triphasic appearance (18). However, non-epileptic TWs with a sharply contoured morphology may resemble epileptic patterns encountered during nonconvulsive status epilepticus (NCSE), thus leading to the misinterpretation and over-interpretation of this pattern as ictal, if the electroencephalogram is considered alone (19). According to a previous study that described the electroencephalographic differences between TWs and NCSE, amplitude predominance of phase two was more common with TWs than with NCSE (40.8% vs. 0%); and the frequency of epileptiform discharge with TWs was lower than that with NCSE (1.8 Hz vs. 2.4 Hz) (20). An electroclinical response to benzodiazepines and the evaluation of consciousness impairment should be considered to distinguish between TWs and NCSE (19).\n\nNeurological symptoms and EEG findings emerge at 1-10 days after the initiation of the cephalosporin treatment and resolve several days after discontinuation (1-3, 21-23). Thus, EEG might be beneficial in the diagnosis and management of ceftriaxone neurotoxicity. The neurotoxicity induced by cephalosporins is reported to be reversible (1-3, 21-23). In the present case, the discontinuation of ceftriaxone resulted in marked improvements in the clinical symptoms without any sequelae.\n\nIn conclusion, ceftriaxone might cause encephalopathy with manifestations such as myoclonus, an altered mental state, a decreased level of consciousness, and changes in EEG findings. Hemodialysis patients are particularly vulnerable to ceftriaxone-induced encephalopathy. This first reported case of high in plasma and CSF concentrations of ceftriaxone in a patient who developed neurological symptoms following ceftriaxone treatment suggests a causal relationship between the administration of ceftriaxone and the onset of encephalopathy. Patients with renal impairment who develop such symptoms during ceftriaxone treatment should be evaluated for potential ceftriaxone-induced encephalopathy, and drug discontinuation should be considered as the treatment of choice.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nSafadi S , Mao M , Dillon JJ \nCeftriaxone-induced acute encephalopathy in a peritoneal dialysis patient . Case Rep Nephrol \n2014 : 108185 , 2014 .25544915 \n2. \nRoncon-Albuquerque R Jr, Pires I , Martins R , Real R , Sousa G , von Hafe P \nCeftriaxone-induced acute reversible encephalopathy in a patient treated for a urinary tract infection . Neth J Med \n67 : 72 -75 , 2009 .19299850 \n3. \nKim KB , Kim SM , Park W , Kim JS , Kwon SK , Kim HY \nCeftriaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review . J Korean Med Sci \n27 : 1120 -1123 , 2012 .22969263 \n4. \nSutter R , Ruegg S , Tschudin-Sutter S \nSeizures as adverse events of antibiotic drugs: a systematic review . Neurology \n85 : 1332 -1341 , 2015 .26400582 \n5. \nWallace KL \nAntibiotic-induced convulsions . Crit Care Clin \n13 : 741 -762 , 1997 .9330839 \n6. \nDe Sarro A , Ammendola D , Zappala M , Grasso S , De Sarro GB \nRelationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats . Antimicrob Agents Chemother \n39 : 232 -237 , 1995 .7695312 \n7. \nCohen D , Appel GB , Scully B , Neu HC \nPharmacokinetics of ceftriaxone in patients with renal failure and in those undergoing hemodialysis . Antimicrob Agents Chemother \n24 : 529 -532 , 1983 .6316845 \n8. \nPatel IH , Sugihara JG , Weinfeld RE , Wong EG , Siemsen AW , Berman SJ \nCeftriaxone pharmacokinetics in patients with various degrees of renal impairment . Antimicrob Agents Chemother \n25 : 438 -442 , 1984 .6329080 \n9. \nGrill MF , Maganti R \nCephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring . Ann Pharmacother \n42 : 1843 -1850 , 2008 .19033476 \n10. \nJoseph J , Vimala A \nCeftazidime-induced myoclonus and encephalopathy in hemodialysis patient . Indian J Nephrol \n25 : 61 -62 , 2015 .25684877 \n11. \nSchliamser SE , Cars O , Norrby SR \nNeurotoxicity of beta-lactam antibiotics: predisposing factors and pathogenesis . J Antimicrob Chemother \n27 : 405 -425 , 1991 .1856121 \n12. \nBhattacharyya S , Darby RR , Raibagkar P , Gonzalez Castro LN , Berkowitz AL \nAntibiotic-associated encephalopathy . Neurology \n86 : 963 -971 , 2016 .26888997 \n13. \nPollock AA , Tee PE , Patel IH , Spicehandler J , Simberkoff MS , Rahal JJ Jr \nPharmacokinetic characteristics of intravenous ceftriaxone in normal adults . Antimicrob Agents Chemother \n22 : 816 -823 , 1982 .6295268 \n14. \nNau R , Sorgel F , Eiffert H \nPenetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections . Clin Microbiol Rev \n4 : 858 -883 , 2010 .\n15. \nNau R , Prange HW , Muth P , et al \nPassage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges . Antimicrob Agents Chemother \n37 : 1518 -1524 , 1993 .8363385 \n16. \nJoynt GM , Lipman J , Gomersall CD , Young RJ , Wong EL , Gin T \nThe pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients . J Antimicrob Chemother \n47 : 421 -429 , 2001 .11266414 \n17. \nSato Y , Morita H , Wakasugi H , et al \nReversible choreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease . Am J Med Sci \n340 : 382 -384 , 2010 .20724905 \n18. \nAdriana Bermeo-Ovalle \nTriphasic waves: swinging the pendulum back in this diagnostic dilemma . Epilepsy Curr \n17 : 40 -42 , 2017 .28331470 \n19. \nBrigo F , Storti M \nTriphasic waves . Am J Electroneurodiagnostic Technol \n51 : 16 -25 , 2011 .21516927 \n20. \nBoulanger JM , Deacon C , Lécuyer D , Gosselin S , Reiher J \nTriphasic waves versus nonconvulsive status epilepticus: EEG distinction . Can J Neurol Sci \n33 : 175 -180 , 2006 .16736726 \n21. \nMartinez-Rodriguez JE , Barriga FJ , Santamaria J , et al \nNonconvulsive status epilepticus associated with cephalosporins in patients with renal failure . Am J Med \n111 : 115 -119 , 2001 .11498064 \n22. \nLam S , Gomolin IH \nCefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review . Pharmacotherapy \n26 : 1169 -1174 , 2006 .16863493 \n23. \nThabet F , Al Maghrabi M , Al Barraq A , Tabarki B \nCefepime-induced nonconvulsive status epilepticus: case report and review . Neurocrit Care \n10 : 347 -351 , 2009 .19034700\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "58(12)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "ceftriaxone; encephalopathy; end-stage kidney disease; triphasic waves", "medline_ta": "Intern Med", "mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001927:Brain Diseases; D002443:Ceftriaxone; D004569:Electroencephalography; D005260:Female; D016481:Helicobacter Infections; D006801:Humans; D006435:Renal Dialysis", "nlm_unique_id": "9204241", "other_id": null, "pages": "1775-1779", "pmc": null, "pmid": "30799339", "pubdate": "2019-06-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11266414;11498064;16736726;16863493;1856121;19033476;19034700;19299850;20724905;20930076;21516927;22969263;25544915;25684877;26400582;26888997;28331470;6295268;6316845;6329080;7695312;8363385;9330839", "title": "Encephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient.", "title_normalized": "encephalopathy induced by high plasma and cerebrospinal fluid ceftriaxone concentrations in a hemodialysis patient" }	[ { "companynumb": "JP-PFIZER INC-2019095052", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE SODIUM" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065230", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GASTROENTERITIS BACTERIAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "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": null, "activesubstance": { "activesubstancename": "BUTYRIC ACID" }, "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": "BUTYRIC ACID" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMEZINIUM METILSULFATE" }, "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": "AMEZINIUM METILSULFATE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE SODIUM" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065230", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 G, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "EVIDENCE BASED TREATMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE SODIUM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "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": "LEVOTHYROXINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RABEPRAZOLE" }, "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": "RABEPRAZOLE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MOSAPRIDE" }, "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": "MOSAPRIDE" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SUZUKI, S.. ENCEPHALOPATHY INDUCED BY HIGH PLASMA AND CEREBROSPINAL FLUID CEFTRIAXONE CONCENTRATIONS IN A HEMODIALYSIS PATIENT. INTERNAL MEDICINE. 2019?58 (12):1775-1779", "literaturereference_normalized": "encephalopathy induced by high plasma and cerebrospinal fluid ceftriaxone concentrations in a hemodialysis patient", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190815", "receivedate": "20190305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16035698, "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" }, { "companynumb": "JP-ATLANTIDE PHARMACEUTICALS AG-2022ATL000028", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065180", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Gastroenteritis bacterial", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065180", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Suzuki S, Naito S, Numasawa Y, Asada M, Shoji N, Zeniya M,etal. Encephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient. Intern Med. 2019;58:1775-1779", "literaturereference_normalized": "encephalopathy induced by high plasma and cerebrospinal fluid ceftriaxone concentrations in a hemodialysis patient", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220509", "receivedate": "20220509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20800419, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]
{ "abstract": "Introduction Amplitude-integrated electroencephalography (aEEG) is one of the most widely used neuromonitoring tools in neonatology today. However, little is known about its clinical indications and potential benefits in pediatric intensive care patients. Based on limited experience, its impact on therapeutic decision-making in this patient population is unclear. Case Description We report the case of a 16-year-old boy who, after a pansinusitis, developed a severe meningoencephalitis and intracranial empyema with increased intracranial pressure that required drainage and decompressive craniectomy. He subsequently developed status epilepticus despite a combination of various anticonvulsants. Only after the initialization of an aEEG, we were able to adequately diagnose and continuously monitor his seizure activity and titrate the effect of the antiepileptic drugs. During his hospital stay, we were able to clearly monitor and guide our therapy by accurately identifying the termination of status epilepticus and the recurrence of seizures. Discussion With the help of aEEG, it was easy to identify the nonconvulsive status epilepticus (NCSE) and the ongoing seizure activity in this teenage patient. NCSE is a clinical problem with an effect on the outcome of the patient and is often underdiagnosed. AEEG enabled a rapid detection and management of seizure activity and thereby reduced the overall seizure burden, which was associated with better neurologic outcome.", "affiliations": "Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.", "authors": "Schettler\|Karl F\|KF\|;Heineking\|Beatrice\|B\|;Fernandez-Rodriguez\|Silvia\|S\|;Pilger\|Angelika\|A\|;Haas\|Nikolaus Alexander\|NA\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1055/s-0036-1587328", "fulltext": null, "fulltext_license": null, "issn_linking": "2146-4626", "issue": "6(2)", "journal": "Journal of pediatric intensive care", "keywords": "amplitude-integrated EEG; antiepileptic therapy; meningoencephalitis; neuromonitoring; nonconvulsive status epilepticus", "medline_ta": "J Pediatr Intensive Care", "mesh_terms": null, "nlm_unique_id": "101592756", "other_id": null, "pages": "136-141", "pmc": null, "pmid": "31073438", "pubdate": "2017-06", "publication_types": "D002363:Case Reports", "references": "11571331;14556030;16162436;17188917;17805245;19150756;19585276;20234318;22797054;23318514;23653183;23690296;23876221;24083894;24236076;24401298;24955189;25129228;25524842;26348553;26719828;26816961;26833985;26889778;26928665;26933532;5354856", "title": "Guiding Antiepileptic Therapy in a Pediatric Patient with Severe Meningoencephalitis and Decompressive Craniectomy with the Use of Amplitude-Integrated Electroencephalography.", "title_normalized": "guiding antiepileptic therapy in a pediatric patient with severe meningoencephalitis and decompressive craniectomy with the use of amplitude integrated electroencephalography" }	[ { "companynumb": "DE-UCBSA-2017022320", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3.5 MG PER KG PER DAY", "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": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED: 35 MG/KG PER DAY", "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": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "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": "1", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "15 MG PER KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ADDITIONAL UNKNOWN DOSE", "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": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFOTAXIME SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFOTAXIME" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "021035", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE INCREASED TO 50 MG/KG PER DAYUNK", "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": "LEVETIRACETAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG PER KG", "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": "PHENYTOIN." } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Brain oedema", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Brain herniation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SCHETTLER KF, HEINEKING B, FERNANDEZ-RODRIGUEZ S, PILGER A, HAAS NA. GUIDING ANTIEPILEPTIC THERAPY IN A PEDIATRIC PATIENT WITH SEVERE MENINGOENCEPHALITIS AND DECOMPRESSIVE CRANIECTOMY WITH THE USE OF AMPLITUDE-INTEGRATED ELECTROENCEPHALOGRAPHY. JOURNAL OF PEDIATRIC INTENSIVE CARE. 2017;6(2):136-41", "literaturereference_normalized": "guiding antiepileptic therapy in a pediatric patient with severe meningoencephalitis and decompressive craniectomy with the use of amplitude integrated electroencephalography", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20170612", "receivedate": "20170612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13641093, "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": "An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.", "affiliations": "Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, Oxfordshire, UK [email protected].;Department of Geratology, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.;Department of Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.;Department of Geratology, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.", "authors": "Attwood\|Jonathan E\|JE\|http://orcid.org/0000-0002-0452-4077;Naseer\|Saniya\|S\|;Michael\|Sophia\|S\|;Riley\|Josie\|J\|", "chemical_list": "D001323:Autoantibodies; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D008775:Methylprednisolone", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-237398", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(1)", "journal": "BMJ case reports", "keywords": "epilepsy and seizures; geriatric medicine; immunology; memory disorders", "medline_ta": "BMJ Case Rep", "mesh_terms": "D061605:Administration, Intravenous; D000369:Aged, 80 and over; D001323:Autoantibodies; D060825:Cognitive Dysfunction; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins; D020363:Limbic Encephalitis; D008032:Limbic System; D008775:Methylprednisolone; D010951:Plasma Exchange; D049268:Positron-Emission Tomography; D012640:Seizures; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33431450", "pubdate": "2021-01-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media", "references": null, "title": "Clinical diagnosis of LGI1 antibody encephalitis in an 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{ "abstract": "American trypanosomiasis, also named Chagas disease (CD), is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi. The disease affects millions of people worldwide, leading yearly to approximately 50,000 deaths. COVID-19, generated by SARS-CoV-2, can lead to lymphopenia and death. We hereby describe the first report of two patients with CD and COVID-19 coinfection, from hospitalization until patients' death.", "affiliations": "Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Technical Division of Medical Biology, Adolfo Lutz Institute, Immunology Center, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.", "authors": "Alberca\|Ricardo Wesley\|RW\|;Yendo\|Tatiana Mina\|TM\|;Leuzzi Ramos\|Yasmim Álefe\|YÁ\|;Fernandes\|Iara Grigoletto\|IG\|;Oliveira\|Luana de Mendonça\|LM\|;Teixeira\|Franciane Mouradian Emidio\|FME\|;Beserra\|Danielle Rosa\|DR\|;de Oliveira\|Emily Araujo\|EA\|;Gozzi-Silva\|Sarah Cristina\|SC\|;Andrade\|Milena Mary de Souza\|MMS\|;Branco\|Anna Cláudia Calvielli Castelo\|ACCC\|;Pietrobon\|Anna Julia\|AJ\|;Pereira\|Nátalli Zanete\|NZ\|;de Brito\|Cyro Alves\|CA\|;Orfali\|Raquel Leão\|RL\|;Aoki\|Valéria\|V\|;Duarte\|Alberto José da Silva\|AJDS\|;Benard\|Gil\|G\|;Sato\|Maria Notomi\|MN\|", "chemical_list": "D012367:RNA, Viral", "country": "United States", "delete": false, "doi": "10.4269/ajtmh.20-1185", "fulltext": "\n==== Front\nAm J Trop Med Hyg\nAm J Trop Med Hyg\ntpmd\ntropmed\nThe American Journal of Tropical Medicine and Hygiene\n0002-9637 1476-1645 The American Society of Tropical Medicine and Hygiene \n\n33025877\ntpmd201185\n10.4269/ajtmh.20-1185\nArticles\nCase Report: COVID-19 and Chagas Disease in Two Coinfected Patients\nAlberca Ricardo Wesley 1* Yendo Tatiana Mina 1 Leuzzi Ramos Yasmim Álefe 1 Fernandes Iara Grigoletto 1 Oliveira Luana de Mendonça 12 Teixeira Franciane Mouradian Emidio 12 Beserra Danielle Rosa 1 de Oliveira Emily Araujo 1 Gozzi-Silva Sarah Cristina 12 Andrade Milena Mary de Souza 1 Branco Anna Cláudia Calvielli Castelo 12 Pietrobon Anna Julia 12 Pereira Nátalli Zanete 1 de Brito Cyro Alves 3 Orfali Raquel Leão 1 Aoki Valéria 1 Duarte Alberto José da Silva 1 Benard Gil 1 Sato Maria Notomi 1 1 Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil;\n2 Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;\n3 Technical Division of Medical Biology, Adolfo Lutz Institute, Immunology Center, São Paulo, Brazil\n* Address correspondence to Ricardo Wesley Alberca, Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo, 05403-000 Brazil. E-mail: [email protected]’ addresses: Ricardo Wesley Alberca, Tatiana M. Yendo, Yasmim Álefe Leuzzi Ramos, Iara Grigoletto Fernandes, Luana de Mendonça Oliveira, Franciane Mouradian Emidio Teixeira, Danielle Rosa Beserra, Emily Araujo, Sarah Cristina Gozzi-Silva, Milena Mary de Souza Andrade, Anna Cláudia Calvielli Castelo Branco, Anna Julia Pietrobon, Nátalli Zanete Pereira, Raquel Leao Orfali, Valeria Aoki, Alberto Jose da Silva Duarte, Gil Benard, and Maria Notomi Sato, Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil, E-mails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], and [email protected]. Cyro Alves de Brito, Technical Division of Medical Biology, Adolfo Lutz Institute, Immunology Center, São Paulo, Brazil, E-mail: [email protected].\n\n\n12 2020 \n06 10 2020 \n06 10 2020 \n103 6 2353 2356\n11 9 2020 29 9 2020 © The American Society of Tropical Medicine and Hygiene2020This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Abstract.\nAmerican trypanosomiasis, also named Chagas disease (CD), is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi. The disease affects millions of people worldwide, leading yearly to approximately 50,000 deaths. COVID-19, generated by SARS-CoV-2, can lead to lymphopenia and death. We hereby describe the first report of two patients with CD and COVID-19 coinfection, from hospitalization until patients’ death.\n==== Body\nINTRODUCTION\nChagas disease (CD) is a vector-borne disease transmitted mainly by the bloodsucking bug from subfamily Triatominae.1 Chagas disease is named after Carlos Chagas, a Brazilian researcher who described the life cycle of the parasite Trypanosoma cruzi. The disease was first described in Latin America,1 but currently it is a neglected health problem, affecting approximately 7 million people worldwide.2\n\nChagas disease presents two distinct clinical phases: an acute one, associated with a strong type 1 immune response,3 and a chronic phase, which may endure for the rest of the patients’ life.3 The chronic phase may evolve to different degrees of severity in 30% of the cases, leading to dilated cardiomyopathy, arrhythmia, cardioembolism, heart failure, and death.3,4 Systemic arterial hypertension (SAH) and dyslipidemia are also common features among elderly CD patients.5\n\nA Trypanosoma cruzi–infected person can also progress to an indeterminate form, in which the patient has no symptoms or signs of the disease, presenting no alteration in gastrointestinal and myocardial functions.6 Nevertheless, coinfections can lead to CD reactivation and influence the overall prognoses of the patient.7,8\n\nCOVID-19 is a disease caused by SARS-CoV-2 infection that leads to high rates of respiratory illness and death.9 Several risk factors have been investigated, such as obesity, type 2 diabetes mellitus, and SAH.10\n\nSARS-CoV-2 infection mainly affects the respiratory tract11 but recently has been associated with significant multiple organ dysfunction syndrome.12 One of the most common critical complications during COVID-19 is myocardial injury,13,14 especially in patients with a higher inflammatory profile.13\n\nAs the pandemic is still ongoing, it is impossible to precise the impact of SARS-CoV-2 infection in the overall population, but to the moment, COVID-19 has caused almost 1 million deaths worldwide. Although CD affects millions, to the moment, there is no report of CD and COVID-19 coinfection in the literature.\n\nWe analyzed two CD-infected patients (aged 69 and 74 years), with confirmed SARS-CoV-2 infection by nasopharyngeal detection of SARS-CoV-2 RNA, using reverse transcriptase–PCR and negative results for influenza and respiratory syncytial virus. The patients were hospitalized in a special ward for COVID-19 patients at the university hospital (Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo[HCFMUSP]) with approval for the usage of data from patients. We hereby describe laboratory data from day one until both patients passed away. The study was approved by the local Ethics Committee (HCFMUSP no. 30800520.7.0000.0068-2020) and was carried out in conformity with the 2013 revision of the Declaration of Helsinki.\n\nCASE PRESENTATIONS\nThe first patient was a woman, aged 74 years, who had COVID-19–associated symptoms on May 26, tested positive for SARS-CoV-2 on May 30, and hospitalized. She had a past diagnosis of CD, with chronic CD cardiomyopathy (Figure 1A) and a pacemaker since 2013 (Figure 1A) for a total atrioventricular block, and, on admission, atrial fibrillation with dilatation of the pulmonary artery trunk (43 mm). Additional past clinical history included a stroke in 2010 and a unilateral mastectomy of the left side due to breast cancer in 2011. The patient’s regular medications were hydralazine, atenolol, losartan, omeprazole, amiodarone, atorvastatin, and isosorbide. On admission, the patient presented dyspnea but not cough, fever, or myalgia. Chest radiography revealed pulmonary ground-glass opacities affecting 50% of the lungs (Figure 1B and C). The level of N-terminal pro–b-type natriuretic peptide (NT-proBNP) was 1,319 pg/mL (reference value of < 125 pg/mL), but D-dimer was below detection, but peaked in 1738 ng/mL in fibrinogen equivalent units (FEUs) on the 10th day at the hospital. Total bilirubin and fractions as well as total protein levels and fractions (albumin and globulin) were within reference levels. No alteration in the levels in serum alanine transaminase or aspartate transaminase was detected during hospitalization. As part of the COVID treatment protocol, she received ceftriaxone from June 1 to 6, methylprednisolone 40 mg on June 7, azithromycin from June 1 to 2, and warfarin on June 7.\n\nFigure 1. Chest X-ray and thoracic computerized tomography scan of patient #1. (A) X-ray from 2015 pre–COVID-19 hospitalization showing the marked cardiomegaly, (B) X-ray from June 2020, and (C) tomography from June 2020 during COVID-19 hospitalization showing COVID-19 ground-glass opacity.\n\nPatient #1 showed normal levels of red blood count, hemoglobin, and hematocrit, but a platelet count reduction since day 1 of hospitalization (Figure 2A–D). White blood counts were normal in the first week, with an increase in neutrophils and monocytes by the end of the second week of hospitalization (Figure 2E–J). The neutrophil-to-lymphocyte ratio remained at normal levels during hospitalization due to the reduced lymphocyte cell count, a common feature in COVID-19 (Figure 2J).15\n\nFigure 2. Daily clinical features of patients. Blood levels of (A) erythrocytes, (B) hemoglobin, (C) hematocrit, (D) platelets, (E) leukocytes, (F) neutrophils, (G) eosinophils, (H) lymphocytes, (I) monocytes, (J) neutrophil-to-lymphocyte ratio, (K) creatinine, (L) glucose, (M) C-reactive protein, (N) urea, (O) pO2, (P) pCO2, (Q) pH, (R) oxygen peripheral saturation, (S) prothrombin time, (T) activated partial thromboplastin time, (U) sodium, (V) potassium, and (X) magnesium. Gray box represents reference values; dot line represents the date the patients passed away.\n\nThere was also a sustained elevation of creatinine levels, C-reactive protein, and urea (Figure 2K, M, and N). On day 8, the patient developed blood glucose alterations, probably caused by SARS-CoV-2 infection, as previously proposed (Figure 2L).16\n\nOther findings included low pO2, but normal levels of pCO2 and pH, with a variable oxygen peripheral saturation (Figure 2O–R). High prothrombin time during COVID-19 was also verified (Figure 2Q). From day 10 onward, the patient presented altered sodium, potassium, and magnesium serum levels (Figure 2U–X). The patient’s clinical situation rapidly deteriorated, evolving into SARS. The patient was transferred to the ICU, and despite all efforts, the patient passed away on day 17 (June 17) because of refractory circulatory shock.\n\nThe second patient was a man, aged 69 years, weighing 62 kg, who had COVID-19–associated symptoms on May 7. He sought the hospital 2 weeks later, and tested positive on May 22 and hospitalized. He was a heavy smoker and has been followed at the HCFMUSP for indeterminate CD. Chest radiography revealed pulmonary ground-glass opacities in 50% of the parenchyma. On admission, the level of NT-proBNP was 458 pg/mL and of D-dimer was 88,868 ng/mL FEUs. Blood troponin T levels were within the normal range during admission (< 0.014 ng/mL), but increased to 0.193 ng/mL on the ninth day. Total bilirubin and fractions as well as total protein levels and fractions (albumin and globulin) were within reference levels. No alteration in the levels in serum alanine transaminase or aspartate transaminase was detected during hospitalization. During hospitalization, he received azithromycin and ceftriaxone from May 22 to 27, enoxaparin, methylprednisolone 30 mg on May 27, piperacillin/tazobactam from May 27 to 31, vancomycin from May 31 until death, and meropenem on May 31.\n\nPatient #2 was admitted already with respiratory distress and immediately transferred to the ICU. Laboratory findings showed normal levels of erythrocytes and hemoglobin, and high levels of platelet since day 1 (Figure 2A–D). High counts on leukocytes, especially on neutrophils, were seen since day 5, with the maintenance of low lymphocyte counts (Figure 2E–J). Creatinine and urea levels were stable, with an abrupt spike on day 10 (Figure 2K and N). Interestingly, C-reactive protein levels were constantly high, and pO2 levels were regularly low, with pCO2 and pH levels under normal levels (Figure 2M and O–Q), but oxygen saturation was regularly below reference values (Figure 2R). Prothrombin time and activated partial prothrombin time increased on day 13 (Figure 2S and T). Sodium and potassium serum levels were always normal during hospitalization time, but the magnesium levels increased rapidly in the last couple of days in the hospital (Figure 2U–X). On day 8, there was an increase in the glucose serum levels, probably related to the SARS-CoV-2 infection (Figure 2L), as previously proposed.16\n\nThe patient progressed with pulmonary thromboembolism and SARS, followed by hypotension and cardiac arrest. Despite all efforts, the patient passed away on day 13 (June 3).\n\nDISCUSSION\nWe hereby describe two patients with CD and SARS-CoV-2 coinfection. Both patients were hospitalized in a reference center for COVID-19 treatment in the metropolitan region of São Paulo, a city in the Southeast of Brazil. The southeast region comprises less than 5% of the CD cases in Brazil. We hypothesize that CD and COVID-19 coinfection may be an important noninvestigated cause of death in regions with a higher incidence of CD.17\n\nChagas disease can manifest as a severe, life-threatening opportunistic infection in patients with immune deficiencies such as HIV.18 COVID-19 may lead to lymphopenia, which could curb the anti–T. cruzi immune response, similar to what is seen in HIV patients.18 Elderly CD patients are also prone to develop SAH and dyslipidemia,5 therefore being at higher risk group for COVID-19.11,19\n\nSome patients with COVID-19 develop severe disease characterized by respiratory and systemic syndromes.20 Chronic underdiagnosed diseases, such as indeterminate form CD, and other coinfections,21–23 may alter the disease course and represent a significant risk factor for poor COVID-19 outcomes.\n\nNevertheless, advanced age in these two case reports could be an additional risk factor, reducing the immune response against CD and COVID-19.5,24 These may be due to SARS-CoV-2 cell entry receptor expression, angiotensin-converting enzyme-2, immunosenescence, or a larger number of medical comorbidities.25\n\nThis report highlights the first report of CD and COVID-19 coinfection. Patients presented a rapid disease progression, and despite all efforts of the medical team, both patients died. We believe that CD may be an important and underrated risk factor for developing severe COVID-19, especially those with chronic CD with cardiomyopathy that may be prone to have poor outcomes, especially in endemic areas with underreported CD infection and/or underreported SARS-CoV-2 infection.\n\nAcknowledgments:\nPublication charges for this article were waived because of the ongoing pandemic of COVID-19.\n==== Refs\nREFERENCES\n1. Lidani KCF Andrade FA Bavia L Damasceno FS Beltrame MH Messias-Reason IJ Sandri TL , 2019 \nChagas disease: from discovery to a worldwide health problem\n. Front Public Health \n7 : 166 .31312626 \n2. World Health Organization , 2020 \nChagas Disease (Also Known as American Trypanosomiasis). Chagas Disease Fact Sheets . Available at: https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)%0Ahttps://www.who.int/en/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis). Accessed August 30, 2020 .\n3. Boscardin SB Torrecilhas ACT Manarin R Revelli S Rey EG Tonelli RR Silber AM , 2010 \nChagas’ disease: an update on immune mechanisms and therapeutic strategies\n. J Cell Mol Med \n14 : 1373 –1384\n.20070438 \n4. MacHado FS \n2012 \nChagas heart disease: report on recent developments\n. Cardiol Rev \n20 : 53 –65\n.22293860 \n5. Alves RMDA Thomaz RP De Almeida EA Wanderley JDS Guariento ME , 2009 \nChagas’ disease and ageing: the coexistence of other chronic diseases with Chagas’ disease in elderly patients\n. Rev Soc Bras Med Trop \n42 : 622 –628\n.20209343 \n6. Issa VS , 2018 \nThe indeterminate form of chagas disease\n. Arq Bras Cardiol \n110 : 111 –112\n.29561988 \n7. de Almeida EA Ramos AN Correia D Shikanai-Yasuda MA , 2011 \nCoinfecção Trypanosoma cruzi/HIV: revisão sistemática (1980–2010)\n. Rev Soc Bras Med Trop \n44 : 762 –770\n.22231251 \n8. Trindade MÂB Carvalho NB Belfort EC Pagliari C Gakiya E Sakai-Valente NY Benard G Shikanai-Yasuda MA , 2011 \nCase report: a patient with erythema nodosus leprosum and chagas cardiopathy: challenges in patient management and review of the literature\n. Am J Trop Med Hyg \n84 : 973 –977\n.21633036 \n9. Huang C \n2020 \nClinical features of patients infected with 2019 novel coronavirus in Wuhan, China\n. Lancet \n395 : 497 –506\n.31986264 \n10. Alberca RW Oliveira LDEM Branco ACCC Pereira NZ Sato MN , 2020 \nObesity as a risk factor for COVID-19: an overview\n. Crit Rev Food Sci Nutr \n15 : 1 –15\n. 10.1080/10408398.2020.1775546 .\n11. Zhang JJ Dong X Cao Y Yuan YD Yang YB qin YQ Akdis CA Gao YD , 2020 \nClinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China\n. Allergy Eur J Allergy Clin Immunol \n75 : 1730 –1741\n.\n12. Wang L Zhang Y Zhang S , 2020 \nCardiovascular impairment in COVID-19: learning from current options for cardiovascular anti-inflammatory therapy\n. Front Cardiovasc Med \n7 : 78 .32426374 \n13. Song Y Gao P Ran T Qian H Guo F Chang L Wu W Zhang S , 2020 \nHigh inflammatory burden: a potential cause of myocardial injury in critically ill patients with COVID-19\n. Front Cardiovasc Med \n7 : 128 .32733921 \n14. Wang Y Zheng Y Tong Q Wang L Lv G Xi Z Liu W , 2020 \nCardiac injury and clinical course of patients with coronavirus disease 2019\n. Front Cardiovasc Med \n7 : 147 .33195443 \n15. Tan L Wang Q Zhang D Ding J Huang Q Tang YQ Wang Q Miao H , 2020 \nLymphopenia predicts disease severity of COVID-19: a descriptive and predictive study\n. Signal Transduct Target Ther \n5 : 33 .32296069 \n16. Rubino F \n2020 \nNew-onset diabetes in COVID-19\n. N Engl J Med \n383 : 789 –790\n.32530585 \n17. Santos EF \n2020 \nAcute Chagas disease in Brazil from 2001 to 2018: a nationwide spatiotemporal analysis\n. PLoS Negl Trop Dis \n14 : e0008445 .32745113 \n18. Vaidian AK Weiss LM Tanowitz HB , 2004 \nChagas’ disease and AIDS\n. Kinetoplastid Biol Dis \n3 : 2 .15142278 \n19. Wu C \n2020 \nRisk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China\n. JAMA Intern Med \n180 : 934 –943\n.32167524 \n20. Jose RJ Manuel A , 2020 \nCOVID-19 cytokine storm: the interplay between inflammation and coagulation\n. Lancet Respir Med \n8 : e46 –e47\n.32353251 \n21. Chauhdary WA Chong PL Mani BI Asli R Momin RN Abdullah MS Chong VH , 2020 \nPrimary respiratory bacterial coinfections in patients with COVID-19\n. Am J Trop Med Hyg \n103 : 917 –919\n.32500854 \n22. Khaddour K Sikora A Tahir N Nepomuceno D Huang T , 2020 \nCase report: the importance of novel coronavirus disease (COVID-19) and coinfection with other respiratory pathogens in the current pandemic\n. Am J Trop Med Hyg \n102 : 1208 –1209\n.32314699 \n23. Lier AJ Tuan JJ Davis MW Paulson N McManus D Campbell S Peaper DR Topal JE , 2020 \nCase report: disseminated strongyloidiasis in a patient with COVID-19\n. Am J Trop Med Hyg \n103 : 1590 –1592\n.32830642 \n24. Liu K Chen Y Lin R Han K , 2020 \nClinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients\n. J Infect \n80 : e14 –e18\n.\n25. Perrotta F Corbi G Mazzeo G Boccia M Aronne L D’Agnano V Komici K Mazzarella G Parrella R Bianco A , 2020 \nCOVID-19 and the elderly: insights into pathogenesis and clinical decision-making\n. Aging Clin Exp Res \n32 : 1599 –1608\n.32557332\n\n", "fulltext_license": "CC BY", "issn_linking": "0002-9637", "issue": "103(6)", "journal": "The American journal of tropical medicine and hygiene", "keywords": null, "medline_ta": "Am J Trop Med Hyg", "mesh_terms": "D000368:Aged; D001938:Brazil; D000086382:COVID-19; D000086742:COVID-19 Testing; D002598:Chagas Cardiomyopathy; D060085:Coinfection; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D010138:Pacemaker, Artificial; D012367:RNA, Viral; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D014349:Trypanosoma cruzi", "nlm_unique_id": "0370507", "other_id": null, "pages": "2353-2356", "pmc": null, "pmid": "33025877", "pubdate": "2020-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": 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{ "abstract": "Despite the successes of tyrosine kinase inhibitors (TKIs) in improving outcomes in patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), allogeneic hematopoietic stem cell transplantation (HSCT) continues to be an important and potentially curative option for selected patients with either disease. After HSCT, TKIs are increasingly being used to treat or prevent disease relapse, and practice patterns suggest that these TKIs are often chosen empirically without regard to pre-HSCT mutation status. We investigated whether ABL kinase domain mutations persist after transplantation and, thus, whether pre-HSCT mutation status should inform the selection of post-HSCT TKIs in these patients. We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph + ALL at our institution between 2000 and 2010, and we identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings. In total, 95 CML and 20 Ph + ALL patients with positive PCR transcripts were identified, of which 10 (10.5%) and 4 (20.0%), respectively, were found to have pre-HSCT ABL kinase mutations known to confer TKI resistance. In 9 (64.2%) of these 14 patients, the same kinase mutation was also detectable at an average time of 191 days after HSCT. Seven (50.0%) of the 14 harboring mutations had relapsed/refractory disease by last follow-up, of which, in retrospect, 6 had received a predictably ineffective TKI within the first 100 days after transplantation based on our mutation analysis. These data support the idea that pre-existing mutations in the ABL kinase domain, frequently associated with resistance to TKIs and prevalent in a transplantation population, are persistently detectable in the majority of patients after transplantation. We propose that such resistance patterns should be considered when selecting TKIs in the post-HSCT setting, including clinical trials of post-HSCT TKI prophylaxis.", "affiliations": "Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington. Electronic address: [email protected].;Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.;Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.", "authors": "Egan\|Daniel N\|DN\|;Beppu\|Lan\|L\|;Radich\|Jerald P\|JP\|", "chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "21(1)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Allogeneic hematopoietic stem cell transplantation; BCR-ABL kinase mutations; Chronic myeloid leukemia; Philadelphia-chromosome acute lymphoblastic leukemia", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors", "nlm_unique_id": "9600628", "other_id": null, "pages": "184-9", "pmc": null, "pmid": "25300870", "pubdate": "2015-01", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "19602874;17881635;15570257;15817679;16533723;22240733;17211436;18615627;19885746;19652056;15747376;21156844;20005967;21193419;23223358;17008892;18471874;21508120;19539217;17119111;16234522;19075254;23212150;12623848;21134983;23794064;15297408;12970768;20460883;1586748;16627254;24382642;17405907;19204710;17664354;16855631;12176876;12399961", "title": "Patients with Philadelphia-positive leukemia with BCR-ABL kinase mutations before allogeneic transplantation predominantly relapse with the same mutation.", "title_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation" }	[ { "companynumb": "PHHY2014US167142", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "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": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Oncologic complication", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Leukaemia recurrent", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EGAN DN, BEPPU L, RADICH JP. PATIENTS WITH PHILADELPHIA-POSITIVE LEUKEMIA WITH BCR-ABL KINASE MUTATIONS BEFORE ALLOGENEIC TRANSPLANTATION PREDOMINANTLY RELAPSE WITH THE SAME MUTATION. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2014;172-195", "literaturereference_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10679249, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014US166541", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DASATINIB" }, "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": "DASATINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "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": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukaemia recurrent", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oncologic complication", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "EGAN DN, BEPPU L, RADICH JP. PATIENTS WITH PHILADELPHIA-POSITIVE LEUKEMIA WITH BCR-ABL KINASE MUTATIONS BEFORE ALLOGENEIC TRANSPLANTATION PREDOMINANTLY RELAPSE WITH THE SAME MUTATION. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2015;172-195", "literaturereference_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10679240, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014US167145", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "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": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukaemia recurrent", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oncologic complication", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "EGAN DN, BEPPU L, RADICH JP. PATIENTS WITH PHILADELPHIA-POSITIVE LEUKEMIA WITH BCR-ABL KINASE MUTATIONS BEFORE ALLOGENEIC TRANSPLANTATION PREDOMINANTLY RELAPSE WITH THE SAME MUTATION. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2015;172-195", "literaturereference_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10679250, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]
{ "abstract": "Glutamic acid decarboxylase antibodies (GAD-Abs) have been implicated in refractory epilepsy. The association with refractory status epilepticus in adults has been rarely described. We discuss our experience in managing three adult patients who presented with refractory status epilepticus associated with GAD-Abs. Case series with retrospective chart and literature review. Three patients without pre-existing epilepsy who presented to our institution with generalized seizures between 2013 and 2014 were identified. Seizures proved refractory to first and second-line therapies and persisted beyond 24 hours. Patient 1 was a 22-year-old female who had elevated serum GAD-Ab titres at 0.49 mmol/l (normal: <0.02) and was treated with multiple immuno- and chemotherapies, with eventual partial seizure control. Patient 2 was a 61-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l. EEG showed persistent generalized periodic discharges despite maximized therapy with anticonvulsants but no immunotherapy, resulting in withdrawal of care and discharge to nursing home. Patient 3 was a 50-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l, and was discovered to have pulmonary sarcoidosis. Treatment with steroids and intravenous immunoglobulin resulted in seizure resolution. Due to the responsiveness to immunotherapy, there may be an association between GAD-Abs and refractory seizures, including refractory status epilepticus. Causation cannot be established since GAD-Abs may be elevated secondary to concurrent autoimmune diseases or formed de novo in response to GAD antigen exposure by neuronal injury. Based on this report and available literature, there may be a role for immuno- and chemotherapy in the management of refractory status epilepticus associated with GAD-Abs.", "affiliations": "Department of Neurology.;Department of Neurology.;Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham Hospital, Birmingham, AL, USA.;Department of Neurology.;Department of Neurology.", "authors": "Khawaja\|Ayaz M\|AM\|;Vines\|Brannon L\|BL\|;Miller\|David W\|DW\|;Szaflarski\|Jerzy P\|JP\|;Amara\|Amy W\|AW\|", "chemical_list": "D000927:Anticonvulsants; D001323:Autoantibodies; D005968:Glutamate Decarboxylase", "country": "France", "delete": false, "doi": "10.1684/epd.2016.0797", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "18(1)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "NORSE; RSE; anti-GAD antibody; chemotherapy; glutamic acid decarboxylase; immunotherapy; refractory seizures; status epilepticus", "medline_ta": "Epileptic Disord", "mesh_terms": "D000927:Anticonvulsants; D001323:Autoantibodies; D004569:Electroencephalography; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D008875:Middle Aged; D012189:Retrospective Studies; D012640:Seizures; D013226:Status Epilepticus; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "100891853", "other_id": null, "pages": "34-43", "pmc": null, "pmid": "26878120", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Refractory status epilepticus and glutamic acid decarboxylase antibodies in adults: presentation, treatment and outcomes.", "title_normalized": "refractory status epilepticus and glutamic acid decarboxylase antibodies in adults presentation treatment and outcomes" }	[ { "companynumb": "US-UCBSA-2016011589", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLONAZEPAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 MG, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLONAZEPAM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "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": "6", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "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": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2000 MG, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "150 MG, 4X/DAY (QID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LACOSAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "5MG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" } ], "patientagegroup": null, "patientonsetage": "50", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHAWAJA AM, VINES BL, MILLER DW, SZAFLARSKI JP, AMARA AW. REFRACTORY STATUS EPILEPTICUS AND GLUTAMIC ACID DECARBOXYLASE ANTIBODIES IN ADULTS: PRESENTATION, TREATMENT AND OUTCOMES. EPILEPTIC DISORD. 2016?18(1):34-43", "literaturereference_normalized": "refractory status epilepticus and glutamic acid decarboxylase antibodies in adults presentation treatment and outcomes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17208024, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-UCBSA-2016011587", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MG, 4X/DAY (QID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENYTOIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOBAZAM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, 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INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LORAZEPAM" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.1 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, 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"drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3MG/KG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXCARBAZEPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2400 MG DAILY (DIVIDED)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "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": "6", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "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": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10MG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "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": "PHENOBARBITAL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "97.2 MG, 4X/DAY (QID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "4", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "97.2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PHENOBARBITAL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MCG/KG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "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": "VIGABATRIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VIGABATRIN." } ], "patientagegroup": null, "patientonsetage": "22", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHAWAJA AM, VINES BL, MILLER DW, SZAFLARSKI JP, AMARA AW. REFRACTORY STATUS EPILEPTICUS AND GLUTAMIC ACID DECARBOXYLASE ANTIBODIES IN ADULTS: PRESENTATION, TREATMENT AND OUTCOMES. EPILEPTIC DISORD. 2016?18(1):34-43", "literaturereference_normalized": "refractory status epilepticus and glutamic acid decarboxylase antibodies in adults presentation treatment and outcomes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17208026, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-UCBSA-2016011588", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": 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"drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "OFF LABEL USE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LACOSAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, 2X/DAY (BID)", "drugenddate": null, "drugenddateformat": null, "drugindication": "STATUS EPILEPTICUS", 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{ "abstract": "BACKGROUND\nCollagenous colitis (CC) is a clinicopathologic syndrome characterized by chronic watery diarrhea and distinctive histopathologic features. Spontaneous perforation of CC is extremely rare, because CC is usually managed medically, and the need for surgical intervention is rare. We report a surgical case of spontaneous colonic perforation of CC with acute abdomen disease.\n\n\nMETHODS\nA 77-year-old man was admitted to our hospital for abdominal pain and watery diarrhea. Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the splenic flexure of the colon. Therefore, we performed emergency surgery with a diagnosis of colonic perforation. Intraoperative findings revealed colonic necrosis at the splenic flexure, so we performed a left hemicolectomy. Histopathological examination revealed typical findings of CC, a thick subepithelial collagenous band and deep ulcers with perforation. The postoperative course was uneventful, and the patient was discharged on the 28th postoperative day. After changing the proton pump inhibitor (PPI) from lansoprazole (LPZ) to rabeprazole (RPZ), he has not complained of diarrhea symptoms.\n\n\nCONCLUSIONS\nAlthough spontaneous perforation is a rare complication of CC, it is possible to be diagnosed by symptom of acute abdomen disease. This is the seventh case of spontaneous colonic perforation of CC worldwide.", "affiliations": "Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan. [email protected].;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.", "authors": "Mori\|Haruki\|H\|;Miyake\|Toru\|T\|;Shimizu\|Tomoharu\|T\|;Yamaguchi\|Tsuyoshi\|T\|;Kaida\|Sachiko\|S\|;Takebayashi\|Katsushi\|K\|;Iida\|Hiroya\|H\|;Otsuki\|Akinori\|A\|;Inatomi\|Osamu\|O\|;Kitoh\|Katsuyuki\|K\|;Andoh\|Akira\|A\|;Tani\|Masaji\|M\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1186/s40792-019-0647-0", "fulltext": "\n==== Front\nSurg Case RepSurg Case RepSurgical Case Reports2198-7793Springer Berlin Heidelberg Berlin/Heidelberg 64710.1186/s40792-019-0647-0Case ReportA case of spontaneous colonic perforation in collagenous colitis Mori Haruki [email protected] 1Miyake Toru 1Shimizu Tomoharu 1Yamaguchi Tsuyoshi 1Kaida Sachiko 1Takebayashi Katsushi 1Iida Hiroya 1Otsuki Akinori 2Inatomi Osamu 2Kitoh Katsuyuki 2Andoh Akira 2Tani Masaji 11 0000 0000 9747 6806grid.410827.8Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga 520-2192 Japan 2 Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga 520-2192 Japan 31 5 2019 31 5 2019 12 2019 5 907 3 2019 20 5 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.Background\nCollagenous colitis (CC) is a clinicopathologic syndrome characterized by chronic watery diarrhea and distinctive histopathologic features. Spontaneous perforation of CC is extremely rare, because CC is usually managed medically, and the need for surgical intervention is rare. We report a surgical case of spontaneous colonic perforation of CC with acute abdomen disease.\n\nCase presentation\nA 77-year-old man was admitted to our hospital for abdominal pain and watery diarrhea. Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the splenic flexure of the colon. Therefore, we performed emergency surgery with a diagnosis of colonic perforation. Intraoperative findings revealed colonic necrosis at the splenic flexure, so we performed a left hemicolectomy. Histopathological examination revealed typical findings of CC, a thick subepithelial collagenous band and deep ulcers with perforation. The postoperative course was uneventful, and the patient was discharged on the 28th postoperative day. After changing the proton pump inhibitor (PPI) from lansoprazole (LPZ) to rabeprazole (RPZ), he has not complained of diarrhea symptoms.\n\nConclusions\nAlthough spontaneous perforation is a rare complication of CC, it is possible to be diagnosed by symptom of acute abdomen disease. This is the seventh case of spontaneous colonic perforation of CC worldwide.\n\nKeywords\nColonic perforationCollagenous colitisSpontaneousissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCollagenous colitis (CC) is characterized by chronic diarrhea and usually occurs in middle-aged women. Endoscopic examinations are generally unremarkable [1], laboratory and radiological test results are usually normal, and stool cultures are sterile in many cases. Thus, there is not a reliable biomarker for CC diagnosis.\n\nEndoscopic evaluation of the colon is often normal, but erythema, edema, changes in blood vessels, and mucosal clefts may be observed [2]. Definitive diagnosis is established by the pathological diagnosis, an endoscopic biopsy revealing a thickened subepithelial collagenous band (10–30 μm) found in the wall of the colon with epithelial damage and chronic inflammation of the lamina propria [3].\n\nCC is a heterogeneous disorder and may have multiple etiologies making pathogenesis unclear. Several medications have been implicated as contributing factors, notably aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), histamine 2 receptor blockers, and proton pump inhibitors, such as lansoprazole and certain selective serotonin reuptake inhibitors [4]. Autoimmune conditions, including rheumatoid arthritis, thyroid disorders, ulcerative colitis, and celiac disease, are also associated with colitis. Furthermore, it has been reported that smoking and bacterial infections are associated with CC. But it is unclear that the family history and genetic abnormalities are risk factors for CC [5, 6]. CC is rarely associated with serious complications; however, spontaneous and post-colonoscopic perforated cases have been reported [3]. Mechanisms of rare spontaneous perforations in patients with CC remain unclear. We report herein an interesting and rare case of the above.\n\nCase presentation\nA 77-year-old man was admitted to Shiga University of Medical Science (SUMS) Hospital complaining of abdominal pain and frequent episodes of non-bloody watery diarrhea, lasting for 2 months. His past medical history included a gastric ulcer 40 years earlier, hypertension, and chemotherapy for multiple myeloma. His current medications were aspirin, prednisolone, melphalan, and lansoprazole (LPZ). His body temperature was within the normal range. Physical examination revealed acute left abdominal pain and muscular defense. Laboratory results revealed a white blood cell count of 2100/μl (normal range, 3000–8000/μl), and C-reactive protein (CRP) level was 0.19 mg/dl (normal range, < 0.30 mg/dl). Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the colonic splenic flexure, and ascites was found on the liver surface (Fig. 1a, b). The patient was diagnosed as having peritonitis with colonic perforation. Emergency laparotomy was performed, and it was observed that the ascites contained intestinal fluid. The colon around the splenic angle was necrotic and edematous. We performed a left hemicolectomy. Macroscopic findings (Fig. 2) showed edematous mucosa and tortuous longitudinal ulcer. Histopathological examination (Fig. 3) revealed typical findings of CC, with a thick subepithelial collagenous band and deep ulcers with perforation. Active lymphocyte infiltration was observed in all layers of the colon. There was no evidence of acute ischemic colitis or inflammatory bowel disease.Fig. 1 Abdominal computed tomography (CT). a Ascites around the liver (arrow). b, c Thickness in bowel wall and involving the free air around the colonic splenic flexure (arrow)\n\nFig. 2 Macroscopy of the resected colon: cross sections of the bowel show normal-appearing mucosa, markedly thickened edematous wall, and longitudinal ulcer. The arrow indicates the perforation site\n\nFig. 3 Histological examination. a Typical findings of collagenous colitis with a thick subepithelial collagenous band (arrowhead). b Collagenous band was stained by Azan (arrowhead). c Ulcerated area with perforation (arrow)\n\n\n\nPostoperative course was uneventful, and the patient was discharged on the 28th postoperative day. PPI-induced CC was suspected due to his past history; therefore, the PPI was subsequently changed from LPZ to RPZ. Following this change, he noted an improvement in diarrhea symptoms.\n\nDiscussion\nCC is a relatively uncommon, but increasingly diagnosed form of microscopic colitis. CC was described in 2 independent reports in 1976 from Canada and Sweden [7, 8]. Patients with CC typically complain of chronic, non-bloody, watery diarrhea. It is pathologically diagnosed by the presence of increased intraepithelial lymphocytes, mixed inflammatory cells in the lamina propria, and pathognomonic appearance of a thickened subepithelial collagen band [5]. CC is usually treated successfully with medication; therefore, the need for surgical intervention is rare [9]. However, emergent surgery is necessary if there is perforation of the bowel tract, which is accompanied by collagen deposition under the mucosal epithelium that reduces intestinal elasticity and extensibility [3]. A colonoscopy or barium enema sometimes can cause colonic perforations in collagenous colitis, and these iatrogenic perforations are thought to occur secondary to mechanical trauma or luminal insufflation causing linear mucosal tears that lead to rupture [10, 11].\n\nOnly 6 patients have been reported to have a spontaneous perforation in CC (Table 1) [9, 10, 12–15]. In all cases, including ours, there was a history of non-bloody diarrhea and no previous diagnosis of CC. CC occurs more frequently in females, and all previous reports described females, but our patient was male. All patients recovered following resection of the perforated segment. Of note, all CC perforations occurred in the left colon, in contrast to a perforation after endoscopic examination, which is commonly on the right side [16–18]. In recent years, reports of cases with characteristic longitudinal ulcers expressed as “mucosal tears” or “linear mucosal defect” are increasing [19–22]. This longitudinal ulcer is elongated and presents a mucosal split form and the boundary is clear, edema and redness of the ulcer margin are poor, and therefore different from a longitudinal ulcer seen in ischemic colitis or Crohn’s disease. A tortuous, longitudinal ulcer, characteristic of CC, was also observed in our case.Table 1 Reported cases of spontaneous perforation in collagenous colitis\n\n\tAuthor\tYear\tAge/sex\tMedications\tPerforation site\tSurgery\tOutcome\t\n1\tFreeman [6]\t2001\t37/F\tNone recorded\tSigmoid\tLaparotomy\tAlive\t\n2\tBohr [4]\t2005\t56/F\tClomipramine\tSplenic angle/descending colon\tSegmental resection\tAlive\t\n3\tBennett [7]\t2013\t67/F\tAspirin, loperamide\tSplenic angle\tPartial colectomy\tAlive\t\n4\tAkamoto [8]\t2014\t64/F\tNone\tDescending colon\tLeft colectomy\tAlive\t\n5\tCottreau [9]\t2016\t49/F\tDexilansoprazole, buproprion, clonazepam, ranitidine\tDescending colon\tLeft colectomy\tAlive\t\n6\tMitchell [5]\t2016\t80/F\tLoperamide, levothyroxine\tSplenic angle\tSegmental resection\tAlive\t\n7\tOur case\t2018\t77/M\tLansoprazole, aspirin, prednisolone, melphalan\tSplenic angle\tPartial colectomy\tAlive\t\nF female, M male\n\n\n\nAlthough the precise mechanism is unknown for the cause of CC, previous articles report that CC is caused by genetic factors [23, 24], intestinal factors due to malabsorption of bile acid [25, 26], and drugs [27]. In recent years, CC related to LPZ has attracted attention [28]. Oral administration rate of LPZ in patients with CC is as high as 53 to 83% in Japan [29, 30], while as low as 8% in European and American reports [31].\n\nProton pumps exist in colonic epithelial cells. Therefore, a proton pump inhibitor is presumed to change the composition and pH values of secretions from colonic mucosa and affect the immune response, which is a possible mechanism in developing CC [32]. LPZ is mainly metabolized by Cytochrome P450 2C19 (CYP2C19) and Cytochrome P450 3A4 (CYP3A4). A genetic polymorphism of CYP2C19 is reported in 18 to 23% of the Japanese population, compared with 1 to 6% in the Western population. This fact is considered as one of the reasons that LPZ-induced CC cases are more frequent in Japan [33]. Rabeprazole (RPZ), however, is not metabolized via CYP2C19 and CC induced by RPZ is rarer than LPZ. Therefore, it is suggested that the different PPI pharmacological action is involved in the pathogenesis of CC [30]. NSAIDs, antihypertensive drugs, and hyperlipidemic drugs are also metabolized by CYP3A4. When these drugs are used in combination with LPZ, CC may develop due to the high blood concentration of LPZ and drug interaction via CYP families [34]. In our case, the patient was taking LPZ because of the history of a gastric ulcer. After surgery, his PPI was subsequently changed from LPZ to RPZ with no changes in his other. After this change, he noted an improvement in his diarrhea symptoms. Therefore, we suggest that CC of this patient seemed to be caused by LPZ.\n\nConclusion\nIn summary, we report a case of CC triggered by a PPI. It is important to note that spontaneous perforation of CC is a possible complication of diagnosed acute abdomen disease.\n\nAbbreviations\nCCCollagenous colitis\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nCYP2C19Cytochrome P450 2C19\n\nCYP3A4Cytochrome P450 3A4\n\nLPZLansoprazole\n\nNSAIDsNon-steroidal anti-inflammatory drugs\n\nPPIProton pump inhibitor\n\nRPZRabeprazole\n\nThis paper is not based on previous communications with a society or meeting.\n\nAcknowledgements\nWe thank Akiko Matsubara from the department of Pathological Diagnosis, Shiga University of Medical Science, for pathological guidance of this manuscript\n\nAuthors’ contributions\nHM is the first author of this manuscript and the corresponding author. SK, TM, and KT performed the surgery. TY, AO, and HI collected the clinical data. OI, KK, AA, TS, and MT revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors received no financial support for the preparation of this case report.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nOral informed consent was obtained from the patient for the publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Tangri V Chande N Microscopic colitis an update J Clin Gastroenterol 2009 43 293 296 10.1097/MCG.0b013e31818f50ce 19169149 \n2. Tysk C Wickbom A Nyhlin N Eriksson S Bohr J Recent advances in diagnosis and treatment of microscopic colitis Ann Gastroenterol. 2011 24 4 253 262 24713787 \n3. 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Fernandez-Banares F Esteve M Salas A Forné TM Espinos JC Martín-Comin J Viver JM Bile acid malabsorption in microscopic colitis and in previously unexplained functional chronic diarrhea Dig Dis Sci. 2001 46 2231 2238 10.1023/A:1011927302076 11680602 \n27. Beaugerie L Pardi DS Review article: drug-induced microscopic colitis―proposal for a scoring system and review of the literature Aliment Pharmacol Ther. 2005 22 277 284 10.1111/j.1365-2036.2005.02561.x 16097993 \n28. Umeno J Matsumoto T Nakamura S Yanai S Hirakawa K Yada S Jo Y Yamagata H Yoshimura R Watanabe T Gushima M Yao T Nakashima Y Iida M Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis Gastrointest Endosc 2008 67 1185 1191 10.1016/j.gie.2008.02.013 18513560 \n29. Umeno J Matsumoto T Nakamura S Iida M Diagnosis and management of collagenous colitis Gastroenterol Endosc 2010 52 1233 1242 \n30. Umeno J, Matsumoto T, Nakamura S, et al. Drug-induces collagenous colitis: special reference to the endoscopic features of lansoprazole-associated cases. Stomach Intestine. 2009;44:1973-1982.\n31. Fernandez-Banares F Esteve M Espinos JC Rosinach M Forne M Salas A Viver JM Drug consumption and the risk of microscopic colitis Am J Gastroenterol. 2007 102 324 330 10.1111/j.1572-0241.2006.00902.x 17100977 \n32. Fernandez-Banares F Salas A Esteve M Espinos J Forne M Viver JM Collagenous and lymphocytic colitis. Evaluation of clinical and histological features, response to treatment, and long-term follow-up Am J Gastroentterol. 2003 98 340 347 10.1111/j.1572-0241.2003.07225.x \n33. Ishizaki T Horai Y Review article: cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on Rabeprazole Aliment Pharmacol Ther. 1999 13 27 36 10.1046/j.1365-2036.1999.00022.x \n34. Yamazaki K Shimizu S Hanai Y Shinohara T Hotta K Kazuyoshi Y Nishiwaki S Fukutomi Y Ibuka T Araki H Shimizu M Mori Y Hitoshi I Kushima R Diagnosis and clinical features of drug-induced collagenous colitis Stomach Intestine. 2016 51 450 462\n\n", "fulltext_license": "CC BY", "issn_linking": "2198-7793", "issue": "5(1)", "journal": "Surgical case reports", "keywords": "Collagenous colitis; Colonic perforation; Spontaneous", "medline_ta": "Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101662125", "other_id": null, "pages": "90", "pmc": null, "pmid": "31152255", "pubdate": "2019-05-31", "publication_types": "D016428:Journal Article", "references": "10491726;10644309;11331929;11521987;11680602;12235088;12591052;12907340;15087693;15647652;16012959;16097993;16716973;17100977;17964451;18513560;18702648;19152884;19169149;19436277;20601144;21303675;23218876;2362097;24711775;24713787;27178398;27716080;934705", "title": "A case of spontaneous colonic perforation in collagenous colitis.", "title_normalized": "a case of spontaneous colonic perforation in collagenous colitis" }	[ { "companynumb": "JP-INVENTIA-000292", "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": 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, 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{ "abstract": "The Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) chemotherapy protocol has been one of the standard treatments for blood cancers, such as Mantle cell lymphoma (MCL), Burkitt's lymphoma (BL) and B-cell and T-cell acute lymphoblastic leukaemia (ALL). Due to high toxicity, it has been progressively replaced with new specific regimens with a better safety profile (GELA protocol for MCL, BURKIMAB for BL and PETHEMA for B-cell and T-cell ALL). The objective of this study is to analyse the toxicity and infectious complications of these therapeutic regimens, as well as the event free survival (EFS).\nThis is a retrospective and descriptive observational study of 81 patients, comparing 42 patients treated with H-CVAD/MTX-AraC (group A) versus 39 patients treated with GELA/BURKIMAB/PETHEMA (group B).\nAll patients in group A developed pancytopenia, but in group B 74.4% neutropenia, 51.3% thrombocytopenia and 69.2% anaemia. The total number of infections in group A was higher than in group B: 154 versus 48, 3.67 versus 1.23 per patient and 0.59 versus 0.25 per cycle. Likewise, febrile neutropenia happened: 106 versus 21 cases, 2.52 versus 0.52 per patient and 0.41 versus 0.11 per cycle. EVS is higher in group B: 33% versus 79% (2-year), and 24% versus 69% (5-year).\nCurrent therapeutic protocols have shown higher EFS due to better safety profile, with less haematological, neurological and haemorrhagic toxicity, as well as lower rates of infectious complications.", "affiliations": "Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Nephrology Department, Hospital Universitario Reina Sofía, Murcia, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Neurology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.", "authors": "Marín-Sánchez\|Alberto\|A\|;Martínez-Fernández\|Gonzalo\|G\|;Gómez-Catalán\|Irene\|I\|;Montoya-Morcillo\|Mari Carmen\|MC\|;Algarra\|Jesús Lorenzo\|JL\|;García\|Ángela Ibañez\|ÁI\|;Hernández-Fernández\|Francisco\|F\|;Romero-Macías\|Juan Ramón\|JR\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3332/ecancer.2021.1206", "fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605\nCancer Intelligence\n\n10.3332/ecancer.2021.1206\ncan-15-1206\nShort Communication\nComparison in safety of chemotherapy protocols for blood cancers: toxicity of H-CVAD versus GELA/BURKIMAB/PETHEMA LAL\nMarín-Sánchez Alberto 1\nMartínez-Fernández Gonzalo 2\nGómez-Catalán Irene 1\nMontoya-Morcillo Mari Carmen 1\nAlgarra Jesús Lorenzo 1\nGarcía Ángela Ibañez 1\nHernández-Fernández Francisco 3\nRomero-Macías Juan Ramón 1\n1 Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain\n2 Nephrology Department, Hospital Universitario Reina Sofía, Murcia, Spain\n3 Neurology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain\nCorrespondence to: Alberto Marín-Sánchez [email protected]\n2021\n22 3 2021\n15 120627 8 2020\n© the authors; licensee ecancermedicalscience.\n2021\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground and objective\n\nThe Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) chemotherapy protocol has been one of the standard treatments for blood cancers, such as Mantle cell lymphoma (MCL), Burkitt’s lymphoma (BL) and B-cell and T-cell acute lymphoblastic leukaemia (ALL). Due to high toxicity, it has been progressively replaced with new specific regimens with a better safety profile (GELA protocol for MCL, BURKIMAB for BL and PETHEMA for B-cell and T-cell ALL). The objective of this study is to analyse the toxicity and infectious complications of these therapeutic regimens, as well as the event free survival (EFS).\n\nPatients and methods\n\nThis is a retrospective and descriptive observational study of 81 patients, comparing 42 patients treated with H-CVAD/MTX-AraC (group A) versus 39 patients treated with GELA/BURKIMAB/PETHEMA (group B).\n\nResults\n\nAll patients in group A developed pancytopenia, but in group B 74.4% neutropenia, 51.3% thrombocytopenia and 69.2% anaemia. The total number of infections in group A was higher than in group B: 154 versus 48, 3.67 versus 1.23 per patient and 0.59 versus 0.25 per cycle. Likewise, febrile neutropenia happened: 106 versus 21 cases, 2.52 versus 0.52 per patient and 0.41 versus 0.11 per cycle. EVS is higher in group B: 33% versus 79% (2-year), and 24% versus 69% (5-year).\n\nConclusions\n\nCurrent therapeutic protocols have shown higher EFS due to better safety profile, with less haematological, neurological and haemorrhagic toxicity, as well as lower rates of infectious complications.\n\nblood cancers\ntoxicity\ninfections\n==== Body\nIntroduction\n\nLymphomas and acute leukaemias are blood cancers with high morbidity and mortality rates. In order to cure them, intensive anticancer therapy is required [1] However, this can lead to significant toxicity and systemic complications. One of the most undesirable effects of the treatment regimens is haematological toxicity, specifically neutropenia, as it predisposes patients to the risk of infection by different germs [2].\n\nChemotherapy treatment targeting different types of haematological malignancies has evolved substantially in recent years [3]. Since 2000, the combined Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) protocol has been the treatment regimen of choice used in many centres for cancers such as Mantle cell lymphoma (MCL) [4], Burkitt’s lymphoma (BL) [5] and acute lymphoblastic leukaemia (ALL), type B (B-cell ALL) and type T (T-cell ALL) [6]. This protocol emerged from a study which obtained promising results carried out in the MD Anderson Cancer Center, Houston [7, 8]. Subsequently its use became widespread internationally due to its encouraging therapeutic success. In the last few years, this general treatment applied to the three disorders has fallen into disuse in favour of a more specific therapy for each type of disease [9–11]. In particular, the protocol of the French group GELA [12] began to be used for MCL, the BURKIMAB regimen (2008, 2013 and 2014 versions) [13] for BL and the recommendations of the Spanish group PETHEMA (2003, 2008 and 2011 versions) for ALL, depending on age and cytogenetic risk [14, 15].\n\nThe synergistic effect of the various drugs used in these regimens exerts an anticancer action on malignant cancer cells, but also in healthy haematopoietic cells, which leads to considerable haematological toxicity in the form of anaemia, thrombocytopenia and neutropenia [16]. Therefore, a decrease in the three haematopoietic cell series (pancytopenia) can occur at an early stage, while patients are progressing to the period of post-chemotherapy aplasia (nadir). This can expose patients to a situation of severe neutropenia for several days or weeks; increasing the risk of contracting infections caused by different microorganisms, and causing a considerable increase in morbidity and mortality rates [17]. These drug combinations also have significant non-haematological toxicity (hepatic, haemorrhagic, neurological, gastrointestinal and mucocutaneous) [18].\n\nThe only study to have analysed the outcomes of the H-CVAD/MTX-AraC regimen compared to a specific protocol for ALL similar to one of the current three (GELA, BURKIMAB, PETHEMA) is a comparative study in 2018 related to H-CVAD/MTX-AraC and the old PETHEMA-93, in which no significant differences were found [19]. However, the most updated versions of PETHEMA in 2008 and 2011 have shown better results in terms of efficacy and safety compared to the traditional PETHEMA-93 version, so hypothetically they could be also better than H-CVAD/MTX-AraC [20]. Nonetheless, comparative studies between H-CVAD/MTX-AraC and the most modern versions of the PETHEMA 2008 and 2011 protocols, together with the other current regimens GELA and BURKIMAB, so far do not exist.\n\nTaking into account these data, the aim of this study was to compare the safety results (haematological toxicity, non-haematological toxicity and infectious complications) for the only general protocol to those for the three recent specific regimens: H-CVAD/MTX-AraC versus GELA/BURKIMAB/PETHEMA, as well as the event free survival (EFS).\n\nMaterial and methods\n\nStudy design\n\nThis was a retrospective and descriptive observational study comparing two groups of patients: those who were treated with H-CVAD/MTX-AraC (group A); and those who were treated with GELA/BURKIMAB/PETHEMA (group B). Data from group A patients were collected retrospectively, using the information compiled in their medical histories, while data from group B were collected prospectively.\n\nPatients\n\nAll patients aged from 18 to 69 years old who were diagnosed with MCL, BL, B-cell ALL or T-cell ALL treated and evaluated at Complejo Hospitalario Universitario de Albacete (CHUA) from 1 January 2002 to 31 December 2018 were included in the study.\n\nOn the one hand, group A patients received a single type of general chemotherapy treatment according to the H-CVAD/MTX-AraC regimen for all disorders, from 1 January 2002 to 31 December 2010. They were followed up throughout that period of time and afterwards. On the other hand, group B patients were studied from 1 January 2011 to 31 December 2018. They received a specific kind of protocol for each disease: French group GELA regimen for patients with MCL; BURKIMAB for those with BL and PETHEMA for those with B-cell ALL or T-cell ALL. Therefore, all patients were monitored for 5 years (median). In addition, the presence of disease progression or death was registered during the follow-up.\n\nStudy variables and objectives\n\nThe following parameters were assessed in each study group:\n\nHaematological toxicity: anaemia, thrombocytopenia and neutropenia.\n\nNon-haematological toxicity: hepatic, haemorrhagic, neurological, gastrointestinal (diarrhoea) and mucocutaneous (mucositis).\n\nInfections and derived complications: number of patients affected by infection, infectious processes per group, episodes of febrile neutropenia, days of admission due to infection, delay of chemotherapy cycles due to infectious episode and death from sepsis/septic shock.\n\nEFS: 2-year and 5-year.\n\nBased on these parameters, the main objective was to compare the EFS between the two groups. The secondary objectives were to compare the rate of infections and their complications, and the incidence of haematological or other toxicity, in both groups.\n\nStatistical analysis\n\nTo analyse the quantitative variables, the arithmetic mean was used as the measure of central tendency and the standard deviation as the measure of dispersion. For qualitative variables, the absolute and relative frequency as a percentage was used for each of the variables, which were reflected in frequency tables and bar charts.\n\nThe quantitative variables were compared in groups using Student’s t test. Contingency tables with Fisher’s exact test were used to compare qualitative variables (appearance or not of a certain event in each group). In both cases, the level of statistical significance considered was 5% (p <0.05).\n\nStatistical calculations were performed with the SPSS 15.0 software package and Microsoft Excel 2010 for Windows.\n\nEthical considerations\n\nThis was an analysis that compared the current therapeutic regimens with an historical cohort of patients retrospectively, so it has not modified current treatment guidelines. The rules of the Declaration of Helsinki were followed and the confidentiality of the data was guaranteed.\n\nThe project and the informed consent forms for this study were submitted to and approved by the CHUA Independent Ethics Committee.\n\nResults\n\nComposition of the analysed sample\n\nThe study included a total of 81 patients diagnosed with haematological malignancies: 42 (51.9%) were treated with H-CVAD/MTX-AraC from 2002 to 2010 (group A) and 39 (48.1%) were treated with the specific treatment regimens for each disorder from 2011 to 2018 (group B). Group A patients received a total of 259 treatment cycles, while group B patients received 194 cycles (Table 1).\n\nIn group A, 13 patients (31.0%) with MCL, 8 (19.0%) with BL, 14 (33.3%) with B-cell ALL and 7 (16.7%) with T-cell ALL were included. In group B, 9 patients (23.1%) with MCL, 10 (25.6%) with BL, 15 (38.5%) with B-cell ALL and 5 (12.8%) with T-cell ALL were included. There were not differences in the distribution of patients between the two groups (p-value = 0.770), so these are balanced out in respect to their composition by disorder (Table 2).\n\nBaseline characteristics at diagnosis\n\nMCL (8 H-CVAD/MTX-AraC cycles versus 7 GELA cycles Þ AutoTPH):\n\nMedian age: 59 versus 56 years.\n\nState of the disease: 100% lymphadenopathy (same distribution: laterocervical 61.5% versus 66.7%), bone marrow (BM) infiltration – stage IV – t(11;14) (84.6% versus 88.9%) (Images 1 and 2), splenomegaly (53.8% versus 44.4%), B symptoms (23.1% versus 22.2%).\n\nBL (8 H-CVAD/MTX-AraC cycles versus 4-6 BURKIMAB cycles):\n\nMedian age: 37 versus 38 years.\n\nState of the disease: lymphadenopathy (37.5% versus 50% with the same distribution), ‘bulky’ mass (37.5% versus 30%), BM infiltration (50% versus 30%) (Images 3 and 4), stage IV (50% versus 50% due to infiltration of other organs), hypertransaminasemia due to hepatic infiltration (50% versus 40%), splenomegaly (25% versus 20%), B symptoms (37.5% versus 30%), human immunodeficiency virus (0% versus 30%).\n\nLAL-B (8 H-CVAD/MTX-AraC cycles versus 4 PETHEMA LAL-B cycles):\n\nMedian age: 36 versus 33 years.\n\nState of the disease: 100% BM infiltration (obvious stage IV), B symptoms (78.6% versus 60%), high risk patients – complex karyotype (35.7% versus 60%).\n\nLAL-T (8 H-CVAD cycles versus 4 PETHEMA LAL-T cycles) :\n\nMedian age: 27 versus 26 years.\n\nState of the disease: 100% BM infiltration (obvious stage IV), high risk patients – hyperleukocytosis and/or complex karyotype (71.5% versus 80%).\n\nHaematological toxicity\n\nIn group A, 100% of the patients had involvement of the three haematopoietic cell lines (anaemia, thrombocytopenia and neutropenia) (Table 3). Neutropenia was mostly severe (76.2% grade IV) and 23.8% grade III. Thrombocytopenia was also severe (47.6% grade IV and 52.4% grade III). In group B, the incidence of neutropenia was 74.4% (41.0% grade IV, 33.3% grade III). Half of patients (51.3%) had thrombocytopenia and 69.2% had anaemia. Differences between both groups regarding haematological toxicity were significant (p < 0.01) (Table 3).\n\nNon-haematological toxicity\n\nHepatic toxicity was higher in group B than group A (46.2% versus 21.4%, respectively, p = 0.033), and mostly grade II (72.2% of hepatic toxicities in 33.3% of all patients in group B) (Table 4). The incidence of haemorrhagic toxicity was significantly higher in group A (23.8% versus 5.1%, p = 0.027), with major bleeding 7.2% versus 0%, and minor bleeding 16.6% versus 5.1%. Neurological toxicity exclusively affected group A patients (14.3% versus 0%, p = 0.026). Conversely, diarrhoea only occurred in group B patients, although with low frequency (10.3% versus 0%, p = 0.049). Mucositis was very uncommon in the two groups (7.1% versus 5.1%, respectively, not significant) (Table 4).\n\nInfections\n\nThe incidence of any infectious adverse event was similar in patients from both groups (81% versus 74.4%, respectively, p = 0.6) (Table 5). However, the total number of infections was higher in group A: 154 total events, 3.67 processes per patient and 0.59 episodes per cycle; compared to 48 events, 1.23 processes per patient and 0.25 episodes per cycle, in group B (p <0.01 for the three events). With regard to febrile neutropenia, in group A there were 106 cases, 2.52 per patient and 0.41 per cycle; while in group B, there were 21 cases, 0.54 per patient and 0.11 per cycle (p < 0.01) (Figure 1).\n\nThese infectious complications caused delay in the next chemotherapy cycle: 23 events, 0.55 per patient and 0.09 per cycle, in group A; compared to 11 events, 0.28 per patient and 0.06 per cycle, in group B (p <0.01); in addition to an average of 23 days of hospital admission per patient in group A versus 9 days in group B (p <0.01). Lastly, there were a total of five deaths caused by septic shock in group A patients versus one in group B (p = 0.2).\n\nBacteraemia was higher in group A: 30 (71.4%) versus 22 (56.4%) patients. In addition, the microbiological isolates in blood cultures were similar: Coagulase negative staphylococcus (38% versus 27%), E. coli (19% versus 20%), E. coli blee (10% versus 6.7%), Klebsiella pneumoniae (10% in group A) and Campylobacter jejuni (10% in group B).\n\nEFS : 2-year and 5-year\n\nEFS 2-year and 5-year was higher in group B (Table 6 and Figure 2). In group A, 2-year EFS is 33% compared to 79% in group B (p <0.001). 5-year EFS is 24% versus 69%, respectively (p <0.001).\n\nDiscussion\n\nThe treatment of haematological malignancies can lead to multiple complications due to its toxicity. Taking into account the aim of minimising its harmful effects, a number of progressively more specific therapeutic regimens have emerged for each type of disorder over the years [21]. The purpose of this study was, therefore, to analyse the differences in the safety profile between the different chemotherapy protocols, which yielded interesting results.\n\nFirstly, haematological toxicity was significantly higher in patients treated with the general regimen (group A), occurring in all cases, and also in a more severe fashion. Due to the important implications in terms of infections, which will be discussed later, now we will focus on neutropenia [22]. All patients in this group developed neutropenia, most reaching grade IV. However, although most of the patients treated with the specific regimens (group B) also developed neutropenia, less than half of them had such a severe form. Approximately half of the patients in group B developed thrombocytopenia, but only a quarter of them grade IV, while in group A almost half of the patients manifested the most severe form. It was also found that a considerably smaller proportion of patients in group B developed anaemia compared to group A. Therefore, the specific therapeutic regimens showed less haematological toxicity and in less severe forms.\n\nIt was also interesting to compare non-haematological toxicity between the two groups. Hepatic toxicity was the most common form, especially in group B, occurring in almost half of the patients, although it was mild in most cases. This could be due to the administration of more hepatotoxic drugs, such as L-asparaginase [23], present in the current PETHEMA protocol but not in the H-CVAD/MTX-AraC one. To control this harmful effect, the corresponding drug dose adjustments are made according to the patient’s liver function, and it is monitored by changes in transaminase levels, without major incidents or clinical repercussions [24]. Another important aspect to highlight is haemorrhagic toxicity, which affected almost a quarter of group A. This alarming complication is probably favoured by the fact that around half of the group A patients had moderate/severe thrombocytopenia, leading to a risk of bleeding which can potentially be life-threatening, especially if it affects certain vital organs. It is also important to stress the complete lack of neurological toxicity of the specific regimens in our patients, compared to some cases in the general protocol group A which, although it was isolated, nevertheless it involved harmful complications and sequelae. In contrast, there was none related to gastrointestinal toxicity (diarrhoea) in group A patients, compared to isolated cases in group B, although almost all of them were self-limiting. The final aspect to mention is the anecdotal incidence of mucositis in both groups, without any clinical significance.\n\nWith this in mind, we would like to focus on the analysis of infections and their consequences which, as stated earlier, is the main objective of this study [25]. It is obvious that infectious complications continue to be the main cause of morbidity and mortality in these patients [26], as the vast majority manifested at least one episode during the course of their treatment, without differences between the two groups. However, this was the source of some of the most interesting questions we were able to explore. On the one hand, in group A there were three times more infectious processes in general, and per patient, compared to group B, with group B having half the number for each chemotherapy cycle versus group A. In addition, there were five times more cases of febrile neutropenia, in total and per patient, in group A (H-CVAD/MTX-AraC), compared to group B (specific regimens), with group B also having four-fold fewer cases per cycle. These data can probably be explained by the lower haematological toxicity found in the current protocols, especially in terms of neutropenia, which means that patients have a lower risk of contracting infections [27]. On the other hand, in group A, twice as many infectious events were the cause of delay in the next chemotherapy cycle compared to group B. This may be explained by a higher frequency and severity of febrile neutropenia that was previously found in group A, which leads to a slower and more difficult recovery from the infectious episode, complicating the ability to administer the next cycle. All the above factors may also have contributed to the higher number of days of hospital admission for infection required by patients in group A; in total almost three times the number, and per patient more than double, compared to group B. This means that these patients are hospitalised, away from their home environment, for longer periods of time, which may affect both their quality of life and their psychosocial well-being [28]. Moreover, these long hospital stays can increase the risk of contracting nosocomial infections and, in turn, could have economic consequences due to the increased occupation of hospital beds [29]. Finally, it was striking that no differences were found between groups in septic shock mortality rates, despite the fact that there were five times more deaths in patients treated with H-CVAD/MTX-AraC. However, one possible explanation for this apparent discrepancy could be the low number of deaths from septic shock in both cases, which makes the sample small in terms of achieving significant differences.\n\nFinally, differences in 2-year and 5-year EFS between the two groups will be discussed. In group A, a third of the patients did not suffer from any event at 2 years into follow-up, in contrast, in group B more than three-quarters of patients did not exhibit any event. These results were corroborated at 5 years, a quarter of the former and almost three-quarters of the latter are free from any event, respectively. Seemingly, the combinations of drugs used in modern regimens have added some benefit to the treatment of these disorders specifically through their synergistic effect which was not present in the single regimen established for all chemotherapeutic cycles in general. Finally, new toxicity prevention strategies could play a very important role in this notable improvement of results [26, 27].\n\nConclusion\n\nIn conclusion, lower haematological, neurological and haemorrhagic toxicity is found with the specific protocols. It is especially important to highlight the lower infection rate and milder profile with the current therapeutic regimens, which clearly benefit patients in many aspects of their daily life. In addition, they have longer EFS, which is an obvious long-term benefit. Therefore, this study has demonstrated a better safety profile of the newer regimens compared to H-CVAD and has now become the treatment of choice for many of our patients, confirming the great therapeutic advances in blood cancers in recent years [30]. Nevertheless, larger studies are necessary to confirm these results.\n\nFunding\n\nThe authors declare that they received no funding to carry out this study.\n\nConflicts of interest\n\nThe authors declare that they have no conflict of interest.\n\nAcknowledgments\n\nThe authors would like to thank Cristina Marín-Sánchez and Dr Jav Ahmad for the English version of the paper. For the Haematology Department of the Albacete University Hospital Complex, patients, relatives and all those who helped me with their support in this study.\n\nFigure 1. Comparison of febrile neutropenia between treatment groups.\n\nFigure 2. Comparison of EFS between treatment groups.\n\nImage 1. Bone marrow infiltration HE in MCL.\n\nImage 2. Bone marrow infiltration CD20(+) in MCL.\n\nImage 3. Bone marrow infiltration HE in BL.\n\nImage 4. Bone marrow infiltration PAX-5(+) in BL.\n\nTable 1. Patients and cycles received according to disorder and treatment regimen.\n\nDisorder\tTotal\tGroup A\nH-CVAD/MTX-AraC\n2002–10\tGroup B\nspecific regimens\n2011–18\t\nLCM\t22\npatients\t137\ncycles\t13\npatients\t75\ncycles\t9\npatients\t62\ncycles\t\nLB\t18\npatients\t89\ncycles\t8\npatients\t42\ncycles\t10\npatients\t47\ncycles\t\nLAL-B\t29\npatients\t143\ncycles\t14\npatients\t86\ncycles\t15\npatients\t57\ncycles\t\nLAL-T\t12\npatients\t84\ncycles\t7\npatients\t56\ncycles\t5\npatients\t28\ncycles\t\nTotal\t81\npatients\t453\ncycles\t42\npatients\t259\ncycles\t39\npatients\t194\ncycles\t\n\nTable 2. Patients groups according to disorder.\n\nDisorder\tGroup A\tGroup B\t\t\nN\t%\tN\t%\tp-value\t\n42\t100%\t39\t100%\t0.770\t\nLCM\t13\t31%\t9\t23.1%\t\t\nLB\t8\t19%\t10\t25.6%\t\t\nLAL-B\t14\t33.3%\t15\t35.8%\t\t\nLAL-T\t7\t16.7%\t2\t12.8%\t\t\n\nTable 3. Differences in haematological toxicity between the two treatment groups.\n\n\tGroup A\tGroup B\t\t\n\tN\t%\tN\t%\tp-value\t\nPatients\t42\t\t39\t\t\t\nNeutropenia\t42\t100.0%\t29\t74.4%\t<0.001\t\n- Grade III\t10\t23.8%\t13\t33.3%\t\n- Grade IV\t32\t76.2%\t16\t41.0%\t\nThrombocytopenia\t42\t100.0%\t20\t51.3%\t<0.001\t\n- Grade III\t22\t52.4%\t10\t25.6%\t\n- Grade IV\t20\t47.6%\t10\t25.6%\t\nAnaemia\t42\t100.0%\t27\t69.2%\t<0.001\t\n\nTable 4. Differences in non-haematological toxicity between the two treatment groups.\n\n\tGroup A\tGroup B\t\t\n\tN\t%\tN\t%\tp-value\t\nPatients\t42\t\t39\t\t\t\nHepatic toxicity\t9\t21.4%\t18\t46.2%\t0.033\t\n- Grade I\t1\t2.4%\t1\t2.6%\t\n- Grade II\t6\t14.3%\t13\t33.3%\t\n- Grade III\t1\t2.4%\t3\t7.7%\t\n- Grade IV\t1\t2.4%\t1\t2.6%\t\nHaemorrhagic toxicity\t10\t23.8%\t2\t5.1%\t0.027\t\n- Major bleeding\t3\t7.2%\t2\t0%\t\n- Minor bleeding\t7\t16.6%\t0\t5.1%\t\nNeurological toxicity\t6\t14.3%\t0\t0.0%\t0.026\t\n- Resting tremor Þ Vincristine suspension\t1\t2.4%\t0\t0.0%\t\n- Mild paresthesias (hands and feet)\t3\t7.2%\t0\t0.0%\t\n- Severe sensory motor neuropathy Þ Death\t2\t4.8%\t0\t0.0%\t\nDiarrhoea\t0\t0.0%\t4\t10.3%\t0.049\t\nMucositis\t3\t7.1%\t2\t5.1%\t0.999\t\n\nTable 5. Mean number of infectious processes and associated characteristics.\n\nInfections\tGroup A\tGroup B\t\t\n\tN\t%\tN\t%\tp-value\t\nPatients with some infectious process\t34\t81.0%\t29\t74.4%\t0.595\t\nTotal of infectious process\t154\t100%\t48\t100%\t<0.01\t\n- Mean per patient\t3.67\t\t1.23\t\t\n- Mean per cycle of treatment\t0.59\t\t0.25\t\t\nFebrile neutropenia\t106\t68.8%\t21\t43.7%\t<0.01\t\n- Mean per patient\t2.52\t\t0.54\t\t\n- Mean per cycle of treatment\t0.41\t\t0.11\t\t\nInfectious events Þ delay CT cycle\t23\t\t11\t\t<0.01\t\n- Mean per patient\t0.55\t\t0.28\t\t\n- Media per cycle of treatment\t0.09\t\t0.06\t\t\nTotal of days of admission due to infection\t968\t100%\t352\t100%\t<0.01\t\n- Mean per patient\t23\t\t9.0\t\t\n- Mean per cycle of treatment\t3.7\t\t1.8\t\t\nDeath from septic shock\t5\t11.9%\t1\t2.6%\t0.2\t\n\nTable 6. EFS between treatment groups.\n\n\tGroup A\tGroup B\t\t\nEst.\t95% CI\tEst.\t95% CI\tp-value\t\nEFS\t\n- At 2 years\t33%\t21%-48%\t79%\t64%-89%\t<0.001\t\n- At 5 years\t24%\t13%-39%\t69%\t54%-81%\t<0.001\n==== Refs\nReferences\n\n1. Sanz M Carreras E Rovira M Manual Práctico de Hematología Clínica 2019 6th Barcelona Ediciones Escofet Zamora SL\n2. Chu E Devita VT Physician´s cancer chemotherapy drug manual 2019\n3. Mathisen MS Kantarjian HM Jabbour EJ Emerging drugs for acute lymphocytic leukemia Expert Opin Emerg Drugs 2014 19 1 37 50 10.1517/14728214.2014.872629 24354521\n4. Romaguera JE Fayad LE Feng L Ten-year follow-up after intense chemoimmunotherapy with rituximab-HyperCVAD alternating with rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma Br J Haematol 2010 150 2 200 208 20528872\n5. 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Kuderer NM Dale DC Crawford J Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients Cancer 2006 106 10 2258 2266 10.1002/cncr.21847 16575919\n\n", "fulltext_license": "CC BY", "issn_linking": "1754-6605", "issue": "15()", "journal": "Ecancermedicalscience", "keywords": "blood cancers; infections; toxicity", "medline_ta": "Ecancermedicalscience", "mesh_terms": null, "nlm_unique_id": "101392236", "other_id": null, "pages": "1206", "pmc": null, "pmid": "33912231", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "24752047;30304722;11376354;20020672;14716755;22718839;18284717;20528872;16531272;21395356;16219571;18457327;17634496;23361927;23975584;24354521;20555092;10653870;16964329;16575919;20660823;18401583", "title": "Comparison in safety of chemotherapy protocols for blood cancers: toxicity of H-CVAD versus GELA/BURKIMAB/PETHEMA LAL.", "title_normalized": "comparison in safety of chemotherapy protocols for blood 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COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. ECANCERMEDICALSCIENCE. 2021?15:10.3332/ECANCER.2021.1206", "literaturereference_normalized": "comparison in safety of chemotherapy protocols for blood cancers toxicity of h cvad versus gela burkimab pethema lal", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210625", "receivedate": "20210625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19463262, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-PFIZER INC-2021771084", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" 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COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. ECANCERMEDICALSCIENCE. 2021?15:10.3332/ECANCER.2021.1206", "literaturereference_normalized": "comparison in safety of chemotherapy protocols for blood cancers toxicity of h cvad versus gela burkimab pethema lal", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210625", "receivedate": "20210625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19463265, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-PFIZER INC-2021488323", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE 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COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. 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"patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARIN?SANCHEZ, A.. COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. ECANCERMEDICALSCIENCE. 2021?15:10.3332/ECANCER.2021.1206", "literaturereference_normalized": "comparison in safety of chemotherapy protocols for blood cancers toxicity of h cvad versus gela burkimab pethema lal", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210625", "receivedate": "20210625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19463263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Histoplasma capsulatum is an environmental fungus commonly found in the Ohio and Mississippi River valleys, Central and South America, and Asia. The most affected areas in Argentina are the Paraná and de La Plata river basins. Patients with histoplasmosis can have a wide range of clinical presentations. Most of them are asymptomatic, while those with compromised cellular immunity are at increased risk for the disseminated form. We present the case of a patient undergoing treatment with methotrexate for seronegative arthritis who developed the disseminated form of the disease, and who represented a diagnostic challenge due to the difficulty in identifying the etiologic agent.", "affiliations": "Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina. E-mail: [email protected].;Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Servicio de Infectología, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Departamento de Patología, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.", "authors": "Vega\|Patricia\|P\|;Aguilar\|Andrea\|A\|;Barahona Rojas\|Janeth\|J\|;Sierra\|Mariela\|M\|;Von Stecher\|Florencia\|F\|;Pisarevsky\|Ana Andrea\|AA\|", "chemical_list": "D008727:Methotrexate", "country": "Argentina", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0025-7680", "issue": "81(4)", "journal": "Medicina", "keywords": "disseminated histoplasmosis; methotrexate", "medline_ta": "Medicina (B Aires)", "mesh_terms": "D001118:Argentina; D001168:Arthritis; D005260:Female; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D008727:Methotrexate", "nlm_unique_id": "0204271", "other_id": null, "pages": "641-644", "pmc": null, "pmid": "34453808", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": null, "title": "Disseminated histoplasmosis in a woman with seronegative arthritis.", "title_normalized": "disseminated histoplasmosis in a woman with seronegative arthritis" }	[ { "companynumb": "AR-TEVA-2021-AR-1986844", "fulfillexpeditecriteria": "1", "occurcountry": "AR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "81099", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20MG WEEKLY ONCE", "drugenddate": null, "drugenddateformat": null, "drugindication": "Seronegative arthritis", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": "5", "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histoplasmosis disseminated", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Systemic candida", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Vega P, Aguilar A, Barahona Rojas J, Sierra M, Von Stecher F, Pisarevsky AA. [Disseminated histoplasmosis in a woman with seronegative arthritis]. [Spanish]. Medicina-B-Aires 2021;81(4):641-644.", "literaturereference_normalized": "disseminated histoplasmosis in a woman with seronegative arthritis", "qualification": "3", "reportercountry": "AR" }, "primarysourcecountry": "AR", "receiptdate": "20220105", "receivedate": "20211215", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20189107, "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": "AR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-319652", "fulfillexpeditecriteria": "1", "occurcountry": "AR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201749", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM, WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Seronegative arthritis", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "7", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE" } ], "patientagegroup": null, "patientonsetage": "36", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histoplasmosis disseminated", "reactionmeddraversionpt": "24.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "Vega P, Aguilar A, Barahona Rojas J, Sierra M, Von Stecher F, Pisarevsky AA. Disseminated histoplasmosis in a woman with seronegative arthritis. Medicina B Aires. 2021;81(4):641-644", "literaturereference_normalized": "disseminated histoplasmosis in a woman with seronegative arthritis", "qualification": "3", "reportercountry": "AR" }, "primarysourcecountry": "AR", "receiptdate": "20211222", "receivedate": "20211210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20168763, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220304" } ]
{ "abstract": "We present a case of endobronchial fusariosis following bilateral sequential lung transplantation for idiopathic pulmonary arterial hypertension in a 13 years old boy who was treated successfully with posaconazole and nebulized amphotericin B. We discuss the role of nebulized amphotericin B in treating invasive pulmonary fungal disease in children. To our knowledge, this is the first pediatric case of endobronchial fusariosis reported in the literature.", "affiliations": "Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Infectious Diseases Department, Alfred Health and Monash University, Melbourne, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Lung Transplant Service, Alfred Hospital, Melbourne, Australia.;Discipline of Child and Adolescent Health, The University of Sydney, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.", "authors": "Al Yazidi\|Laila S\|LS\|;Huynh\|Julie\|J\|;Britton\|Philip N\|PN\|;Morrissey\|C Orla\|CO\|;Lai\|Tony\|T\|;Westall\|Glen P\|GP\|;Selvadurai\|Hiran\|H\|;Kesson\|Alison\|A\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2019.01.002", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(18)30132-510.1016/j.mmcr.2019.01.002Case ReportEndobronchial fusariosis in a child following bilateral lung transplant Al Yazidi Laila S. [email protected]⁎Huynh Julie [email protected] Philip N. [email protected] C. Orla [email protected] Tony [email protected] Glen P. [email protected] Hiran [email protected] Alison adea Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australiab The School of Women's and Children's Health, University of New South Wales, New South Wales, Australiac Sultan Qaboos University, College of Medicine, Muscat, Omand Discipline of Child and Adolescent Health, The University of Sydney, Australiae Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Australiaf Infectious Diseases Department, Alfred Health and Monash University, Melbourne, Australiag Lung Transplant Service, Alfred Hospital, Melbourne, Australiah Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia⁎ Corrosponding author. [email protected] 1 2019 3 2019 14 1 2019 23 77 80 7 11 2018 8 1 2019 11 1 2019 © 2019 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present a case of endobronchial fusariosis following bilateral sequential lung transplantation for idiopathic pulmonary arterial hypertension in a 13 years old boy who was treated successfully with posaconazole and nebulized amphotericin B. We discuss the role of nebulized amphotericin B in treating invasive pulmonary fungal disease in children. To our knowledge, this is the first pediatric case of endobronchial fusariosis reported in the literature.\n\nKeywords\nEndobronchialFusariosisLung transplantationNebulized amphotericinPediatric\n==== Body\n1 Introduction\nInvasive fungal disease (IFD) causes significant morbidity and mortality in the lung transplant population; however, the epidemiologic data in children have been sparse with a variable prevalence reported as ranging from 0% to 20%. Aspergillus and Candida infections are the most common infections in children following lung transplantation. Endobronchial fuseriosis is very rare. To our knowledge, this is the first pediatric case of endobronchial fusariosis reported in the literature.\n\n2 Case\nA 13 year old boy underwent bilateral sequential lung transplantation in July 2016 for idiopathic pulmonary arterial hypertension diagnosed 2 years earlier. At routine surveillance bronchoscopy few weeks post-transplantation, Aspergillus species was grown from a bronchoalveolar lavage (BAL) sample. There was no evidence of radiological or endobronchial changes and treatment with posaconazole modified release tablet was started as a prophylaxis (100 mg daily). Routine post-transplant immunosuppression regimen included tacrolimus (2 mg daily), mycophenolate mofetil (MMF) (250 mg twice daily) and prednisolone (0.3 mg/kg daily). Post-transplantation course was also complicated by steroid-induced diabetes mellitus (DM), stenosis of left main bronchial anastomosis and drug-induced neutropenia likely related to trimethoprim-sulphamethoxazole, and valganciclovir administered for Pneumocystis jirovecii and cytomegalovirus (CMV) prophylaxis, respectively. CMV reactivation eight-month post-transplantation (while on valaciclovir) was treated with two weeks of intravenous ganciclovir (5 mg/kg bd) and then valganciclovir (450 mg daily) as maintenance therapy.\n\nA surveillance bronchoscopy one month later (nine months post-lung transplantation) revealed white plaques at the left main bronchus anastomotic site and this was defined as day 0. (Fig. 1) Broncho-alveolar lavage (BAL) washings revealed fungal elements on cytology and Fusarium species grew on Sabouraud agar. Clinically, the patient was asymptomatic but severely neutropenic (count of 0.0 × 109/L). His trough posaconazole level was 0.91 mg/L. Given the risk of anastomotic breakdown and consequent disseminated fusariosis in a severely neutropenic patient, we increased the posaconazole dose to 300 mg daily whilst awaiting antifungal susceptibility results. We aimed for a trough level of posaconazole of > 2 mg/L. The patient was also commenced on daily granulocyte-colony stimulating factor (G-CSF) and trimethoprim-sulphamethoxazole was changed to atovaquone/proguanil to reverse the neutropenia. Histopathology revealed changes suggestive of early rejection (A1B1), so we were unable to reduce the immunosuppression any further. The isolate was later identified as Fusarium mundagurra using DNA sequencing (Plant Pathology Unit, Royal Botanic Gardens Sydney). Drug susceptibility testing was performed using Sensititre™ YeastOne™ (CLSI-compatible) at the Mycology Reference Laboratory at the Royal North Shore Hospital, New South Wales, Australia and showed minimum inhibitory concentrations of 1 mg/L for amphotericin B, posaconazole and voriconazole, ≥ 8 mg/L for the echinocandin class.Fig. 1 Photo of the endo-bronchial white plaque seen at the lower left lobe anastomotic site during a surveillance bronchoscopy.\n\nFig. 1\n\nFive weeks later, the patient remained asymptomatic, had stable lung function, was mildly neutropenic (0.8 × 109/L) and his posaconazole trough level was 2.3 mg/L. His chest computed tomography (CT) demonstrated progressive focal stenosis of the distal left main-stem bronchial anastomotic site. There were no features suggestive of lung parenchymal fungal disease and blood cultures remained sterile. Follow-up bronchoscopy demonstrated persistent white plaques at the anastomotic site; but now there was also evidence of bleeding from the friable endobronchial surface and displacement of the staple/suture suggestive of some anastomotic dehiscence. A trans-bronchial biopsy yielded inadequate tissue to assess for fungal invasion. Fusarium mundagurra grew again from BAL sample and the antifungal susceptibility testing showed increased MICs; 8 mg/L to amphotericin B and 2 mg/L to both posaconazole and voriconazole. Given the progression of endobronchial disease, posaconazole dosing was increased to 500 mg daily to achieve a target area under the concentration-time curve over MIC (AUC/MIC) ratio of > 100 (trough level > 3.8 mg/L) and nebulized liposomal amphotericin B (Ambisome) 25 mg thrice weekly was added. The patient initially developed cough and bronchospasm with nebulized liposomal amphotericin B; however, this was successfully managed with salbutamol pre-treatment. Whilst Fusarium mundagurra was grown again from a BAL sample taken two months post-commencement of dual antifungal therapy; subsequent BAL samples were culture negative at the 5 and 8 month mark. Eight months from commencing nebulized amphotericin B and increased posaconazole dose the surveillance bronchoscopy showed no evidence of white plaques and the anastomotic site looked healthy. In addition, his neutrophil count had recovered to > 1.0 × 109/L three months post commencement of G-CSF and so the dose was reduced to thrice weekly. Seventh month post commencement of G-CSF the patient was able to maintain a neutrophil count above 2 × 109/L, and so the GCSF ceased. He is being monitored closely for potential recrudescence and is continuing on the same antifungal regimen indefinitely. His progress is summarised in Fig. 2.Fig. 2 Summary of the patient BAL cultures and the antifungal agents used for treatment during the course of his disease. LTx: lung transplantation; D: day, L-AMP B: liposomal amphotericin B; Plus. Sign (+): Growth in BAL culture; Minus sign (-): no growth. D0: 1st day when the fusarium grew from the BAL.\n\nFig. 2\n\n3 Discussion\nInvasive fungal disease (IFD) causes significant morbidity and mortality in the lung transplant population; however, the epidemiologic data in children have been sparse with a variable prevalence reported as ranging from 0% to 20% [1]. Aspergillus and Candida species are the most common causes of IFD in this setting; however, endobronchial fusariosis following lung transplantation has rarely been reported [1], [2]. There are only 10 cases of endobronchial fusarosis reported in the adult lung transplant population with a 70% mortality rate [2], [3]. Here, we present the first pediatric case of endobronchial fusariosis that was successfully eradicated. Disseminated fusariosis usually occurs in immunocompromised patients with severe and persistent neutropenia; however, one third (3/10) of the reported adult cases of endobronchial fusariosis post lung-transplantation developed disseminated fusariosis in the setting of normal neutrophil counts [2]. Overall, outcome of fusariosis in immunocompromised patients appears proportional to the ongoing level of immunosuppression [4]. Factors that have been associated with increased mortality include disseminated infection, persistent neutropenia and corticosteroid use [2], [4].\n\nFusarium mundagarra is one of six novel species of Fusarium isolated from natural ecosystems in Australia in the last few years. Carnarvon Gorge is the geographic origin of the first recognized isolate in central Queensland, Australia. It is considered as a part of the Fusarium redolens species complex [5]. There are no clinical antifungal breakpoints or epidemiological cut-off values to guide therapy for this species [6].\n\nManagement of fusariosis in immunocompromised patients can be challenging given the intrinsic resistance of Fusarium species to most antifungal agents [4]. In vitro susceptibility testing has shown intrinsic resistance to fluconazole, itraconazole and the echinocandin class, while susceptibility to amphotericin B, voriconazole and posaconazole is unpredictable [4]. Despite the early diagnosis, invasive fusariosis is associated with high morbidity and up to 70% mortality [4]. There are no comparative studies to compare clinical efficacy with the in vitro susceptibility of different antifungal agents for treatment of Fusarium species. The current recommendations in lung transplant recipients are voriconazole or liposomal amphotericin B as first-line therapy and posaconazole for refractory disease [2], [4]. Antifungal combination for fusariosis has not been evaluated either in animal models or in humans [4]. From first principles, antifungal therapy should be combined with surgical resection where possible and reduction of immunosuppression when possible [4]. Antifungal choice should take into account the known characteristics of the fungal isolate, in vitro susceptibility results and host-specific factors [4]. Our patient was on posaconazole for Aspergillus colonization and he was tolerating it very well. We optimized the dose of posaconazole according to the AUC/MIC ratio to maximize time dependent killing. In vitro and In vivo modelling studies have indicated that that the AUC/MIC is the pharmacokinetic/dynamic target for posaconazole treatment response; however studies looking at this relationship is limited to Aspergillus and Mucorales infections where the target is defined as > 100 [7], [8]. Nebulized liposomal amphotericin B (Ambisome) was added when the patient didn’t show any signs of improvement. His tacrolimus dose was reduced when possible, and G-CSF was given to reverse the severe neutropenia.\n\nThere is convincing evidence for using nebulized amphotericin B for IFD prophylaxis in adult lung transplant recipients but very little evidence for its use for IFD treatment [1], [9], [10]. A 10 year observational study showed significant reduction of Aspergillus species colonization and infection among lung-transplant recipients receiving prophylactic nebulized liposomal amphotericin B [9]. Several comparative studies showed no significant differences between deoxycholate and lipid formulation of amphotericin in reducing the incidence of IA, when used as single agents [10], [11]. Although it has been a widely studied agent for antifungal prophylaxis, the optimal dosages, formulations, and duration of therapy remains undetermined [10]. Studies using daily administration of amphotericin B products for short durations (up to 2 weeks) followed weekly or fortnightly for 1–3 months have generally proved to be successful as prophylaxis [10]. Studies showed that inhaled deoxycholate (conventional) amphotericin B achieves high concentrations in the lower airway of transplanted lungs, but concentration at the anastomotic sites and in the native lung are lower [10]. The concentration of inhaled amphotericin B (in BAL aliquots) and amphotericin B lipid complex (measured in epithelial lining fluid) remained above the generally reported MIC of Aspergillus for at least 7 days which enables once-weekly administration [10], [12].\n\nThe limitation of this route of administration is that it does not protect against extra-pulmonary infections, especially early post-operative pleural space infection with Candida species. In addition, emerging species with reduced amphotericin susceptibility in lung transplant recipients on lifetime nebulized amphotericin B prophylaxis has been reported [9]. Systemic absorption of nebulized amphotericin B is minimal and quite safe compared with systemic antifungal therapy; however, it can cause cough, dyspnea, bronchospasm, wheezing and nausea in a small proportion which may affect compliance [10], [12]. A recent retrospective study comparing adverse events of the inhaled deoxylate with lipid formulations of amphotericin B observed no difference in the rates of adverse events concluding that both the nebulized deoxycholate and lipid (Abelcet) amphotericin B can be safely used [13].\n\nAlthough there has been increased use of nebulized amphotericin B (both deoxycholate and lipid formulations) in children for IFD prophylaxis in the lung-transplantation setting, there are still limited data on its efficacy and safety in children. An international multicenter survey of antifungal prophylaxis in pediatric lung transplantation reported that most centers use either voriconazole or nebulized amphotericin B as a mono-therapy for IFD prophylaxis [14]; however, the updated international guidelines [1] could not give any recommendations for effective, safe anti-fungal prophylaxis in children and no specific recommendations were made regarding nAmB given the absence of published data.\n\nIn regards to using nebulized amphotericin B for treatment of IFD in lung transplant recipients, the updated guidelines from the International Society for Heart and Lung Transplantation for management of fungal infections recommend azole therapy, with therapeutic drug monitoring to ensure maximal efficacy, as a primary monotherapy for Aspergillus endobronchial fungal infections but did not give any specific recommendations for the addition of nebulized amphotericin B to the standard azole regimens for treatment of pulmonary fungal infections [1]. Evidence for an additive benefit of nebulized amphotericin B in the treatment of invasive aspergillosis is limited however; nebulized amphotericin B could be used in combination with systemic anti-fungal drugs, depending on the severity of IFD, or possibly in situations in which large cavitary lesions might render the penetration of systemic agents difficult [1]. There is a single case report of a complex airway infection involving an endobronchial prosthesis that was treated with a combination of systemic voriconazole and nebulized amphotericin [1]. There are not enough published data to give any specific recommendations for using nebulized amphotericin B in the treatment of IFD in children following lung transplantation [1].\n\nAlthough our patient showed clinical improvement after adding nebulized liposomal amphotericin, we are not certain that adjunctive nebulized amphotericin contributed to bronchoscopic and microbiological cure above the optimal posaconazole therapy and reduced immunosuppression. It is also possible that fusarium mundagarra is a less virulent species compared to the more well-known fusarium solani. There is, however, an argument in our case that given the high rates of dissemination following endobronchial fusariosis in lung transplant recipients, nebulized amphotericin in addition to a systemic anti-fungal agent was at least able to contain the infection until some level of immune reconstitution could be achieved. This case suggests that adjunctive nebulized amphotericin should be considered in similar cases where there is slow response to or progress on systemic antifungal therapy.\n\nIn conclusion, Fusarium species are an important but uncommon pathogen post-lung transplantation with a potentially high mortality rate. Treatment is difficult because of high levels of intrinsic resistance of Fusarium species to many antifungal agents and reduction of immunosuppression is essential for achieving a good outcome. Multicenter, observational studies and randomized trials are needed to ascertain the optimal prophylactic and therapeutic strategies for fungal infections in pediatric lung transplant recipients [10].\n\nAcknowledgements\nThe Mycology Reference Laboratory at the Royal North Shore Hospital who helped with identification of the clinical isolates and with the anti-fungal susceptibility.\n\nConflict of interest\nNone to declare.\n\nFunding source\nNone.\n==== Refs\nReferences\n1 Husain S. Sole A. Alexander B.D. Aslam S. Avery R. Benden C. The 2015 International Society for heart and lung transplantation guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: executive summary J. Heart Lung Transplant. 35 3 2016 261 282 26970469 \n2 Carneiro H.A. Coleman J.J. Restrepo A. Mylonakis E. Fusarium infection in lung transplant patients: report of 6 cases and review of the literature Medicine 90 1 2011 69 80 21200188 \n3 Terasaki J. Shah S. Schnadig V. Valentine V. Airway complication contributing to disseminated fuseriosis after lung transplantation Transpl. Infect. Dis. 16 2014 621 624 24890670 \n4 Al-Hatmi A.M.S. Bonifaz A. Ranque S. Sybren de Hoog G. Verweij P.E. Meis J.F. Current antifungal treatment of fusariosis Int. J. Antimicrob. Agents 51 3 2018 326 332 28705676 \n5 Laurence M. Walsh J. Shuttleworth L. Robinson D. Johansen R. Petrovic T. Six novel species of Fusarium from natural ecosystems in Australia Fungal Divers. 77 2016 349 366 \n6 Espinel-Ingroff A. Colombo A. Cordoba S. Dufresne P. Fuller J. Ghannoum M. Evaluation of MIC distributions and epidemiological Cutoff value (ECV) Definitions for Fusarium species identified by Molecular methods for the CLSI Broth Microdilution method Antimicrob. Agents Chemother. 60 2 2015 1079 1084 26643334 \n7 Dekkers B.G.J.B.M. van der Elst K.C.M. Sturkenboom M.G.G. Veringa A. Span L.F.R. Therapeutic drug monitoring of Posaconazole: an update Curr. Fungal Infect. Rep. 10 2 2016 51 61 27358662 \n8 Lewis R.E.A.N. Kontoyiannis D.P. Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis Antimicrob. Agents Chemother. 58 11 2014 6767 6772 25182639 \n9 Peghin M. Monforte V. Martin‐Gomez M.T. Ruiz‐Camps I. Berastegui C. Saez B. 10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation Transplant. Int. 29 2016 51 62 \n10 Patel T.S. Eschenauer G.A. Stuckey L.J. Carver P.L. Antifungal prophylaxis in lung transplant recipients Transplantation 100 9 2016 1815 1826 26950711 \n11 Drew R. Dodds A. Benjamin D. Duane D. Palmer S. Perfect J. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients Transplantation 77 2 2004 232 237 14742987 \n12 Husain S. Capitano B. Corcoran T. Studer S.M. Crespo M. Johnson B. Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients Transplantation 90 11 2010 1215 1219 20881664 \n13 Lowry C. Marty F. Vargas S. Lee J. Fiumara K. Deykin A. Safety of aerosolized liposomal versus deoxycholate amphotericin B formulations for prevention of invasive fungal infections following lung transplantation: a retrospective study Transpl. Infect. Dis. 9 2 2007 121 125 17461997 \n14 Mead L. Danziger-Isakov L. Michaels M. Goldfarb S. Glanville A. Benden C. Antifungal prophylaxis in pediatric lung transplantation: an international multicenter survey Pediatr. Transplant. 18 4 2014 393 397 24802346\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "23()", "journal": "Medical mycology case reports", "keywords": "Endobronchial; Fusariosis; Lung transplantation; Nebulized amphotericin; Pediatric", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "77-80", "pmc": null, "pmid": "30723665", "pubdate": "2019-03", "publication_types": "D002363:Case Reports", "references": "14742987;17461997;20881664;21200188;24802346;24890670;25182639;26339864;26643334;26950711;26970469;27358662;28705676", "title": "Endobronchial fusariosis in a child following bilateral lung transplant.", "title_normalized": "endobronchial fusariosis in a child following bilateral lung transplant" }	[ { "companynumb": "AU-009507513-1901AUS011665", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": 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"patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspergillus test positive", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP, SELVADURAI H, KESSON A. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. DOI: 10.1016/J.MMCR.2019.01.002. 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null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR/VALGANCICLOVIR HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "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": "SULFAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bronchostenosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP ET AL. 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"VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "AL YAZIDI L, HUYNH J, BRITTON P, MORRISSEY C, LAI T, WESTALL G. 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"patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bronchial anastomosis complication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Steroid diabetes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. 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"reactionmeddrapt": "Steroid diabetes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspergillus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP, ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. MED-MYCOL-CASE-REPORTS 2019?23:77-80.", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190225", "receivedate": "20190225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16002433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-200114", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", 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"drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM-SULPHAMETHOXAZOLE" }, { "actiondrug": "5", "activesubstance": { 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DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP, ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT.. MED MYCOL CASE REPORTS. 2019?JAN 23 (9):77-80", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190228", "receivedate": "20190228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16016123, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]
{ "abstract": "Crizotinib is an oral small-molecule inhibitor of anaplastic lymphoma kinase (ALK) tyrosine-kinase that has been approved for treating patients with advanced echinoderm microtubule associated protein like 4-ALK rearranged non-small-cell lung cancer (NSCLC). Toxic epidermal necrolysis (TEN) is a rare adverse event associated with crizotinib. The present study reported a case of a 75-year-old Chinese male patient with advanced NSCLC with ALK fusion, who developed TEN after 56 days of crizotinib treatment and demised due to this dermatological adverse event. The occurrence of severe cutaneous necrolysis that predominantly involves the skin and mucous membranes during crizotinib treatment should alert clinicians to be aware of TEN and take prompt actions.", "affiliations": "Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Dermatology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Dermatology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.", "authors": "Yang\|Shaoyu\|S\|;Wu\|Liming\|L\|;Li\|Xin\|X\|;Huang\|Jie\|J\|;Zhong\|Jianbo\|J\|;Chen\|Xueqin\|X\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2018.1553", "fulltext": null, "fulltext_license": null, "issn_linking": "2049-9450", "issue": "8(3)", "journal": "Molecular and clinical oncology", "keywords": "crizotinib; epidermal; necrolysis; non-small-cell lung cancer; toxic", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "457-459", "pmc": null, "pmid": "29456853", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": "28000240;24108082;28190531;28202399;15057820;23169500;17509004;23724913;25994067;27212422;23891512;27040849", "title": "Crizotinib-associated toxic epidermal necrolysis in an ALK-positive advanced NSCLC patient.", "title_normalized": "crizotinib associated toxic epidermal necrolysis in an alk positive advanced nsclc patient" }	[ { "companynumb": "CN-PFIZER INC-2017471842", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CRIZOTINIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202570", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20160511", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CRIZOTINIB" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Oedema peripheral", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "YANG, S.. CRIZOTINIB-ASSOCIATED TOXIC EPIDERMAL NECROLYSIS IN AN ALK-POSITIVE ADVANCED NSCLC PATIENT. MOLECULAR AND CLINICAL ONCOLOGY. 2018?8(3):457-459", "literaturereference_normalized": "crizotinib associated toxic epidermal necrolysis in an alk positive advanced nsclc patient", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180208", "receivedate": "20171107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14165046, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180508" } ]
{ "abstract": "We present a case of common challenges in assessment and treatment of substance use disorders in patients with advanced heart failure requiring left ventricular assist device (LVAD). Top experts in the field of consultation-liaison psychiatry, cardiology, and cardiac surgery provide guidance for this commonly encountered clinical case based on their experience and review of the available literature. Key teaching topics include the role of LVAD in heart failure management, the impact of substance use disorder on heart failure and LVAD patient outcomes, and recommendations for assessment and management of substance use disorder in a patient with LVAD. Specifically, we highlight the challenges of assessing for substance use disorder in LVAD candidates and the limited literature available to guide treatment in this challenging patient population.", "affiliations": "Division of Collaborative Care and Wellness, Department of Psychiatry, University of Rochester Medical Center, Rochester, NY. Electronic address: [email protected].;Division of Cardiology, Department of Medicine, University of Rochester Medical Center, Rochester, NY.;Division of Cardiac Surgery, Department of Surgery, University of Rochester Medical Center, Rochester, NY.;Department of Psychiatry, Yale University, New Haven, CT.;Division of Collaborative Care and Wellness, Department of Psychiatry, University of Rochester Medical Center, Rochester, NY.", "authors": "Choi\|Joy\|J\|;Alexis\|Jeffrey\|J\|;Gosev\|Igor\|I\|;Zimbrean\|Paula\|P\|;Nickels\|Mark\|M\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaclp.2021.07.015", "fulltext": null, "fulltext_license": null, "issn_linking": "2667-2960", "issue": "62(6)", "journal": "Journal of the Academy of Consultation-Liaison Psychiatry", "keywords": "heart failure; left ventricular assist device; substance use disorder; transplant", "medline_ta": "J Acad Consult Liaison Psychiatry", "mesh_terms": null, "nlm_unique_id": "101775059", "other_id": null, "pages": "568-576", "pmc": null, "pmid": "34391977", "pubdate": "2021", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device.", "title_normalized": "management of substance use disorders in a patient with left ventricular assist device" }	[ { "companynumb": "US-NOVARTISPH-NVSC2022US132586", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78679", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "78679", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "78679", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Euphoric mood", "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": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. JOURNAL OF ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY. 2021;62(6):568-76", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220611", "receivedate": "20220611", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20948397, "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" }, { "companynumb": "US-INDIVIOR EUROPE LIMITED-INDV-133424-2022", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "22410", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Drug use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NICOTINE" }, "drugadditional": null, "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (SMOKING)", "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": "NICOTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ALCOHOL" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALCOHOL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Body mass index increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Joy Choi, Jeffrey Alexis, Igor Gosev, Paula Zimbrean and Mark Nickels.. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device.. Journal of the Academy of Consultation-liaison Psychiatry.. 2021;62:568-576", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220324", "receivedate": "20220324", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20632248, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-MACLEODS PHARMACEUTICALS US LTD-MAC2022034975", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "203359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "203359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "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": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. Journal of the Academy of Consultation-Liaison Psychiatry. 2021;62(6):568-76", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220329", "receivedate": "20220329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20646959, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "US-drreddys-SPO/USA/22/0147884", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077380", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077380", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077380", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205299", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. J Acad Consult Liaison Psychiatry. 2021;62(6):568-76. doi:10.1016/j.jaclp.2021.07.015", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220328", "receivedate": "20220322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20621049, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-MYLANLABS-2022M1044776", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "090323", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "090323", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Euphoric mood", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. 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Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. J-Acad-Consult-Liaison-Psychiatry 2021;62(6):568-576.", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220615", "receivedate": "20220615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20961852, "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" }, { "companynumb": "US-MLMSERVICE-20220310-3425696-1", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "202152", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "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": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. 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"drugadditional": "4", "drugadministrationroute": "065", "drugauthorizationnumb": "091388", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "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": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "091388", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "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": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "091388", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "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": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "091388", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Euphoric mood", "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": "4", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "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": "METHAMPHETAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M.. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device.. Journal of the Academy of Consultation-Liaison Psychiatry.. 2021;62(6)::568-576", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220623", "receivedate": "20220328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20641325, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "US-MLMSERVICE-20220310-3425696-1", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201109", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Euphoric mood", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. 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INDICA TOP" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": "4", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROMORPHONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": "4", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPRENORPHINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of substance use disorders in a patient with left ventricular assist device. Journal of the Academy of Consultation-Liaison Psychiatry. 2021;62(6):568-576", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220617", "receivedate": "20220408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20688711, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]
{ "abstract": "A 71-year-old man presented with ulcerating yellow-red plaques of the back, chest, face, and extremities (Figure 1). He had a 10-year history of these lesions. The initial plaque appeared on the back followed by rapid progression of multiple similar lesions involving the face, chest, abdomen, and extremities. The plaques on his face were predominately in the periorbital and eyelid regions. Skin biopsy revealed an ulcerated epidermis. Dense sheets of foamy histiocytes were present in the dermis and contained foci of necrobiosis. Numerous Touton giant cells were present and cholesterol clefts were prominent. Special stains for organisms were negative. On further laboratory evaluation, serum protein electrophoresis revealed a monoclonal spike of 0.5 g/dL IgG lambda. Results from bone marrow biopsy were negative. Other significant laboratory findings included an elevated sedimentation rate and low serum complement. Clinical findings, histopathology, and laboratory evaluations were consistent with the diagnosis of necrobiotic xanthogranuloma (NXG).", "affiliations": "University of Nebraska Medical Center, 2212 South 64th Plaza #401, Omaha, NE 68106, USA. [email protected]", "authors": "Sutton\|Leigh\|L\|;Sutton\|Stephanie\|S\|;Sutton\|Margaret\|M\|", "chemical_list": "D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007146:Immunoglobulin lambda-Chains; D017338:Cladribine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1540-9740", "issue": "11(2)", "journal": "Skinmed", "keywords": null, "medline_ta": "Skinmed", "mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001706:Biopsy; D001797:Blood Protein Electrophoresis; D017338:Cladribine; D018450:Disease Progression; D006801:Humans; D007074:Immunoglobulin G; D007146:Immunoglobulin lambda-Chains; D008297:Male; D058252:Necrobiotic Xanthogranuloma; D016896:Treatment Outcome", "nlm_unique_id": "101168327", "other_id": null, "pages": "121-3", "pmc": null, "pmid": "23745232", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of necrobiotic xanthogranuloma with 2-chlorodeoxyadenosine.", "title_normalized": "treatment of necrobiotic xanthogranuloma with 2 chlorodeoxyadenosine" }	[ { "companynumb": "US-JNJFOC-20130712043", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DAYS 1, 2, 3, 4 AND 5 OF A 28 DAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020229", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DAYS 1, 2, 3, 4 AND 5 OF A 28 DAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "XANTHOGRANULOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SUTTON L, SUTTON S, SUTTON M. TREATMENT OF NECROBIOTIC XANTHOGRANULOMA WITH 2-CHLORODEOXYADENOSINE. SKINMED 2013;11 (2):121-123.", "literaturereference_normalized": "treatment of necrobiotic xanthogranuloma with 2 chlorodeoxyadenosine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150717", "receivedate": "20150717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11280214, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "Androgen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer. Studies addressing the efficacy of different depot formulations of long acting luteinizing hormone releasing hormone agonists in the Brazilian population are lacking. We aimed to compare the efficacy of three schedules of leuprolide acetate in lowering PSA in a real world population.\n\n\n\nWe reviewed the medical records of patients with prostate cancer seen at our institution between January 2007 and July 2018. We analyzed patients treated with long-acting leuprolide acetate and grouped these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the serum prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels at baseline and at 6 and 12 months within each treatment stratum. We considered two-sided P values < 0.05 as statistically significant. We analyzed toxicity descriptively.\n\n\n\nWe analyzed a total of 932 patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Nearly half of the patients had locally advanced disease. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (P < 0.001 in all cases). Sexual impotence and hot flashes were the most frequently reported toxicities.\n\n\n\nTo our knowledge, this is the largest assessment of real-world data on alternative schedules of leuprolide in a Brazilian population. Our study suggests that PSA levels can be effectively be reduced in most patients treated with monthly, quarterly, or semiannual injections of long-acting leuprolide acetate.", "affiliations": "Hospital do Câncer de Muriaé, MG, Brasil.;Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil.", "authors": "de Freitas\|Carla S M\|CSM\|;Soares\|Aleida N\|AN\|", "chemical_list": "D000085:Acetates; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C493311:luprolide acetate gel depot; D017430:Prostate-Specific Antigen; D016729:Leuprolide", "country": "Brazil", "delete": false, "doi": "10.1590/S1677-5538.IBJU.2019.0212", "fulltext": "\n==== Front\nInt Braz J Urol\nInt Braz J Urol\nibju\nInternational Brazilian Journal of Urology : official journal of the Brazilian Society of Urology\n1677-5538 1677-6119 Sociedade Brasileira de Urologia \n\n32167701\nS1677-5538.IBJU.2019.0212\n10.1590/S1677-5538.IBJU.2019.0212\nOriginal Article\nEfficacy of Leuprorelide acetate (Eligard®) in daily practice in Brazil: a retrospective study with depot formulations in patients with prostate cancer\nhttp://orcid.org/0000-0002-9397-9777de Freitas Carla S. M. 1 Soares Aleida N. 2 \n1 \nHospital do Câncer de Muriaé\nMG\nBrasil\nHospital do Câncer de Muriaé, MG, Brasil\n\n\n2 \nInstituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte\nBelo HorizonteMG\nBrasil\nInstituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil\n\nCorrespondence address: Carla Simone Moreira de Freitas, MD, MSc Hospital do Câncer de Muriaé Av. Cristiano Ferreira Varella, 555, Universitário Muriaé, Minas Gerais, 36.880-000, Brasil. Fax: +55 32 3729-7000, E-mail: [email protected] OF INTEREST\n\nNone declared.\n\n\n20 2 2020 \nMay-Jun 2020 \n46 3 383 389\n29 3 2019 01 11 2019 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.ABSTRACT\nIntroduction:\nAndrogen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer. Studies addressing the efficacy of different depot formulations of long acting luteinizing hormone releasing hormone agonists in the Brazilian population are lacking. We aimed to compare the efficacy of three schedules of leuprolide acetate in lowering PSA in a real world population.\n\nMaterials and Methods:\nWe reviewed the medical records of patients with prostate cancer seen at our institution between January 2007 and July 2018. We analyzed patients treated with long-acting leuprolide acetate and grouped these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the serum prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels at baseline and at 6 and 12 months within each treatment stratum. We considered two-sided P values <0.05 as statistically significant. We analyzed toxicity descriptively.\n\nResults:\nWe analyzed a total of 932 patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Nearly half of the patients had locally advanced disease. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (P <0.001 in all cases). Sexual impotence and hot flashes were the most frequently reported toxicities.\n\nConclusion:\nTo our knowledge, this is the largest assessment of real-world data on alternative schedules of leuprolide in a Brazilian population. Our study suggests that PSA levels can be effectively be reduced in most patients treated with monthly, quarterly, or semiannual injections of long-acting leuprolide acetate.\n\nKeywords:\nProstatic Neoplasmsagonists [Subheading]Prostate-Specific Antigen\n==== Body\nINTRODUCTION\nAccording to GLOBOCAN, it is estimated that 1.276.106 men were diagnosed with prostate cancer worldwide in 2018, with an expect 6.3% increase in incidence for the year of 2020 (1-3). By the year 2030, the burden from prostate cancer in Central and South America is expected to nearly double as a result of population growth and aging, moreover, increased early detection and public awareness are likely to lead to further increase in incidence in this world region (4). In Brazil, prostate cancer is the most frequent non--cutaneous tumor and the second leading cause of death from cancer in men (5).\n\nGiven the androgen dependence that characterizes prostate cancer, androgen deprivation therapy plays a key role in distinct phases of the disease. Among patients with advanced disease, androgen deprivation is the mainstay of therapy for both hormone-sensitive and castration-resistant prostate cancer (6), with long-acting luteinizing-hormone-releasing hormone (LHRH) agonists being currently the main form of achieving androgen deprivation (7). Most patients treated with a LHRH agonist achieve castrate testosterone levels similar to those found after bilateral orchiectomy (8). As a result of testosterone suppression, disease control can be achieved in the majority of patients as indicated, for example, by decreased levels of prostate specific antigen (PSA). Clinical trials of different LHRH agonists have demonstrated the efficacy of these agents in different settings. In particular, the efficacy and safety of Eligard® (a depot formulation of leuprolide acetate for subcutaneous injection every 1, 3 or 6 months) have been assessed and confirmed in clinical trials (9, 10). However, such studies are often limited by strict selection criteria, and a need remains for “real-world” data collected in observational studies (9-14).\n\nOBJECTIVES\nIn the current study, we sought to investigate the efficacy of Eligard® used monthly, quarterly and semiannually, in a heterogeneous population of patients from routine clinical practice at the Muriaé Cancer Hospital, state of Minas Gerais, Brazil.\n\nMATERIALS AND METHODS\nStudy design and patient eligibility\nThe study protocol was reviewed and approved by the Institutional Ethics Committee, and written informed consent was waived due to the observational nature of the investigation. In this retrospective study, we reviewed the medical records of 932 patients with prostate cancer seen at our institution between January 2007 and July 2018. Given the observational nature of the study, diagnostic and treatment decisions, including the choice of androgen deprivation therapy, formulation and schedule, as well as use of concomitant medication, were at the discretion of the attending physicians.\n\nEligible patients were men with prostate cancer, aged ≥18 years old, and treated with Eligard® (henceforward referred to as androgen de-privation) at some point during the study period. We included in this study all the patients who had baseline serum PSA results. We grouped patients into three separate strata according to the administration of androgen deprivation therapy every 1, 3 or 6 months.\n\nData collection, outcomes of interest, and statistical analysis\nWe collected data on demographic patient characteristics, features of prostate cancer, dates and clinical events related to treatment, serum PSA results, and toxicity. The primary outcome measure was the serum PSA levels at 6 months and 12 months after treatment initiation. After using the Kolmogorov-Smirnov test to demonstrate that PSA levels did not have normal distribution, we used Friedman test to compare, within each treatment stratum (monthly, quarterly, or semiannually), the distribution of PSA levels at baseline and at 6 and 12 months. Moreover, we used Wilcoxon's rank sum test to make pairwise comparisons between adjacent time points within strata. We made no comparisons between strata. We considered two-sided P values <0.05 as statistically significant and performed the analyses with SPSS, version 22.0.\n\nRESULTS\nPatient characteristics\nA total of 932 patients fulfilled the selection criteria and were analyzed, with their key characteristics being displayed in Table-1. The median age was 72 years (interquartile range, 65 to 78 years). Comorbidities were reported in 43.8% of the study population, most of which cardiovascular (85.0%). The median time since diagnosis of prostate cancer was 8.5 months, with 598 (64.2%) patients being diagnosed ≤12 months and 158 (17.0%) >4 years. The Gleason score was distributed relatively evenly between, low (Gleason ≤6), intermediate (Gleason 7) and high (Gleason ≥8) grade, and nearly three quarters of patients had non-metastatic disease. Bone metastases were reported in 161 (74%) of the patients in stage IV, while 5 patients (2.3%) had metastases at other distant sites and 12 (5.5%) had lymph node metastases. Radiotherapy and radical prostatectomy were the most frequent treatment modalities, in the beginning of the use of Eligard®.\n\nTable 1 Patient characteristics (n=932).\nCharacteristic\tValue\t\nAge, years\t\n\tMedian (interquartile range)\t72 (65 to 78)\t\nTime since diagnosis of prostate cancer in months\t\n\tMedian (interquartile range)\t8.5 (5 to 26)\t\nEthnicity\t\n\tWhite\t307 (32.9%)\t\n\tBlack\t619 (66.5%)\t\n\tNot available\t6 (0.6%)\t\nGleason score\t\n\tLow\t320 (34.3%)\t\n\tIntermediate\t318 (34.1%)\t\n\tHigh\t274 (29.4%)\t\n\tNot available\t20 (2.1%)\t\nProstate cancer stage at diagnosis\t\n\tI\t35 (3.8%)\t\n\tII\t369 (39.6%)\t\n\tIII\t269 (28.9%)\t\n\tIV\t218 (23.4%)\t\n\tNot available\t41 (4.4%)\t\nTreatment\t\n\tRadical prostatectomy\t163 (17.5%)\t\n\tTransurethral resection of the\t72 (7.7%)\t\n\tprostate\t\n\tRadiotherapy\t588 (63.1%)\t\n\t\tRT locally advanced\t235 (39.9%)\t\n\t\tRT rescue\t104 (17.7%)\t\n\t\tRT adjuvant\t122 (20.7%)\t\n\t\tRT palliative\t127 (21.7%)\t\nChemotherapy\t52 (5.6%)\t\nNot available\t57 (6.1%)\t\nIndication for androgen deprivation\nAndrogen deprivation therapy was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Overall across strata, 711 (76.3%) of the patients were treated concomitantly with other modalities, and 129 (13.8%) patients had received previous hormone therapy for the underlying disease. Nearly half of the patients were considered to have locally advanced prostate cancer, and this was the main indication for androgen deprivation. There was biochemical recurrence after prostatectomy in 104 of the 235 (44.3%) patients who underwent prostatectomy and in 122 (20.7%) of the 588 treated with radiotherapy. RT locally advanced (235, 39.9%), rescue radiotherapy 104 (17.7%), adjuvant radiation therapy 122 (20.7%), palliative radiotherapy 127 (21.7%).\n\nAmong the 932 patients, 803 (86.2%) were treated with the LHRH agonist alone, while 129 (13.8%) of the patients received it in combination with an antiandrogen (bicalutamide [8.4%], flutamide [4.8%], or cyproterone acetate [0.6%]).\n\nPSA levels\n\nTable-2 presents summary results for the serum PSA levels in each stratum at the three time points of interest. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (arrows in Figure-1). As shown in Figure-1, all pairwise comparison between adjacent time points within strata were statistically significant, with the exception of the comparison between 6 and 12 months for the monthly administration.\n\nTable 2 Serum prostate specific antigen (PSA) levels versus leuprolide schedule.\nStratum\tMedian PSA (interquartile range), ng/mL\tP value\t\n\tBaseline\t6 months\t12 months\t\t\nMonthly\tn=115\tn=108\tn=104\t<0.001\t\n\t25.6 (13.7 to 86.0)\t0.18 (0.05 to 1.6)\t0.08 (0.1 to 0.7)\t\t\nQuarterly\tn=637\tn=588\tn=512\t<0.001\t\n\t28.8 (13.0 to 87.0)\t0.54 (0.05 to 3.59)\t0.09 (0.01 to 1.0)\t\t\nSemiannualy\tn=180\tn=151\tn=103\t<0.001\t\n\t23.2 (9.4 to 70.5)\t0.39 (0.04 to 2.08)\t0.04 (0.01 to 0.37)\t\t\nFigure 1 Median levels of serum prostate specific antigen (PSA) in each stratum over time.\nSafety and tolerability\nA total of 72 (7.7%) patients reportedly had treatment-associated toxicity registered in the medical records. Among these cases, sexual impotence and hot flashes were the most frequent and were reported in 58 (6.2%) and 23 (2.5%) patients, respectively. More severe toxicity that was possibly associated with treatment was reported in only 9 (0.9%) of patients: there were two cases of hemorrhagic stroke, and one case each of heart failure secondary to coronary insufficiency, peripheral vascular insufficiency, angina, pulmonary embolism, and acute myocardial infarction. Despite this potential association with treatment, all these cases had comorbidity whose causal link with the toxicity could not be ruled out by chart review. In many cases, treatment for the comorbidity was reportedly used irregularly by the affected patients. No patient reportedly discontinued treatment prematurely due to toxicity.\n\nDISCUSSION\nTo our knowledge, the current study is the largest reported assessment of real-world data on patients with prostate cancer in Brazil. The study confirms the effectiveness and safety of this depot formulation of leuprolide acetate in clinical practice. Effectiveness was assessed on the basis of serum PSA declines during the first year of treatment, and safety was ascertained on the basis of toxicity reported in the medical records. Although the reliability and state of completion of medical records are well-known limitations of retrospective studies, the toxicity profile disclosed by our study overlaps with the profile of adverse events reported in clinical trials. On the other hand, the PSA data are objective and were available for the vast majority of time points. As a result, we believe our results add to the current literature by confirming the effectiveness of this LHRH agonist and the validity of a flexible approach, in terms of the choice of administration schedule, which may suit individual patients and clinicians according to their priorities.\n\nThree other observational studies have been conducted with the objective of evaluating the effectiveness, tolerability and/or impact on the quality of life of this depot formulation of leuprolide acetate in daily clinical practice among patients with prostate cancer. In the ELIRE study, conducted in France, the formulation used was for administration every 3 or every 6 months (11). Among 1.853 registered patients, the mean age was 75 years, and the mean time to diagnosis was 7 months. Interestingly, the criteria for choosing between the quarterly or semiannual administration were different, with patients using the latter schedule being more likely to be older and less autonomous than those using the former. The authors concluded that semiannual administration provides more flexibility in the management and follow-up of patients with locally advanced or metastatic prostate cancer. The results suggest that the semiannual use of the LHRH agonist is as effective as the other regimens, resulting in a difference in treatment cost between groups, impacting positively on Brazilian public health. The MANTA study, conducted in Belgium, assessed both a monthly and a quarterly schedule in 243 patients and confirmed that both depot formulations of leuprolide acetate are well tolerated and reliably lowered serum PSA and testosterone levels in routine clinical practice (13). Finally, a study in Germany assessed the administration of leuprolide acetate every 6 months in 1.273 patients (12). At 12 months, there was a median reduction of 96% (to 0.5ng/mL) in serum PSA levels. Interestingly, further PSA and serum testosterone decreases were observed in a subpopulation of patients treated initially with other LHRH analogues and who switched to 6-monthly leuprolide acetate. Similar to the present study, toxicity was reported in the German study in 9% of patients, and the majority were not considered serious. Of note, this LHRH agonist was found to be the most frequently used form of medical castration in another study from Germany, in this case based on a claims database (15).\n\nClinical trials usually demonstrate the efficacy and tolerability of therapeutic agents in relatively homogeneous populations of patients meeting strict selection criteria. Real-world studies are important because they have broader criteria and may include far more patients in populations that are likely to be observed in routine clinical practice. Compared with patients enrolled in clinical trials (9, 10), patients in observational studies usually display larger variability in tumor staging, Gleason scores, indications for androgen deprivation, and comorbidity. Many of the patients analyzed in observational studies, including ours, would have been excluded from clinical trials (11-13). Reassuringly, however, the results of clinical trials and observational studies with this LHRH analogue overlap to show that PSA levels can be effectively reduced in most patients treated with monthly, quarterly, and semiannual injections.\n\nOur study did not aim at formally to compare the effectiveness or tolerability of the three schedules of administration of this LHRH analogue. Nevertheless, the results show that median serum PSA levels were reduced by at least 99.7% across the three strata, with no notable differences among them. Moreover, these results were seen in spite of the fact that most patients received the LHRH analogue alone, unlike in some studies, in which variable proportions of patients were treated with combinations containing an anti-androgen, a bisphosphonate, or chemotherapy. In such a heterogeneous population as ours, and considering the ease of use and local tolerability of this depot formulation, we believe that the choice among the different schedules has to be individualized based on preference and health-care system convenience. Arguably, semiannual injections can provide benefits in terms of patient visits and use of resources, but this hypothesis remains to be tested formally in our specific health-care scenario. In Japan, for example, the 6-month formulation was found to reduce medical costs, loss of productivity, and intangible costs in comparison with the 3-month formulation (16). Likewise, in a cost-minimization analysis conducted in Europe, the 6-month formulation was found to offer the greatest cost savings, and the authors considered that it should be the treatment of choice in eligible European patients (17). In the Brazilian health-care system, which aims at providing universal coverage for all citizens (18), it is conceivable that a reduced number of patient visits, especially for the elderly and for those living far from the treatment center, may bring efficiencies and allow for the opening of vacancies for other patients in need.\n\nCONCLUSIONS\nOur study confirms that serum PSA levels can be effectively reduced in most of the patients with prostate cancer treated with monthly, quarterly, or semiannual injections of this LHRH agonist. This therapeutic goal is achieved at the expense of a relatively favorable toxicity profile, and it is hoped that schedules of administration every 6 months will bring the added benefit of convenience and cost savings in clinical practice in Brazil and elsewhere.\n==== Refs\nREFERENCES\n1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 136 E359 E386 25220842 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-86.\n2 Taitt HE Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location Am J Mens Health 2018 12 1807 1823 30203706 2. Taitt HE. 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Year 8, nr. 2 Jul-Dec 2017 Monitoramento das ações de controle do câncer de prostata Available at. <http://www.saude.df.gov.br/wp-conteudo/uploads/2018/03/Informativo-C%C3%A2ncer-de-Pr%C3%B3stata-2017.pdf > Accessed 21 December 2018 5. Brasil. Ministério da Saúde. Instituto Nacional de Câncer. Informativo Detecção Precoce. Year 8, nr. 2, July/December 2017. Monitoramento das ações de controle do câncer de prostata. Available at. <http://www.saude.df.gov.br/wp-conteudo/uploads/2018/03/Informativo-C%C3%A2ncer-de-Pr%C3%B3stata-2017.pdf> (Accessed 21 December 2018).\n6 Merseburger AS Alcaraz A von Klot CA Androgen deprivation therapy as backbone therapy in the management of prostate cancer Onco Targets Ther 2016 9 7263 7274 27942220 6. Merseburger AS, Alcaraz A, von Klot CA. Androgen deprivation therapy as backbone therapy in the management of prostate cancer. Onco Targets Ther. 2016;9:7263-74.\n7 Mottet N Van den Bergh RCN Briers E European Association of Urology Prostate Cancer Guidelines Available at. <https://uroweb.org/guideline/prostate-cancer/ > Accessed 22 December 2018 7. Mottet N, Van den Bergh RCN, Briers E, et al. European Association of Urology. Prostate Cancer Guidelines. Available at. <https://uroweb.org/guideline/prostate-cancer/> (Accessed 22 December 2018).\n8 Grant JB Ahmed SR Shalet SM Costello CB Howell A Blacklock NJ Testosterone and gonadotrophin profiles in patients on daily or monthly LHRH analogue ICI 118630 (Zoladex) compared with orchiectomy Br J Urol 1986 58 539 544 2946356 8. Grant JB, Ahmed SR, Shalet SM, Costello CB, Howell A, Blacklock NJ. Testosterone and gonadotrophin profiles in patients on daily or monthly LHRH analogue ICI 118630 (Zoladex) compared with orchiectomy. Br J Urol. 1986;58:539-44.\n9 Chu FM Jayson M Dineen MK Perez R Harkaway R Tyler RC A clinical study of 22.5mg. La-2550: A new subcutaneous depot delivery system for leuprolide acetate for the treatment of prostate cancer J Urol 2002 168 1199 1203 12187267 9. Chu FM, Jayson M, Dineen MK, Perez R, Harkaway R, Tyler RC. A clinical study of 22.5mg. La-2550: A new subcutaneous depot delivery system for leuprolide acetate for the treatment of prostate cancer. J Urol. 2002;168:1199-203.\n10 Crawford ED Sartor O Chu F Perez R Karlin G Garrett JS A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer J Urol 2006 175 533 536 16406989 10. Crawford ED, Sartor O, Chu F, Perez R, Karlin G, Garrett JS. A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer. J Urol. 2006;175:533-6.\n11 Ouzaid I Rouprêt M The role of a 6-month depot form of hormone therapy in the treatment of advanced hormone-dependent prostate cancer: Results from the ‘ELIRE’ observational study Prog Urol 2011 21 866 874 22035913 11. Ouzaid I, Rouprêt M. [The role of a 6-month depot form of hormone therapy in the treatment of advanced hormone-dependent prostate cancer: Results from the ‘ELIRE’ observational study]. Prog Urol. 2011;21:866-74.\n12 Tunn UW A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1273 patients BMC Urol 2011 11 15 15 21801354 12. Tunn UW. A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1273 patients. BMC Urol. 2011;11:15.\n13 Braeckman J Michielsen D Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard(®)/ Depo-Eligard(®)) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study Arch Med Sci 2014 10 477 483 25097577 13. Braeckman J, Michielsen D. Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard(®)/ Depo-Eligard(®)) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study. Arch Med Sci. 2014;10:477-83.\n14 Ohlmann CH Gross-Langenhoff M Efficacy and Tolerability of Leuprorelin Acetate (Eligard®) in Daily Practice in Germany: Pooled Data from 2 Prospective, Non-Interventional Studies with 3- or 6-Month Depot Formulations in Patients with Advanced Prostate Cancer Urol Int 2018 100 66 71 29197875 14. Ohlmann CH, Gross-Langenhoff M. Efficacy and Tolerability of Leuprorelin Acetate (Eligard®) in Daily Practice in Germany: Pooled Data from 2 Prospective, Non-Interventional Studies with 3- or 6-Month Depot Formulations in Patients with Advanced Prostate Cancer. Urol Int. 2018;100:66-71.\n15 Hupe MC Hammerer P Ketz M Kossack N Colling C Merseburger AS Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes Front Oncol 2018 8 543 543 30538951 15. Hupe MC, Hammerer P Ketz M, Kossack N, Colling C, Merseburger AS. Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes. Front Oncol. 2018;8:543.\n16 Goto R Uda A Hiroi S Iwasaki K Takashima K Oya M Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations J Med Econ 2017 20 1155 1162 28758810 16. Goto R, Uda A, Hiroi S, Iwasaki K, Takashima K, Oya M. Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations. J Med Econ. 2017;20:1155-62.\n17 Wex J Sidhu M Odeyemi I Abou-Setta AM Retsa P Tombal B Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation Clinicoecon Outcomes Res 2013 5 257 269 23836996 17. Wex J, Sidhu M, Odeyemi I, Abou-Setta AM, Retsa P, Tombal B. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation. Clinicoecon Outcomes Res. 2013;5:257-69.\n18 Lopes LC Barberato-Filho S Costa AC Osorio-de-Castro CG. Rational use of anticancer drugs and patient lawsuits in the state of São Paulo, Southeastern Brazil Rev Saude Publica 2010 44 620 628 20676553 18. Lopes LC, Barberato-Filho S, Costa AC, Osorio-de-Castro CG. Rational use of anticancer drugs and patient lawsuits in the state of São Paulo, Southeastern Brazil. Rev Saude Publica. 2010;44:620-8.\n\n", "fulltext_license": "CC BY", "issn_linking": "1677-5538", "issue": "46(3)", "journal": "International braz j urol : official journal of the Brazilian Society of Urology", "keywords": "Prostate-Specific Antigen; Prostatic Neoplasms; agonists [Subheading]", "medline_ta": "Int Braz J Urol", "mesh_terms": "D000085:Acetates; D000368:Aged; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001938:Brazil; D006801:Humans; D016729:Leuprolide; D008297:Male; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D012189:Retrospective Studies", "nlm_unique_id": "101158091", "other_id": null, "pages": "383-389", "pmc": null, "pmid": "32167701", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "21801354;23836996;20676553;30203706;27942220;22424666;2946356;25097577;12187267;30538951;25220842;22035913;16406989;28758810;29197875;27678315", "title": "Efficacy of Leuprorelide acetate (Eligard®) in daily practice in Brazil: a retrospective study with depot formulations in patients with prostate cancer.", "title_normalized": "efficacy of leuprorelide acetate eligard in daily practice in brazil a retrospective study with depot formulations in patients with prostate cancer" }	[ { "companynumb": "BR-TOLMAR, INC.-20BR020872", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUBCUTANEOUS INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELIGARD" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "DE FREITAS C.S.M., SOARES A.N.. 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EFFICACY OF LEUPRORELIDE ACETATE (ELIGARD?) IN DAILY PRACTICE IN BRAZIL: A RETROSPECTIVE STUDY WITH DEPOT FORMULATIONS IN PATIENTS WITH PROSTATE CANCER. INTERNATIONAL BRAZ J UROL : OFFICIAL JOURNAL OF THE BRAZILIAN SOCIETY OF UROLOGY. 2020?46:3:383-389", "literaturereference_normalized": "efficacy of leuprorelide acetate eligard in daily practice in brazil a retrospective study with depot formulations in patients with prostate cancer", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20200408", "receivedate": "20200408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17644055, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]
{ "abstract": "BACKGROUND\nPatients with relapsed diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Gemcitabine, methylprednisolone, cisplatin +/- rituximab (GEM-P+/-R) is a salvage regimen with limited overlap in toxicity with first-line therapy and short duration of inpatient delivery.\n\n\nMETHODS\nWe assessed the efficacy and safety of GEM-P+/-R in a retrospective single-centre analysis including patients meeting criteria of ≥ 18 yr of age, histologically proven DLBCL, treated between 2001 and 2011 in second-line with gemcitabine 1000 mg/m(2) day 1, 8 and 15, methylprednisolone 1000 mg day 1-5, cisplatin 100 mg/m(2) day 15 (replaced with carboplatin AUC5 if contraindication/toxicity) +/- rituximab 375 mg/m(2) day 1 and 15, every 28 d.\n\n\nRESULTS\nForty-five patients aged 25-74 received a median of three cycles of GEM-P+/-R; 64% received rituximab. In 44 evaluable patients receiving GEM-P+/-R, overall response rate (ORR) was 48%; in 28 evaluable patients treated with rituximab + GEM-P (R-GEM-P), ORR was 61%. With median follow-up of 50.5 months (95% CI: 28.3-72.7), 3-yr overall survival (OS) from start of GEM-P+/-R was 31.4% (95% CI: 16.5-46.3); in patients treated with R-GEM-P, 3-yr OS was 49.1% (95% CI: 28.7-69.5). Predominant grade ≥ 3 toxicities were haematological; thrombocytopenia 69%, neutropenia 60% and febrile neutropenia 7%.\n\n\nCONCLUSIONS\nR-GEM-P is a deliverable regimen with useful activity in second-line treatment of DLBCL. Our data suggest that rituximab should be given concurrently.", "affiliations": "The Royal Marsden NHS Foundation Trust, London, Surrey, UK.", "authors": "Barton\|Sarah\|S\|;Hawkes\|Eliza A\|EA\|;Cunningham\|David\|D\|;Peckitt\|Clare\|C\|;Chua\|Sue\|S\|;Wotherspoon\|Andrew\|A\|;Attygalle\|Ayoma\|A\|;Horwich\|Alan\|A\|;Potter\|Mike\|M\|;Ethell\|Mark\|M\|;Dearden\|Claire\|C\|;Gleeson\|Mary\|M\|;Chau\|Ian\|I\|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D003841:Deoxycytidine; D000069283:Rituximab; C056507:gemcitabine; D016190:Carboplatin; D002945:Cisplatin; D008775:Methylprednisolone", "country": "England", "delete": false, "doi": "10.1111/ejh.12416", "fulltext": null, "fulltext_license": null, "issn_linking": "0902-4441", "issue": "94(3)", "journal": "European journal of haematology", "keywords": "cisplatin; diffuse; gemcitabine; large B-cell; lymphoma; relapse; rituximab", "medline_ta": "Eur J Haematol", "mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009503:Neutropenia; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D016879:Salvage Therapy; D016019:Survival Analysis; D013921:Thrombocytopenia; D016896:Treatment Outcome", "nlm_unique_id": "8703985", "other_id": null, "pages": "219-26", "pmc": null, "pmid": "25039915", "pubdate": "2015-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Rituximab, Gemcitabine, Cisplatin and Methylprednisolone (R-GEM-P) is an effective regimen in relapsed diffuse large B-cell lymphoma.", "title_normalized": "rituximab gemcitabine cisplatin and methylprednisolone r gem p is an effective regimen in relapsed diffuse large b cell lymphoma" }	[ { "companynumb": "GB-MYLANLABS-2015M1044260", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MG/M2 ON DAY 15 EVERY 28 DAYS", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, 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RITUXIMAB, GEMCITABINE, CISPLATIN AND METHYLPREDNISOLONE (R-GEM-P) IS AN EFFECTIVE REGIMEN IN RELAPSED DIFFUSE LARGE B-CELL LYMPHOMA. 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RITUXIMAB, GEMCITABINE, CISPLATIN AND METHYLPREDNISOLONE (R-GEM-P) IS AN EFFECTIVE REGIMEN IN RELAPSED DIFFUSE LARGE B-CELL LYMPHOMA. EUR-J-HAEMATOL 2015? 94(3):219-226.", "literaturereference_normalized": "rituximab gemcitabine cisplatin and methylprednisolone r gem p is an effective regimen in relapsed diffuse large b cell lymphoma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11828395, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]
{ "abstract": "BACKGROUND\nHemophagocytic lymphohistiocytosis is a disease process characterized by unregulated hyperactivation of the immune system associated with multiorgan involvement and high mortality rates. Early recognition is crucial and a recently validated diagnostic schema, the H-Score, may facilitate diagnosis particularly in secondary hemophagocytic lymphohistiocytosis cases. We present a patient with secondary hemophagocytic lymphohistiocytosis in association with metastatic renal cell carcinoma in whom high-dose steroid therapy induced a remarkable response.\n\n\nMETHODS\nA 35-year-old Vietnamese man with quiescent systemic lupus erythematosus was diagnosed 5 months prior to admission with left-sided renal cell carcinoma metastatic to the pancreas and spine. Ten days prior to admission, a febrile illness (temperatures to 39 °C) associated with flu-like symptoms unresponsive to levofloxacin developed. He took only two doses of pazopanib prior to admission. High fevers unresponsive to antimicrobial therapy, cytopenias, disseminated intravascular coagulation, and progressive multiorgan failure led to intubation and intensive care unit stay. Extensive infectious disease workup showed only negative results, but elevation of interleukin-2 receptor, exceedingly high ferritin levels and other features earned an H-Score of 302, consistent with >99% diagnostic probability for secondary hemophagocytic lymphohistiocytosis. High-dose steroid therapy produced a rapid clinical and biochemical response.\n\n\nCONCLUSIONS\nHemophagocytic lymphohistiocytosis is a life-threatening disorder which is likely to be under-recognized. Increased awareness of this disease entity and its diagnosis is crucial toward early recognition and treatment. To our knowledge, our patient is only the second reported with secondary hemophagocytic lymphohistiocytosis occurring in the setting of renal cell carcinoma.", "affiliations": "Department of Internal Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA, 92868, USA.;Department of Internal Medicine, Arrowhead Regional Medical Center, 400 N Pepper Avenue, Colton, CA, 92324, USA.;Department of Pathology and Laboratory Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA, 92868, USA. [email protected].", "authors": "El-Masry\|Monica\|M\|;Eisenbud\|Lauren\|L\|;Tran\|Minh-Ha\|MH\|http://orcid.org/0000-0002-9974-5277", "chemical_list": "D005938:Glucocorticoids; D015375:Receptors, Interleukin-2; D003907:Dexamethasone; D005293:Ferritins", "country": "England", "delete": false, "doi": "10.1186/s13256-016-1196-9", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 119610.1186/s13256-016-1196-9Case ReportSecondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report El-Masry Monica [email protected] 1Eisenbud Lauren [email protected] 2http://orcid.org/0000-0002-9974-5277Tran Minh-Ha [email protected] 31 0000 0000 9632 6718grid.19006.3eDepartment of Internal Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA 92868 USA 2 0000 0004 0383 4879grid.413942.9Department of Internal Medicine, Arrowhead Regional Medical Center, 400 N Pepper Avenue, Colton, CA 92324 USA 3 0000 0000 9632 6718grid.19006.3eDepartment of Pathology and Laboratory Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA 92868 USA 2 3 2017 2 3 2017 2017 11 5614 7 2016 29 12 2016 © The Author(s). 2017\nOpen 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\nHemophagocytic lymphohistiocytosis is a disease process characterized by unregulated hyperactivation of the immune system associated with multiorgan involvement and high mortality rates. Early recognition is crucial and a recently validated diagnostic schema, the H-Score, may facilitate diagnosis particularly in secondary hemophagocytic lymphohistiocytosis cases. We present a patient with secondary hemophagocytic lymphohistiocytosis in association with metastatic renal cell carcinoma in whom high-dose steroid therapy induced a remarkable response.\n\nCase presentation\nA 35-year-old Vietnamese man with quiescent systemic lupus erythematosus was diagnosed 5 months prior to admission with left-sided renal cell carcinoma metastatic to the pancreas and spine. Ten days prior to admission, a febrile illness (temperatures to 39 °C) associated with flu-like symptoms unresponsive to levofloxacin developed. He took only two doses of pazopanib prior to admission. High fevers unresponsive to antimicrobial therapy, cytopenias, disseminated intravascular coagulation, and progressive multiorgan failure led to intubation and intensive care unit stay. Extensive infectious disease workup showed only negative results, but elevation of interleukin-2 receptor, exceedingly high ferritin levels and other features earned an H-Score of 302, consistent with >99% diagnostic probability for secondary hemophagocytic lymphohistiocytosis. High-dose steroid therapy produced a rapid clinical and biochemical response.\n\nConclusions\nHemophagocytic lymphohistiocytosis is a life-threatening disorder which is likely to be under-recognized. Increased awareness of this disease entity and its diagnosis is crucial toward early recognition and treatment. To our knowledge, our patient is only the second reported with secondary hemophagocytic lymphohistiocytosis occurring in the setting of renal cell carcinoma.\n\nKeywords\nHemophagocytic lymphohistiocytosisDisseminated intravascular coagulationFeverFever of unknown originAltered mental statusissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHemophagocytic lymphohistiocytosis (HLH) is a disease process characterized by unregulated hyperactivation of the immune system resulting in variable combinations of fever, multiorgan involvement (particularly transaminase elevation), and peripheral blood cytopenias [1]. Presentations are generally divided into primary and secondary forms, the former typically occurring in infants or young children and often incorporating either autosomal recessive mutations in any of several recognized familial hemophagocytic lymphohistocytosis (FHL) genes, or as a feature of other, non-FHL immunodeficiency syndromes (see Table 1) [2, 3]. Primary HLH, which has an incidence of 1.2 per million children per year [4], is diagnosed based upon criteria set forth by the Histiocyte Society [5] (see Table 1).Table 1 Hemophagocytic lymphohistiocytosis (HLH) 2004 diagnostic criteria (Adapted with permission from John Wiley and Sons Ltd. from Brisse et al. [3] and Henter et al. [5]). Diagnostic criteria 1–5 represent the original 1991 diagnostic criteria; the HLH 2004 revision adds criteria 6–8. The diagnosis of primary HLH can be made either on a molecular or clinical basis\n\nHLH Molecular diagnosis\tAt least 5 of the following 8 diagnostic criteria\t\nFHL genes\t\nPRF1, UNC13D, STX11, STXBP2\n\t1. Fever\t2. Splenomegaly\t\n3. Cytopenias (≥2/3 lineages)a\n\t4. High triglyceride/low fibrinogen levelsb\n\t\nNon-FHL genes\t\nRAB27A, LYST, AP3B1, SH2D1A, XIAP\n\t5. Hemophagocytosis\t6. Low/absent NK-cell activity\t\n7. Ferritin ≥500 ng/mL\t8. Soluble IL-2 receptor ≥2400 U/mL\t\n\nFHL Familial hemophagocytic lymphohistocytosis, NK Natural Killer, and IL Interleukin. non-FHL gene mutations occur in Gricselli syndrome, Chediak-Higashi syndrome, Hermansky-Pudlak syndrome type 2, and X-linked lymphoproliferative disease\n\n\naHb <9 g/dL, platelets <100 K/mcL, neutrophils <1.0 K/mcL. bTriglycerides ≥265 mg/dL, fibrinogen ≤150 mg/dL\n\n\n\n\nSecondary HLH occurs typically in adolescents or adults and in the setting of infectious, rheumatologic (i.e., juvenile idiopathic inflammatory arthritis), or malignant conditions (i.e., lymphoma) [6]. The HLH-2004 criteria may have reduced sensitivity and specificity in secondary HLH - where sufficient criteria may not be met at disease onset but develop later in the course and associated malignancy and inflammatory conditions may predispose to higher baseline ferritin values [3]. It has, therefore, been suggested that this disorder is likely under-recognized in modern practice [7]. Treatment is largely based upon the original HLH-94 protocol [8] incorporating an initial 8-week induction regimen using corticosteroids in most patients and chemotherapy (etoposide) in selected patients (i.e., when Epstein-Barr virus (EBV)-driven disease is present). Despite treatment, the mortality of secondary HLH ranges from 32.4% to as high as 87.5% [9, 10].\n\nWe recently encountered a 35-year-old male patient with a history of systemic lupus erythematosus (SLE) and metastatic renal cell carcinoma, who presented with a flu-like illness. Fevers, multiorgan failure, altered mental status, cytopenias, and disseminated intravascular coagulation (DIC) findings progressed rapidly in the face of empiric antimicrobial and antiviral therapy. Diagnosis of secondary HLH and immediate institution of corticosteroid therapy was associated with a dramatic clinical response.\n\nCase presentation\nA 35-year-old Vietnamese man with underlying SLE who was taking hydroxychloroquine, azathioprine, and prednisone was diagnosed 5 months prior to admission with metastatic renal cell carcinoma with a 6.6 × 6.0 × 7.2-cm left renal mass with disruption of fat planes, suggestive of involvement of the tail of the pancreas, as well as a 4.1 × 3.2 × 2.6-cm mass at the T8 spinal vertebra. On hospital day (HD) -43, he underwent hemivertebrectomy with fusion of adjacent vertebral levels; pathologic examination of the T8-mass demonstrated renal cell carcinoma. He was first evaluated at our institution for a second opinion for his malignancy on HD −21. Plans were put forth to obtain outside records and undertake multidisciplinary treatment planning during tumor board.\n\nHowever, on approximately HD −10, he developed a febrile illness (temperatures to 38.9 °C measured at home) with flu-like symptoms comprised of shortness of breath, frontal headaches, sore throat with neck pain, nausea, vomiting, diarrhea, and generalized weakness. He took pazopanib 800 mg daily, which had been prescribed prior to onset of illness, on HDs −3 and −2. Despite an outpatient course of levofloxacin, progression of symptoms led ultimately to presentation on HD 0.\n\nPresenting vital signs in the emergency department included fever of 39.2 °C, tachycardia of 101 beats per minute (bpm), and relative hypotension at 106/66 mmHg. Initial laboratory studies demonstrated multiorgan involvement with pancytopenia, acute kidney injury, hyponatremia, abnormal liver function tests, and elevations in lactic acid, procalcitonin, and lipase levels. Clinically, he was judged to be euvolemic. Further studies noted that serum osmolality was low at 267 mOsm/kg, spot urine sodium 24 mmol/L, and urine osmolality 776 mOsm/kg. A plain film of the chest was normal, save for spinal hardware, and cranial computed tomography showed no acute intracranial process. His SLE was clinically judged to be quiescent, corroborated by an anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody screen and an extensive infectious disease workup both of which showed only negative results (see Table 2).Table 2 Results of infectious disease workup\n\nSource\tTest result\t\nBlood\tCultures: no growth (bacterial/fungal)\tNegative for HIV 1/2 and HIV p24 Ag\tNonreactive for Lyme antibody and Treponema pallidum immunoassay\tNegative for Coccidioides IgM and IgG. Negative for Histoplasma Ag\tViral hepatitis panel (A, B, C) significant only for hepatitis B core Ab\tEBV serology consistent with seropositive statusa\n\tCMV serology consistent with seronegative status\t\nUrine\tUrinalysis significant only for trace proteinuria\tNegative for Legionella Ag\tNegative for Streptococcus pneumoniae Ag\t\t\nNasopharyngeal swab\tNegative for Group A Streptococcus (direct antigen test)\tNegative for influenza A, B, RSV (rt-PCR)\tNegative for MSSA and MRSA\t\t\t\t\t\nCerebrospinal fluid (CSF)\tCSF showed 14 nucleated cells/mm3 (normal 0–5/mm3) consisting of 84% polymorphonuclear leukocytes, 9% lymphocytes, and 7% monocytes; 44 mg/dL glucose (normal 41–70 mg/dL); 70 mg/dL protein (normal 15–45 mg/dL)\t\nCryptococcus neoformans Ag and C. gattii Ag\tNonreactive for West Nile virus IgG/IgM\tNegative for HSV 1, 2 and enterovirus (PCR)\tNegative for acid fast bacilli, no growth occurred during fungal and mycobacterial culture\t\nStool\tNegative for Clostridium difficile toxin B (PCR)\t\t\t\t\t\t\t\nOther\tPPD skin test 0-mm induration\tQuantiferon Gold tuberculosis test indeterminate\t\t\t\t\t\t\n\nAb antibody, Ag antigen, CMV cytomegalovirus, EBV Epstein-Barr virus, HSV herpes simplex virus, Ig immunoglobulin, MSSA methicillin-sensitive Staphylococcus aureus, MRSA methicillin-resistant Staphylococcus aureus, PCR polymerase chain reaction, PPD purified protein derivative, RSV respiratory syncytial virus\n\n\naEBV viral capsid, nuclear, and early diffuse IgG Abs reactive, viral capsid IgM nonreactive; EBV PCR not performed\n\n\n\n\nHe was started on broad-spectrum antibiotics (vancomycin and piperacillin-tazobactam) and admitted to the internal medicine service. On HD 2, given a declining mental status and concern for meningitis, piperacillin-tazobactam was discontinued, and ceftriaxone, acyclovir, and ampicillin were added to the vancomycin. Ultimately, the patient required intubation for airway protection and was transferred to the medical intensive care unit (ICU). Lumbar puncture was performed and the results are presented in Table 2.\n\nOn HD 2 he developed urinary retention with a 600-ml output following straight catheterization prompting placement of a Foley catheter. Also on HD 2, loose stools developed along with increased abdominal rigidity and a rise in lactic acid levels from an admission value of 1.8 mmol/L (normal 0.5–2.2) to 4.9 mmol/L. Stool polymerase chain reaction (PCR) was negative for Clostridium difficile toxin B. His mental status deteriorated and he became agitated and required intubation on HD 2 for airway protection and was transferred to the medical ICU.\n\nLaboratory values on HD 2 included elevated aspartate aminotransferase (AST, normal range 13-39 U/L)/alanine aminotransferase (ALT, normal range 7-52 U/L) of 547 and 118 U/L, respectively; declining albumin from 2.7 to 1.7 mg/dL; and elevated LDH of 2833 U/L (normal 140-271 U/L), lipase of 501 U/L (normal 11–82 U/L), and triglycerides of 500 mg/dL (normal <150 mg/dL). Iron studies revealed a low transferrin of 99.3 mg/dL (normal 203–362 mg/dL) and TIBC of 139 mcg/dL (284–507 mcg/dL), low-normal serum iron of 50 mcg/dL (normal 49–181 mcg/dL), and normal saturation of 36% (normal 20–55%). Ferritin was substantially elevated at >7500 ng/mL (normal 23–233 ng/mL) and later peaked at >15,000 ng/mL.\n\nThe Quantiferon Gold tuberculosis (TB) test resulted as indeterminate due to a high degree of nonspecific reactivity produced by the patient’s specimen (i.e., NIL (negative control tube) >10 IU/mL). This was in concert with a very high C-reactive protein (CRP) result of 25.9 mg/dL (normal range 0.0–1.0 mg/dL) and an elevated soluble interleukin (IL)-2 receptor result of 1112 pg/mL (normal ≤1033 pg/mL). A purified protein derivative (PPD) skin test yielded 0-mm induration.\n\nDespite broad-spectrum antibiotics, the patient remained persistently febrile, with daily fevers exceeding 38.4 °C (maximal temperature was on HD 2 at 38.9 °C). He developed rigors and a subsequent mild rhabdomyolysis with creatinine kinase values increasing to a maximum of 7546 U/L (normal 30–223 U/L) on HD 2. Aggressive cooling measures were required, including acetaminophen and a cooling blanket. Continuous rigors with abdominal rigidity precluded accurate physical examination for hepatosplenomegaly. A kidneys-ureters-bladder (KUB) plain film taken on HD 2, however, had findings consistent with possible hepatosplenomegaly.\n\nA coagulopathy developed with maximal values on HD 5 of Prothrombin Time (PT) 29.7 s (normal 11.5–14.1 s), International Normalized Ratio (INR) of 2.91 (0.87–1.13), Partial Thromboplastin Time (PTT) 63.5 s (normal 24.7–37.0 s), and nadir fibrinogen level of 76 mg/dL (211–410 mg/dL). The latter prompted cryoprecipitate transfusions on HD 4 and HD 6. Progression of coagulopathy occurred in parallel with progression of thrombocytopenia, with nadir platelet count by HD 9 of 25 K/mcL (normal 150–400 K/mcL). Nadir hemoglobin also occurred on HD 9 at 7 g/dL. Schistocytosis was absent and neither red blood cell nor platelet transfusions were required throughout the hospital stay.\n\nThe combination of fever (maximal recorded 39.2 °C) in the setting of an infectious disease workup which showed only negative results, with trilineage cytopenias, elevated AST and ALT, hypofibrinogenemia (nadir of 76 mg/dL), significant hyperferritinemia (peak >15,000 ng/mL), triglycerides of 500 mg/dL, as well as suggestion on KUB imaging for hepatosplenomegaly, was compatible with a secondary HLH diagnosis. Involvement of the central nervous system (CNS) was evident given his mental status changes and agitation. Additionally, natural killer (NK)-cell function was reduced with a Lytic Unit 30 value of 5 lytic sets (normal LU30 = 7–125 lytic sets) and soluble IL-2 receptor level modestly elevated at 1112 pg/mL (normal ≤1033).\n\nHigh-dose steroids were, therefore, initiated. Dexamethasone, preferred because it can cross the blood-brain barrier, was initiated at 10 mg/m2 daily for weeks 1 and 2, followed by 5 mg/m2 daily for weeks 3 and 4, then 2.5 mg/m2 daily for weeks 5 and 6, then 1.25 mg/m2 daily for week 7 with tapering to zero during week 8. Clinical response was immediately noted with resolution of fevers and rigors and rapidly improving mental status. Laboratory abnormalities also improved; their trends following initiation of dexamethasone are further detailed in Fig. 1. Our patient was subsequently extubated on HD 5 and discharged in ambulatory condition with full cognitive ability on HD 20.Fig. 1 Timeline. Improvement in laboratory values with initiation of dexamethasone. PLT platelet count (normal 150–400 K/mcL), AST aspartate aminotransferase (normal 13–39 U/L), CK creatinine kinase (normal 30–223 U/L)\n\n\n\n\nDiscussion\nOur 35-year-old patient developed secondary HLH in the setting of preexisting immunosuppression due to underlying SLE and metastatic renal cell carcinoma. To our knowledge, this is the first case of HLH reported in the setting of pazopanib therapy and only the second case reported in association with renal cell carcinoma (RCC) [11].\n\nBased upon a validated cohort of secondary HLH patients [12], Fardet et al. developed a diagnostic H-Score [13] to predict the likelihood of secondary HLH. Points are assigned based upon presence of:Three clinical features○ Known immunosuppression – no: 0/yes: 18; high temperature <38.4 °C: 0, 38.4 to 39.4 °C: 33, >39.4 °C: 49; neither hepatomegaly nor splenomegaly: 0, either: 23, or both: 38\n\n\n\n\nFive biologic features○ Triglycerides mg/dL <132.9: 0, 132.9 to 354.3: 44, >354.3: 64; ferritin ng/mL <2000: 0, 2000–6000: 35, >6000: 50; AST U/L <30: 0, ≥30: 19; fibrinogen mg/dL >250: 0, ≤250: 30; number of cytopenic lineages – 1: 0, 2: 24, 3: 34\n\n\n\n\nOne cytologic feature○ Hemophagocytosis – no: 0, yes: 35\n\n\n\n\n\n\n\nIn regards to the validation cohort, the median (IQR) H-Score in the group with and without secondary HLH was 230 (203–257) and 125 (91–150), respectively. At H-Scores of 90, 150, 190, 200, 220, 230, 240, and 250, the probability for secondary HLH was <1%, 25%, 80%, 88%, 96%, 98%, 99%, and >99%, respectively [13]. Performance of the H-Score was compared against that of the adapted HLH-2004 criteria in a validation study by Debaugnies et al. [14]. In their comparison, the HLH-2004 criteria were shortened to exclude low NK-cell activity and soluble IL-2 receptor levels, thereby having six total criteria instead of the original eight. Among adult patients at initial presentation, the H-Score outperformed the modified HLH-2004 criteria at disease recognition: an H-Score of >138 offered 90% sensitivity, 79% specificity, and 86% diagnostic accuracy compared to the scenario in which five out of six HLH-2004 criteria are met, where respective values were: 55%, 100%, and 80%. For established disease, and using maximal score values, the two diagnostic criteria (using an H-Score >185) performed similarly.\n\nIn addition to meeting at least five out of the eight criteria in the original HLH-2004 diagnostic guidelines [5], our patient also had a diagnostic H-Score. Qualifying elements included: known immunosuppression (SLE on hydroxychloroquine, azathioprine, and steroids), a maximum temperature of 39.6 °C, hepatosplenomegaly, triglycerides of 500 mg/dL, AST >30 U/L, ferritin >6000 ng/mL, fibrinogen nadir <250 mg/dL, and trilineage cytopenias, earning an H-Score of 302, consistent with a diagnostic probability of >99%. The dramatic improvement on all fronts that ensued following initiation of steroid therapy lends further confidence to accuracy of our diagnosis.\n\nOther features consistent with secondary HLH in our patient include the presence of a euvolemic, hypo-osmolar hyponatremia with spot urine sodium of 24 mmol/L, consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) [1]. Additionally, our patient manifested CNS involvement with encephalopathy and agitation requiring intubation for airway protection.\n\nThe most common viral drivers for secondary HLH are EBV, HIV, herpes viruses, cytomegalovirus (CMV), viral hepatitis, and influenza [1]. In our patient, viral-testing was negative for these entities. Bacterial, fungal, and mycobacterial cultures also tested negative. SLE is also a recognized driver [1], but our patient did not appear to have signs of active disease, suggesting that the HLH was secondary to metastatic renal cell carcinoma.\n\nConclusions\nHLH is a life-threatening disorder resulting from immunologic hyperactivation that can progress to multiorgan failure. Early recognition is critical so that progression may be interrupted. However, this disease entity is likely under-recognized which is of concern given its high mortality rate. In pediatric cases, diagnosis is based upon the HLH-2004 criteria; which, for adult cases, may be insensitive for diagnosis earlier in the disease course. The H-Score is a validated diagnostic tool more appropriate for use among secondary HLH cases. For pediatric or EBV/lymphomatous cases, chemotherapeutic agents are often added. For adult cases, a high-dose dexamethasone regimen based upon the HLH-94 protocol may be used.\n\nAcknowledgements\nWe wish to acknowledge our respective mentors, who have guided us throughout our careers.\n\nFunding\nNo external funding was utilized to support publication of this manuscript.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nMEM and LE performed relevant data extraction and analysis. MT drafted the manuscript. MEM and LE participated at all stages in editing and revision of the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nEthics approval and consent to participate\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n==== Refs\nReferences\n1. Ramos-Casals M Brito-Zeron P Lopez-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome Lancet 2014 383 1503 1516 10.1016/S0140-6736(13)61048-X 24290661 \n2. Online Mendelian Inheritance in Man, OMIM®. Baltimore: Johns Hopkins University. MIM Number: {267700}: {05/21/2015}. World Wide Web URL: https://omim.org/.\n3. Brisse E Matthys P Wouters CH Understanding the spectrum of haemophagocytic lymphohistiocytosis: update on diagnostic challenges and therapeutic options Br J Haematol 2016 174 175 87 10.1111/bjh.14144 27292929 \n4. Henter JI Elinder G Söder O Ost A Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis Acta Paediatr Scand 1991 80 4 428 35 10.1111/j.1651-2227.1991.tb11878.x 2058392 \n5. Henter JI Horne A Arico M Egeler RM Filipovich AH Imashuku S HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 48 124 131 10.1002/pbc.21039 16937360 \n6. Emmenegger U Schaer D Larroche C Neftel K Haemophagocytic syndromes in adults: current concepts and challenges ahead Swiss Med Wkly 2005 135 289 314 \n7. Raschke RA Garcia-Orr R Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults Chest 2011 140 4 933 938 10.1378/chest.11-0619 21737492 \n8. Henter JI Arico M Egeler RM Elinder G Favara BE Filipovich AH HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis Med Pediatr Oncol 1997 28 342 347 10.1002/(SICI)1096-911X(199705)28:5<342::AID-MPO3>3.0.CO;2-H 9121398 \n9. Oto M Yoshitsugu K Uneda S Nagamine M Yoshida M Prognostic factors and outcomes of adult-onset hemophagocytic lymphohistiocytosis: a retrospective analysis of 34 cases Hematol Rep 2015 7 5841 10.4081/hr.2015.5841 26331000 \n10. Hayden A Park S Giustini D Lee AYY Chen LYC Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review Blood Rev 2016 30 6 411 420 10.1016/j.blre.2016.05.001 27238576 \n11. Chao CT Cao CC Lee SY Ho SJ Jhuang YJ Li LH Kao TW Renal cell carcinoma with secondary hemophagocytic syndrome: a case report Can Urol Assoc J 2012 6 2 e64 e66 10.5489/cuaj.10188 22511436 \n12. Riviere S Galicier L Coppo P Marzac C Aumont C Lambotte O Fardet L Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients Am J Med 2014 127 1118 1125 10.1016/j.amjmed.2014.04.034 24835040 \n13. Fardet I Galicier L Lambotte O Marzac C Aumont C Chahwan D Development and validation of the H-Score, a score for the diagnosis of reactive hemophagocytic syndrome Arthritis Rheumatol 2014 66 9 2613 20 10.1002/art.38690 24782338 \n14. Debaugnies F Mahadeb B Ferster A Meuleman N Rozen L Demulder A Corazza F Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients Am J Clin Pathol 2016 145 6 862 870 10.1093/ajcp/aqw076 27298397\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "11(1)", "journal": "Journal of medical case reports", "keywords": "Altered mental status; Disseminated intravascular coagulation; Fever; Fever of unknown origin; Hemophagocytic lymphohistiocytosis", "medline_ta": "J Med Case Rep", "mesh_terms": "D000328:Adult; D002292:Carcinoma, Renal Cell; D003907:Dexamethasone; D004211:Disseminated Intravascular Coagulation; D005293:Ferritins; D005938:Glucocorticoids; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009102:Multiple Organ Failure; D010198:Pancytopenia; D015375:Receptors, Interleukin-2; D016896:Treatment Outcome", "nlm_unique_id": "101293382", "other_id": null, "pages": "56", "pmc": null, "pmid": "28249615", "pubdate": "2017-03-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "24835040;21737492;16937360;2058392;27292929;26331000;24290661;27298397;24782338;22511436;27238576;16034684;9121398", "title": "Secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report.", "title_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report" }	[ { "companynumb": "PHHY2017US048289", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, QD", "drugenddate": null, 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"reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Influenza like illness", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transferrin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Interleukin-2 receptor increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Procalcitonin increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood osmolarity decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lipase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Abdominal rigidity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "C-reactive protein increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatosplenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Activated partial thromboplastin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Iron binding capacity total decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Serum ferritin increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M, EISENBUD L, TRAN M-H. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT. J-MED-CASE-REP 2017;11NO. 1.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170525", "receivedate": "20170525", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13581477, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-HORIZON-PRE-0203-2017", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202020", "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": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "HYDROXYCHLOROQUINE" } ], "patientagegroup": "5", "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histiocytosis haematophagic", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M, EISENBUD L, TRAN MH. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT. J MED CASE REP. 2017;11(1):56.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170522", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13566587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "US-MYLANLABS-2017M1028449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040274", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAZOPANIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histiocytosis haematophagic", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M, EISENBUD L, TRAN M-H. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT. J-MED-CASE-REP 2017;11:NO. 1.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170516", "receivedate": "20170516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13550301, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201703-001825", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "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": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLUENZA LIKE ILLNESS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "009768", "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": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB" }, "drugadditional": "3", "drugadministrationroute": null, "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": "PAZOPANIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "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": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transferrin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neck pain", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "C-reactive protein increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood osmolarity decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prothrombin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Histiocytosis haematophagic", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood albumin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Inappropriate antidiuretic hormone secretion", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oropharyngeal pain", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatosplenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iron binding capacity total decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Activated partial thromboplastin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Interleukin-2 receptor increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lipase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypofibrinogenaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Influenza like illness", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperferritinaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Procalcitonin", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Natural killer cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M,EISENBUD L,TRAN M. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT.. JOURNAL OF MEDICAL CASE REPORTS 2017 MAR 02;11:56:.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170406", "receivedate": "20170322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13358263, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170830" } ]
{ "abstract": "BACKGROUND\nIn Turkey, pharmacovigilance began in 1985. A fully structured adverse drug reaction (ADR)-reporting system was established with the publication of the first pharmacovigilance regulation in 2005. Subsequent regulation published in 2014 brought further improvements to the system.\n\n\nOBJECTIVE\nIn this study, we aimed to analyse the ADR-reporting pattern in the context of the first pharmacovigilance legislation in Turkey.\n\n\nMETHODS\nWe analysed ADR reports submitted to the Turkish Pharmacovigilance Center (TUFAM) from 2005 to 2014 with respect to reporting rate (RR), patient characteristics, type of the ADRs, suspected drugs, source of the report and the profession of the reporter.\n\n\nRESULTS\nThe annual RR increased gradually over the study period. RRs for females were greater than those for males. RRs were highly correlated with age. Most commonly reported ADRs were skin and subcutaneous tissue disorders. Most commonly suspected drugs were antineoplastic and immunomodulating agents. There was no remarkable change in reporting pattern of ADRs, patient characteristics or classes of suspected drugs over the years. The most common source of reports was spontaneous reporting. Contribution of the reports from studies increased gradually. Most of the reports were reported by physicians. RRs by pharmacists increased substantially over the years.\n\n\nCONCLUSIONS\nThis study showed that the annual RR increased gradually over the 9-year study period. This increase was neither due to an increased reporting of a specific group of ADRs or drugs, nor to an increased reporting in a specific group of patients. There was a general increase in RR in parallel to pharmacovigilance activities.", "affiliations": "Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey. [email protected].", "authors": "Ozcan\|Gulnihal\|G\|;Aykac\|Emel\|E\|;Kasap\|Yelda\|Y\|;Nemutlu\|Nergiz T\|NT\|;Sen\|Ebru\|E\|;Aydinkarahaliloglu\|N Demet\|ND\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1007/s40801-015-0054-1", "fulltext": "\n==== Front\nDrugs Real World OutcomesDrugs Real World OutcomesDrugs - Real World Outcomes2199-11542198-9788Springer International Publishing Cham 270737555410.1007/s40801-015-0054-1Original Research ArticleAdverse Drug Reaction Reporting Pattern in Turkey: Analysis of the National Database in the Context of the First Pharmacovigilance Legislation Ozcan Gulnihal Aykac Emel Kasap Yelda Nemutlu Nergiz T. Sen Ebru Aydinkarahaliloglu N. Demet [email protected] Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520 Ankara, Turkey 8 1 2016 8 1 2016 3 2016 3 1 33 43 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.Introduction\nIn Turkey, pharmacovigilance began in 1985. A fully structured adverse drug reaction (ADR)-reporting system was established with the publication of the first pharmacovigilance regulation in 2005. Subsequent regulation published in 2014 brought further improvements to the system.\n\nObjective\nIn this study, we aimed to analyse the ADR-reporting pattern in the context of the first pharmacovigilance legislation in Turkey.\n\nMethods\nWe analysed ADR reports submitted to the Turkish Pharmacovigilance Center (TUFAM) from 2005 to 2014 with respect to reporting rate (RR), patient characteristics, type of the ADRs, suspected drugs, source of the report and the profession of the reporter.\n\nResults\nThe annual RR increased gradually over the study period. RRs for females were greater than those for males. RRs were highly correlated with age. Most commonly reported ADRs were skin and subcutaneous tissue disorders. Most commonly suspected drugs were antineoplastic and immunomodulating agents. There was no remarkable change in reporting pattern of ADRs, patient characteristics or classes of suspected drugs over the years. The most common source of reports was spontaneous reporting. Contribution of the reports from studies increased gradually. Most of the reports were reported by physicians. RRs by pharmacists increased substantially over the years.\n\nConclusion\nThis study showed that the annual RR increased gradually over the 9-year study period. This increase was neither due to an increased reporting of a specific group of ADRs or drugs, nor to an increased reporting in a specific group of patients. There was a general increase in RR in parallel to pharmacovigilance activities.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s40801-015-0054-1) contains supplementary material, which is available to authorized users.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\nReporting rate of adverse drug reactions increased gradually over the years in Turkey in parallel to awareness activities on drug safety.\t\nIn Turkey, the reporting rate of adverse drug reactions was higher in females and elderly patients.\t\nThe number of ADRs reported per million boxes of drug consumption was highest for antineoplastic and immunomodulating agents.\t\n\n\nIntroduction\nAdverse drug reactions (ADRs) are common causes of mortality and morbidity all around the world [1, 2]. They represent an important economic burden for health systems [3, 4]. ADRs that occur in real-world medical practice cannot always be predicted by pre-marketing data since a limited number of selected patients are enrolled in clinical trials for specific indications and monitored for a limited period of time. Therefore, post-marketing surveillance is the most important tool for pharmacovigilance systems for early detection of unexpected and serious ADRs [5].\n\nWorld data on ADRs are collected at the Uppsala Monitoring Center (UMC) constituted under the auspices of the World Health Organization’s (WHO) Programme for International Drug Monitoring [5, 6]. All member countries send national ADR reports to the UMCs individual case safety reports (ICSR) database system, VigiBase [7, 8]. UMC continuously monitors the VigiBase for possible signals and alerts. Alerts from UMC constitute an important reference for decision-making processes of national pharmacovigilance authorities. However, ADR profiles vary from country to country owing to differences in genetics, diet and traditions of populations, and medical practices [5, 6, 9]. Additionally, pharmacovigilance legislations and the structure of the pharmacovigilance systems vary among WHO member countries [10, 11]. Because of these factors, information derived from the cumulative data may not always be relevant or applicable to individual populations. To be able to detect local signals and take accurate actions for minimization of the risk, it is important for countries to monitor and analyse their own national ADR databases continually. Such analysis can also guide actions to stimulate ADR reporting, and help to assess the effectivity of national legislations and pharmacovigilance activities.\n\nIn Turkey, pharmacovigilance activities started in 1985 with the establishment of the “Turkish Adverse Drug Reaction Monitoring and Evaluation Center” (TADMER) under the General Directorate of Pharmaceuticals and Pharmacy. In 1987, TADMER joined the WHO Programme as an official member. In 2005, first pharmacovigilance regulation, “Regulation on the Monitoring and Assessment of the Safety of Medicinal Products for Human Use”, became effective [12]. With this regulation, TADMER started to conduct pharmacovigilance activities under the name “Turkish Pharmacovigilance Center” (TUFAM), in order to stress the term “Pharmacovigilance”. In the regulation, major responsibilities of TUFAM were defined as: monitoring national ADR reports and drug safety alerts worldwide, communicating drug safety alerts to healthcare professionals, educating physicians and pharmacists on pharmacovigilance, conducting risk minimization methods, and assessing conformity of risk management plans and periodic safety update reports. Taking this first regulation as reference, responsibilities of Authorization Holders, Pharmacovigilance Inspections and Structure of Risk Management Systems were addressed in detail in the guidelines published in 2005, 2009 and 2011, respectively. In 2012, the General Directorate of Pharmaceuticals and Pharmacy became an agency called the Turkish Medicines and Medical Devices Agency. With this structural change, a Risk Management Unit was formed to take over risk minimization activities. Since then, TUFAM has been concentrating on monitoring and assessing national ADR reports.\n\nNational ADR reports reach TUFAM from two major sources: healthcare professionals and marketing authorization holders (MAHs). Healthcare professionals can notify spontaneous reports to the TUFAM either directly or by means of the pharmacovigilance contact points (PvCPs) within the health organization that they are employed in. PvCPs are physicians or pharmacists who are responsible for encouraging the notification of ADRs, collecting and communicating information to TUFAM, and carrying out training and awareness activities at hospitals they work in. According to regulation, a PvCP should be assigned to work at university hospitals, training and research hospitals, and private hospitals with a bed capacity of 50 or more. This regulation was later expanded to cover all hospitals. This method is different from many countries, and has the intention of communicating information faster between TUFAM and health-care professionals.\n\nMAHs are responsible for keeping the records of all suspected ADRs and notifying serious ADRs occurring in Turkey to the TUFAM within 15 days. They collect both spontaneous reports and solicited reports from patient support programmes where they receive and collect information relating to the use of their medicinal products. In Turkey, MAHs are also responsible for screening national and international literature for ADRs regarding the local population and forwarding a copy to TUFAM.\n\nSpontaneous and solicited ADR reports reaching TUFAM from healthcare professionals and MAHs are sent to the VigiBase as ICSRs. In this way TUFAM contributes to the integration of world data on ADRs as intended by the WHO programme. In 2014, national pharmacovigilance regulation was revised in the context of harmonization with EU directives [13]. With these new regulations, patient reports also started to be accepted and sent to the VigiBase by TUFAM. Additionally national ADRs mentioned in the literature started to be sent to the Vigibase if they complied with the requirements of an ICSR.\n\nIn this study, we aimed to analyse the national ADR reports submitted to VigiBase in the period for which the first pharmacovigilance legislation was effective and present the ADR reporting pattern in Turkey. This is the first detailed study on the National ADR Database of Turkey.\n\nMethods\nData\nThis study included national ADR reports for all the marketed drugs that were submitted to VigiBase by TUFAM between 1 July 2005 and 31 December 2013. In the study period all of the spontaneous and solicited reports that reach TUFAM and satisfy the minimum criteria of reporting were submitted to Vigibase. Minimum criteria of reporting were defined in the regulation as: (a) an identifiable reporter, (b) an identifiable patient, (c) at least one suspected drug, and (d) at least one ADR. The reports for which missing information could not be completed were not submitted to the VigiBase, since they did not comply with a valid ICSR.\n\nFor each report, information about the type of the report, qualification of the reporter, age and sex of the patient, suspected medications, ADRs and seriousness of the ADRs was extracted from the VigiBase. Number of reports in individual categories was counted for each study-year. Data were presented as report count, percentage of reports and/or RR for individual groups. RR was used as a measure of annual frequency of reporting in each category and estimated by adjusting the number of reports in the individual category in a year by the number of individuals residing in the corresponding category for that year. Different from other years, data for 2005 were given only for the second half of the year since the first pharmacovigilance regulation became effective on 30 June 2005.\n\nRRs for specific age or sex groups were estimated to observe the differences in RRs within age or sex groups. The Turkish Statistical Institute’s population by sex and age groups data were used for estimation [14]. Additionally, RRs per million patient visits and million inpatients were estimated as a measure of frequency of reporting for a million visits and a million hospitalizations. RRs for a million boxes of drug consumption and a thousand individuals in health profession groups were estimated to investigate the pattern of reporting for different drug and reporter groups, respectively. The Turkish Ministry of Health’s data on number of hospital visits by years, number of inpatients by years, consumption of drugs by years and number of healthcare professionals by years were used for estimation [15]. Estimation was done only for the years in which Ministry of Health’s data are available.\n\nClassification of Reports\nIn Vigibase there are two categories for defining the type of report: spontaneous reports and reports from studies. The terminology for spontaneous reports in our database and Vigibase is the same but solicited reports from patient support programmes in our database were coded as reports from studies during entry into the Vigibase.\n\nReporters were classified according to six groups: physicians, pharmacists, other health professionals, consumers, lawyers and unknown.\n\nFor age grouping 5-year interval age groups were used. Accordingly, patients were divided into the following age groups: 0–4, 5–9, 10–14, 15–19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74 and +75 years. In order to calculate age-specific RRs, the number of ADR reports within each 5-year interval age group was adjusted by the number of individuals in the age group for the corresponding year [14].\n\nADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) [16]. Seriousness of ADRs was classified according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E2A criteria used in VigiBase [17].\n\nSuspected drugs were classified according to the Anatomical Therapeutic Chemical (ATC) Classification system at level 2 at most, which provides information about pharmacological/therapeutic subgroup [18].\n\nStatistics\nStudent’s t test was used for analysing the significance of difference between RRs for a million inhabitants and a million inpatients per year, and the difference between RRs in sex groups. Pearson’s correlation coefficient (r) was calculated for correlation analysis.\n\nResults\nWe examined spontaneous and solicited reports that were submitted to TUFAM for all the marketed drugs in the period from June 2005 to the end of 2013. During the study period, a total of 8065 reports satisfied the minimum criteria for reporting and were thus included in the study.\n\nAdverse Drug Reaction (ADR) Reporting Rates\nThe number of ADR reports submitted in a year increased gradually over the study period (Fig. 1).Fig. 1 Annual number of adverse drug reaction (ADR) reports submitted to Vigibase by the Turkish Pharmacovigilance Centre (TUFAM) between 2005 and 2013. Asterisk data was given for the second half of the year\n\n\n\nAn increase in population, hospital visits or drug consumption may cause bias in favour of an increase in reporting of ADRs over years. To address these possibilities we adjusted the number of reports with the number of inhabitants (in millions), patient visits (in millions) and boxes of drug consumed (in millions) in a year, and estimated annual RRs (Table 1). We observed that the annual RR for a million inhabitants increased from 1.5 in 2005 to 32.1 in 2013 in parallel with the annual number of reports. The greatest increase in RR was observed in 2012 with a 10.7 increase. The annual RR for a million patient visits and a million boxes of drug consumption also increased over the years, and were highly correlated with the increase in RR for a million inhabitants (r = 0.99). Additionally, we observed that the annual RRs for a million inhabitants were significantly higher than those for a million patient visits (p < 0.05).Table 1 Annual reporting rate of adverse drug reactions per million inhabitants, million patient visits and million boxes of drug consumption in Turkey between 2005 and 2013\n\nYear\t2005a\n\t2006\t2007\t2008\t2009\t2010\t2011\t2012\t2013\t\nRRb (#/mill. inhab./year)\t1.5\t4.3\t5.0\t5.4\t7.1\t13.5\t14.6\t25.3\t32.1\t\nRate of increase in RR b\n\t\t2.8\t0.7\t0.4\t1.7\t6.4\t1.1\t10.7\t6.8\t\nRRc (#/mill. visits/year)\t\t\t\t\t1.8\t3.3\t3.2\t5.4\t6.5\t\nRRd (#/mill. boxes /year)\t\t\t0.3\t0.3\t0.4\t0.7\t0.7\t1.1\t1.6\t\n\nRR reporting rate\n\n\naData was given for the second half of the year only\n\n\nbNumber of reports/million inhabitants/year\n\n\ncNumber of reports/million patient visits/year\n\n\ndNumber of reports/million boxes of drug consumption/year\n\n\n\nType of Reports\nThe most common type of reporting was spontaneous reports in all years investigated (Table 2). Contribution of reports from studies increased gradually starting from 2010. The greatest increase in reporting from studies was observed in 2012.Table 2 Percentage distribution of adverse drug reaction reports by type in Turkey between 2005 and 2013\n\nYear\t2005a\n\t2006\t2007\t2008\t2009\t2010\t2011\t2012\t2013\t\nSpontaneous\t100.0\t99.0\t100.0\t99.5\t99.6\t92.3\t81.8\t71.1\t74.5\t\nReport from study\t0.0\t1.0\t0.0\t0.5\t0.4\t7.7\t18.2\t28.9\t25.5\t\nTotal\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t\n\naData were given for the second half of the year\n\n\n\nADRs by Sex\nOverall, 56.5 % of reports were reported for females. The percentage of reports for females was greater than that for males for all years (data not shown). When the number of reports for sex groups was standardized for the corresponding population in millions, annual RRs for females were still significantly greater than those for males (p < 0.05) (Table 3).Table 3 Annual reporting rate of adverse drug reactions for females and males in Turkey between 2005 and 2013\n\nYear\t2005a\n\t2006\t2007\t2008\t2009\t2010\t2011\t2012\t2013\t\nReporting rateb\n\t\n Female\t2.2\t4.8\t5.5\t6.1\t8.0\t15.2\t17.6\t28.5\t35.7\t\n Male\t0.8\t3.7\t4.3\t4.7\t6.0\t11.5\t11.2\t20.7\t26.7\t\n\naData were given for the second half of the year\n\n\nbNumber of reports/million individuals in the sex group/year\n\n\n\nADRs by Age\nWe calculated the RRs per million inhabitants in 5-year age group intervals to observe the pattern of reporting with respect to age groups (Fig. 2). The 9-year averages of RRs were highest in age groups 65–69, 70–74, 60–64 and +75 years, and tended to decrease with the decrease in age of the patients. Despite the high positive correlation between RRs and age (r = 0.93), we observed a higher RR in 0–4 years age group compared to adjacent age groups. When this age group was removed from the correlation analysis, strength of correlation increased further (r = 0.97).Fig. 2 Reporting rate (RR) of adverse drug reactions by 5-year interval age groups in Turkey between 2005 and 2013 (9-year average)\n\n\n\nType of Reporter\nIn general, most of the ADR reports were reported by physicians (59.8 %), followed by other health professionals (28.7 %) and pharmacists (9.1 %). A small percentage of reports was reported by consumers (2.3 %) (data not shown).\n\nIn Table 4, RRs are given that were calculated by adjusting the number of reports with the number of actively working professionals (in thousands) in the corresponding year. In general, RRs of physicians were greater than those of pharmacists. However, RRs of pharmacists increased substantially over the years and even exceeded the RRs for physicians in the year 2013. RRs of other health professionals could not be calculated since the definition of “other health professionals” used in the Health Statistics in Turkey is more comprehensive, and included: surgery technician, biologist, environmental health technician, child development specialist, dental technician, dietitian, physical therapy technician, physiotherapist, first aid and emergency care repairman, heart-lung pump operation technician, laboratory repairman, laboratory technician, audiologist, audiometric repairman, audiometric technician, orthopaedic technician, pathological anatomy technician, perfusion pump technician, prosthetics technician, psychologist, radiographer, health physicist, war health officer, health technician, health repairman, cytopathologist, social worker, medical secretary, medical technologist and public health technician in addition to nurse, anaesthesia technician, and emergency and first aid technician included in national pharmacovigilance system.Table 4 Annual reporting rate of adverse drug reactions by physicians and pharmacists in Turkey between 2009 and 2013\n\nHealth professional\t2009\t2010\t2011\t2012\t2013\t\nPhysician\t3.6\t6.2\t5.5\t6.7\t8.0\t\nPharmacist\t1.9\t2.9\t4.3\t6.6\t10.3\t\nNumber of reports/thousand professionals actively working in Turkey/year\n\n\n\nADRs According to Seriousness\nIn the study period a total of 16,248 ADRs were reported in 8065 reports. The average number of ADRs per report showed a slight increase from 1.8 in 2005 to 2.3 in 2013 with a 9-year average of 2.0 (data not shown).\n\nAmong all the reports, 70.5 % included a serious ADR. The most commonly specified seriousness criterion was medically important conditions (44.8 %), which was followed by hospitalization or prolongation of existing hospitalization (36.6 %), life-threatening conditions (14.3 %), death (8.6 %), persistent or significant disability/incapacity (2.7 %) and congenital anomalies (0.2 %) (data not shown).\n\nWe wanted to estimate the frequency of reporting of ADRs as a cause of hospitalization or prolongation of existing hospitalization among hospitalized patients. We observed a gradual increase in RR over years with a 32.5 increase per million inpatients from 2009 to 2013 (Fig. 3).Fig. 3 Annual reporting rate (RR) of adverse drug reactions as a cause of hospitalization or prolongation of hospitalization between 2009 and 2013. Asterisk number of reports in which hospitalization or prolongation of hospitalization was reported as the seriousness criterion /number of inpatients in Turkey/year\n\n\n\nDuring the study period, seriousness criterion was reported as congenital anomaly in 14 reports. Suspected drugs and ADR terms for these reports are listed in Table 5.Table 5 Suspected drugs and adverse drug reaction (ADR) terms in the reports where congenital anomaly was reported as the seriousness criterion in Turkey between 2005 and 2013\n\nCase\tSuspected drug\tADR terms\t\n1\tAdalimumab\tMaternal exposure during pregnancy; abortion\t\n2\tAdefovir dipivoxil\tCongenital anomaly, third finger first phalanx deficiency\t\n3\tButamirate citrate\tDysmorphism; alopecia areata; hypotonia; mental retardation; failure to thrive; brain malformation; congenital deafness; congenital blindness\t\n4\tDasatinib\tFlatulence; maternal exposure during pregnancy\t\n5\tDrospirenone/ethinylestradiol\tTherapeutic abortion due to anomaly\t\n6\tEntecavir\tCongenital musculoskeletal anomaly\t\n7\tEscitalopram, mirtazapine, hyoscine n-butylbromide, medazepam\tMaternal exposure during pregnancy; congenital anomaly not otherwise specified, abnormality of right forearm reduction of the fetus\t\n8\tInsulin aspart\tCongenital anomaly (5-alfa reductase enzyme deficiency dependent ambiguous genitalia, left coronary artery variation anomaly and horse-shoe kidney)\t\n9\tInsulin regular/insulin isophane\tMaternal exposure during pregnancy; congenital hand malformation; limb malformation\t\n10\tInsulin regular/insulin isophane\tPremature baby; breech presentation; fetal exposure during pregnancy\t\n11\tIsotretinoin\tCongenital hydrocephalus; eyelid ptosis; cleft palate; ear malformation\t\n12\tOlanzapine\tMaternal exposure during pregnancy; hypotonia neonatal; cyanosis neonatal; talipes\t\n13\tRanibizumab\tVentricular septal defect\t\n14\tTenofovir disoproxil fumarate\tPremature baby; fetal death; placental disorder\t\n\n\nADRs by System Organ Classification (SOC)\nThe percentage distribution of most frequently reported ADRs by SOC is given in Fig. 4. These 14 SOCs listed in the figure covered 90.2 % of all ADRs in the database.Fig. 4 Percentage distribution of adverse drug reactions by most frequently reported system organ classes in Turkey between 2005 and 2013\n\n\n\nSkin and subcutaneous tissue disorders, general disorders and administration site conditions, gastrointestinal disorders and nervous system disorders were the most frequently reported ADR SOCs, constituting together approximately 50 % of ADR SOCs in the database (Fig. 4). There was no remarkable change in reporting pattern of ADRs by SOCs over time. These four SOCs were in the top five of most frequently reported ADR SOCs in all years investigated (data not shown).\n\nADRs by Therapeutic Groups\nIn the study period a total of 9394 drugs were reported in 8065 reports. In 88.8 % of the reports only one drug was reported as the suspected drug. In the rest of the reports mostly two drugs (6.8 %) or three drugs (3.9 %) were suspected to cause the ADR. The average number of drugs per report was around 1.2 for all years.\n\nMost commonly reported drugs belong to the ATC classes antineoplastic and immunomodulating agents (26.5 %), anti-infectives for systemic use (24.5 %) and nervous system drugs (14.3 %) (Fig. 5). These three ATC classes were the most frequently reported drug groups in all years investigated (data not shown) and covered 65.5 % of all the suspected drugs reported in the 9-year period.Fig. 5 Percentage distribution of adverse drug reaction reports by Anatomical Therapeutic Chemical (ATC) class (first level) of suspected drugs in Turkey between 2005 and 2013\n\n\n\nReporting rate with respect to million boxes of drug consumption slightly increased over the study period (Table 1). RR for antineoplastic and immunomodulating agents was significantly high compared to overall RR (p < 0.01) (Supplementary Table 1). With the second-level ATC subgroups, most commonly reported drug groups were antibacterials for systemic use, immunosuppressants and antineoplastic agents (Supplementary Table 2). Most commonly reported active substances and percentage of serious ADRs reported for these drugs were listed in Table 6.Table 6 Report counts and Anatomical Therapeutic Chemical (ATC) codes for most commonly reported active substances in Turkey between 2005 and 2013 and percentage of serious adverse drug reactions (ADRs) for each substance\n\n\tSuspected drug\tReport count\tPercent of serious ADRs\tATC code\t\n1\tAdalimumab\t457\t98\tL04\t\n2\tInterferon beta-1b\t289\t74\tL03\t\n3\tEtanercept\t230\t59\tL04\t\n4\tCeftriaxone sodium\t214\t32\tJ01\t\n5\tPeginterferon alfa\t210\t96\tL03\t\n6\tRibavirin\t209\t98\tJ05\t\n7\tTelaprevir\t196\t100\tJ05\t\n8\tInfliximab\t147\t61\tL04\t\n9\tMoxifloxacin\t138\t63\tJ01\t\n10\tCefazolin sodium\t106\t26\tJ01\t\n\n\nADR reports related to vaccines constitute a very small percentage of the database (1.46 %, 118 reports) since safety of vaccines has being monitored by immunization programmes in Turkey. Most commonly reported vaccines in our database were pneumococcal conjugate vaccine (40 reports), rotavirus vaccine (19 reports) and influenza vaccines (19 reports) in the 9-year study period.\n\nDiscussion\nADR Reporting Rates and Report Types\nThis is the first study to analyse general ADR reporting patterns in the national pharmacovigilance database of Turkey. Our analyses showed that ADR RRs for a million inhabitants in Turkey increased remarkably over the last 9 years (Table 1). Most remarkable increases were observed in 2010, 2012 and 2013. There were salient advances in these years likely to contribute to the increased RR. In 2010, patient support programmes became effective and contribution of these programmes to the ADR database increased after that (Table 2). With the structural change in our National Pharmacovigilance Center in 2012, TUFAM started to concentrate mostly on monitoring and assessment of national ADR reports and was given the opportunity to dedicate more resources on the activities to raise awareness on pharmacovigilance and encourage ADR reporting nationwide. In 2012, a remarkable increase was observed in the rate of reporting from both patient support programmes and spontaneous sources. This observation can be evaluated as a translation of the effectivity of the structural change. In 2013, TUFAM started to accept patient notifications in the context of a pilot project via an electronic system developed by UMC. The system was incorporated into the Turkish Medicines and Medical Devices Agency’s website. In the first year of the project, a remarkable number of reports were submitted by consumers and contributed to the increasing trend in annual RR (data not shown).\n\nIn the study, we observed a significantly higher annual RR for million inhabitants than that for million patient visits. This observation suggests a considerable frequency of ADRs related to self-medication. Self-medication is a public health problem all over the world and studies have shown that self-medication-related ADRs should not be ignored [19, 20]. This point should also be addressed in Turkey by future studies.\n\nADRs by Sex and Age\nIn the study period RR for female patients was significantly high than that for males (Table 3). This is consistent with other studies [21–23]. There can be different factors contributing to the higher rate of reporting in females: the incidence of ADRs may be higher in females, hospital visits may more frequently involve female patients or female patients may more frequently consult a healthcare professional concerning an ADR. However, it is not possible to discern the individual contribution of these factors to the existing data.\n\nIn accordance with the results of previous studies [21, 23, 24], RRs were higher in the elderly where drug consumption is high (Fig. 2). Interestingly, RRs for the 0–4 years age group was remarkably high compared to those of adjacent age groups. In the study period, a patient support programme regarding use of palivizumab was active. Since palivizumab is used mostly in neonates, a large number of reports that reached TUFAM from the palivizumab patient support programme in the study period could be an explanation for the relatively high RR in the 0–4 year age group.\n\nADRs by Type of Reporter\nReports from physicians constituted the greatest percentage of reports, followed by reports from other health professionals and pharmacists. However, these data does not reflect reporting behaviors of profession groups since number of individuals in each profession group vary greatly. Therefore, number of reports was adjusted with the number of individuals in each profession group for the years between 2009 and 2013 in which corresponding data are available. It was observed that RR of physicians was greater than that of pharmacists for the years 2009–2012. However, RR of pharmacists increased substantially over the years and exceeded the RR of physicians in 2013 (Table 4). This increase in RR of pharmacists may be explained by the fact that mostly pharmacists being employed as PvCPs.\n\nADRs by Seriousness\nOverall, 70.5 % of the reports included a serious ADR. This is expected since there is emphasis on reporting of serious ADRs in pharmacovigilance regulations in Turkey. Reporting of hospitalization or prolongation of existing hospitalization as seriousness criteria increased gradually over time and reached 48.3 per million inpatients in 2013 (Fig. 3). This may be a reflection of the increased awareness regarding ADRs and the overall increase in RRs.\n\nDuring the study period, the seriousness criterion was reported as congenital anomaly in 14 reports (Table 5). In two of the reports the suspected drugs were drospirenone/ethinylestradiol and isotretinoin which have a pregnancy category of X. In the first report, “therapeutic abortion due to anomaly” was reported with exposure to drospirenone/ethinylestradiol (Case 5). In the literature there are reports that relate oral contraceptive use to malformations of the genitals in male infants [25, 26]. However, in the report mentioned above, the anomaly was not specified. In the second report (Case 11), “Congenital hydrocephalus; Eyelid ptosis; Cleft palate; Ear malformation” were reported which are well-defined congenital anomalies related to isotretinoin exposure during pregnancy [27–29]. Two out of 14 reports concern drugs with a pregnancy category of D, dasatinib and ranibizumab. For dasatinib, congenital anomaly was not specified in the report (Case 4) but in the product information hydrops fetalis, fetal leukopenia and fetal thrombocytopenia were reported and the possibility of congenital malformations, including neural tube defects, were mentioned [30]. For ranibizumab, ventricular septal defect was reported (Case 13). As far as we know, there is no such case in the literature. Among the suspected drugs with pregnancy category C, only adefovir and olanzapine had been mentioned in congenital anomaly cases in the literature. Congenital heart defect was reported with paternal administration of adefovir in the literature [31], which is not associated with “phalanx deficiency” reported in our case (Case 2). An increased risk of neonatal extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder) were reported to be associated with exposure to antipsychotic drugs during the third trimester of pregnancy [32–34]. Neonatal hypotonia and cyanosis reported for olanzapine in our database (Case 12) is compatible with withdrawal symptoms. Additionally “talipes” was observed in the case. Although a specific pattern of fetal limb or organ malformation have not been reported to be related to antipsychotics, there is a case report where hip dysplasia was observed after olanzapine exposure during pregnancy [35]. Other drugs listed in Table 5 do not appear to be associated with an increased risk for major malformations. Interestingly, three congenital anomaly cases were reported for insulin analogs (Case 8–10) which are preferred during pregnancy owing to their inability to pass transplacentally. Congenital anomalies reported in these cases were: (1) 5-alfa reductase enzyme deficiency dependent ambiguous genitalia, left coronary artery variation anomaly and horse-shoe kidney, (2) congenital hand malformation and limb malformation, and (3) premature baby and breech presentation. The high relative reporting rate for this therapeutic group might be considered a coincidence since pregnancy exposure registries and patient support programmes have being conducted for use of insulin analogues during pregnancy in Turkey.\n\nADRs by System Organ Classification\nAmong 36 SOCs for ADRs, skin and subcutaneous tissue disorders, general disorders and administration site conditions, gastrointestinal disorders, and nervous system disorders were the most frequently reported ADR SOCs covering approximately 50 % of total ADRs (Fig. 4). This pattern is similar to the global pattern of ADRs between the years 2000–2009, where general disorders and administration site conditions, skin and subcutaneous tissue disorders, nervous system disorders and gastrointestinal disorders were the most frequently reported SOCs for ADRs [10].\n\nADRs by Therapeutic Groups\nIn the majority of the reports, only one drug was reported as the suspected drug. RRs per million boxes of drug consumption increased slightly over the study period (Table 1). Similar to patterns of ADRs in upper-middle income countries reported by Aagard et al. [10], drugs from ATC classes of “antiinfectives for systemic use” (24.5 %) and “nervous system” (14.4 %) had high rates of reporting in Turkey (Fig. 5). However, “Antineoplastic and immunomodulating agents” (26.5 %) was the most frequently reported ATC drug group in Turkey; although it was the eighth most common ATC group in the upper-middle income countries [10]. It should be noticed that the study by Aagard et al. analysed only spontaneous reports submitted to VigiBase from 2000 to 2009, whereas our study included both spontaneous reports and reports from studies submitted between 2005 and 2013. These differences in the inclusion criteria for report type and the study periods may be the reason for the difference in rank of reporting for ATC groups. Differences in the characteristics of consumption of these drugs could also be a factor affecting the frequency of reporting in each country. However, number of reports adjusted by the consumption of million boxes of drugs in Turkey was still highest for antineoplastic and immunomodulating agents (Supplementary Table 1). Estimated RRs for this ATC group even reached to 77 times the overall reporting rate in 2011. The most probable explanation for this remarkably high RR is the high number of antineoplastic and immunomodulating agents involved in patient support programmes in Turkey. Examples for these drugs include interferon, eculizumab, fingolimod, adalimumab, etanercept, golimumab, infliximab, tacrolimus and lenalidomide which are highly represented in the database with solicited reports from patient support programmes. Among these, five drugs, namely adalimumab, interferon, etanercept, peginterferon and infliximab were in the list of ten most commonly reported drugs over the study period (Table 6). Percentage of serious ADRs reported with these drugs was generally higher than the overall percentage of serious ADRs in the database. This may be a reflection of the legislation, since MAHs are responsible for notifying serious ADR reports to TUFAM. Accordingly antivirals, Ribavirin and Telaprevir which are also included in patient support programs are represented in the list of most commonly reported drugs with high percentage of serious ADRs. The rest of the drugs in the list were all anti-infectives for systemic use. RR for a million boxes of consumption in this therapeutic group is not different from overall RR for a million boxes of drug consumption (Supplementary Table 1). However, the high reporting rate for these therapeutic groups may be due to higher consumption of these drugs. Additionally these agents mostly cause immediate and easily observable reactions defined under skin and subcutaneous tissue disorders and general disorders, and administration site conditions, for which causality between the drug and the reaction can easily be made. Accordingly, the percentage of serious ADRs reported with these drugs was relatively low in the database (Table 6).\n\nConclusion\nThis study showed that annual RRs in Turkey increased gradually in the 9-year study period. Major factors that might increase RR are: training activities conducted by TUFAM that raise awareness of pharmacovigilance, widening the scope of hospitals to all hospitals for employment of PvCPs, initiation of PV inspections in March 2010, authorization of a large number of biotechnological drugs and initiation of patient support programmes for these drugs. Though regulations that allow patient reporting became effective in April 2014 with the publication of “Regulation on safety of medicines”, patient reports were started to be accepted by TUFAM in 2013. This is also a contributing factor for the increased rate of reporting in the study period.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (DOCX 16 kb)\n\n \n\nThe authors gratefully acknowledge Professor Hakan Ergun (Ankara University Faculty of Medicine) for his helpful comments and advice on the manuscript.\n\nCompliance with Ethical Standards\nConflict of interest\nGulnihal Ozcan, Emel Aykac, Yelda Kasap, Nergiz Temiz Nemutlu, Ebru Sen and Nigar Demet Aydinkarahaliloglu have no conflicts of interest that are directly relevant to the content of this study.\n\nEthical approval\nEthical approval was not required for the study.\n\nFunding\nNo sources of funding were used to assist in the preparation of this study.\n\nAuthor contributions\nN. D. Aydinkarahaliloglu, E. Aykac and G. Ozcan designed the study. G. Ozcan analysed the data and wrote the manuscript. N. D. Aydinkarahaliloglu, E. Aykac, G. Ozcan, Y. Kasap, N. T. Nemutlu, and E. Sen collected the data. All authors saw and approved the final version of the manuscript.\n==== Refs\nReferences\n1. Jönsson AK. Drug-related morbidity and mortality: pharmacoepidemiological aspects: Linköping, Sweden: Linköping University, Faculty of Health Sciences; 2007.\n2. Pirmohamed M James S Meakin S Green C Scott AK Walley TJ Farrar K Park BK Breckenridge AM Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients BMJ. 2004 329 7456 15 19 10.1136/bmj.329.7456.15 15231615 \n3. Sultana J Cutroneo P Trifiro G Clinical and economic burden of adverse drug reactions J Pharmacol Pharmacother. 2013 4 Suppl 1 S73 S77 10.4103/0976-500X.120957 24347988 \n4. Bates DW Spell N Cullen DJ Burdick E Laird N Petersen LA Small SD Sweitzer BJ Leape LL The costs of adverse drug events in hospitalized patients JAMA. 1997 277 4 307 311 10.1001/jama.1997.03540280045032 9002493 \n5. 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Asseray N Ballereau F Trombert-Paviot B Bouget J Foucher N Renaud B Roulet L Kierzek G Armand-Perroux A Potel G Schmidt J Carpentier F Queneau P Frequency and severity of adverse drug reactions due to self-medication: a cross-sectional multicentre survey in emergency departments Drug Saf. 2013 36 12 1159 1168 10.1007/s40264-013-0114-y 24163273 \n20. Schmiedl S Rottenkolber M Hasford J Rottenkolber D Farker K Drewelow B Hippius M Saljé K Thürmann P Self-medication with over-the-counter and prescribed drugs causing adverse-drug-reaction-related hospital admissions: results of a prospective, long-term multi-centre study Drug Saf. 2014 37 4 225 235 10.1007/s40264-014-0141-3 24550104 \n21. Martin RM Biswas PN Freemantle SN Pearce GL Mann RD Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies Br J Clin Pharmacol 1998 46 505 511 10.1046/j.1365-2125.1998.00817.x 9833605 \n22. Zopf Y Rabe C Neubert A Gabmann KG Rascher W Hahn EG Dormann H Women encounter ADRs more often than do men Eur J Clin Pharmacol 2008 64 999 1004 10.1007/s00228-008-0494-6 18604529 \n23. Fattinger K Roos M Vergeres P Holenstein C Kind B Masche U Stocker DN Braunschweig S Kullak-Ublick GA Galeazzi RL Follath F Gasser T Meier PJ Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine Br J Clin Pharmacol 2000 49 158 167 10.1046/j.1365-2125.2000.00132.x 10671911 \n24. Routledge PA O’Mahony MS Woodhouse KW Adverse drug reactions in elderly patients Br J Clin Pharmacol. 2004 57 2 121 126 10.1046/j.1365-2125.2003.01875.x 14748810 \n25. Hemminki E Gissler M Toukomaa H Exposure to female hormone drugs during pregnancy: effect on malformations and cancer Br J Cancer 1999 80 7 1092 1097 10.1038/sj.bjc.6690469 10362122 \n26. Kim MR Qazi QH Anderson VM Valencia GB A genetic male infant with female phenotype in camptomelic syndrome: a relationship to exposure to oral contraceptives during pregnancy Am J Obstet Gynecol 1995 172 1042 1043 10.1016/0002-9378(95)90042-X 7892846 \n27. Hersh JH Danhauer DE Hand ME Weisskopf B Retinoic acid embryopathy: timing of exposure and effects on fetal development JAMA 1985 254 909 910 10.1001/jama.1985.03360070047015 4021019 \n28. Benke PJ The isotretinoin teratogen syndrome JAMA 1984 251 3267 3269 10.1001/jama.1984.03340480049027 6587131 \n29. Braun JT Franciosi RA Mastri AR Drake RM O’Neil BL Isotretinoin dysmorphic syndrome Lancet 1984 1 506 507 10.1016/S0140-6736(84)92866-6 6142222 \n30. Product information: SPRYCEL(R) oral tablets, dasatinib oral tablets. Istanbul: Bristol-Myers Squibb Company (per manufacturer); 2015.\n31. Gu Y Ru T Zhou YH Hu Y Adefovir as a possible teratogen: evidence from paternal exposure Dig Liver Dis 2014 46 12 1134 1135 10.1016/j.dld.2014.08.035 25174874 \n32. Product information: ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, olanzapine solution for IM injection, oral tablets, orally disintegrating tablets. Istanbul: Eli Lilly and Company; 2013.\n33. Newport DJ Calamaras MR DeVane CL Donovan J Beach AJ Winn S Knight BT Gibson BB Viguera AC Owens MJ Nemeroff CB Stowe ZN Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes Am J Psychiatry. 2007 164 8 1214 1220 10.1176/appi.ajp.2007.06111886 17671284 \n34. Kulkarni J Storch A Baraniuk A Gilbert H Gavrilidis E Worsley R Antipsychotic use in pregnancy Expert Opin Pharmacother. 2015 16 9 1335 1345 10.1517/14656566.2015.1041501 26001182 \n35. Spyropoulou AC Zervas IM Soldatos CR Hip dysplasia following a case of olanzapine exposed pregnancy: a questionable association Arch Womens Ment Health. 2006 9 4 219 222 10.1007/s00737-006-0138-8 16755330\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2198-9788", "issue": "3(1)", "journal": "Drugs - real world outcomes", "keywords": null, "medline_ta": "Drugs Real World Outcomes", "mesh_terms": null, "nlm_unique_id": "101658456", "other_id": null, "pages": "33-43", "pmc": null, "pmid": "27747800", "pubdate": "2016-03", "publication_types": "D016428:Journal Article", "references": "10362122;25174874;26001182;6142222;18604529;24347976;24347988;24347987;7892846;23072620;24550104;15231615;9002493;24163273;9833605;4021019;6587131;17671284;16755330;10671911;14748810", "title": "Adverse Drug Reaction Reporting Pattern in Turkey: Analysis of the National Database in the Context of the First Pharmacovigilance Legislation.", "title_normalized": "adverse drug reaction reporting pattern in turkey analysis of the national database in the context of the first pharmacovigilance legislation" }	[ { "companynumb": "TR-GILEAD-2016-0226660", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "021356", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "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": "VIREAD" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Placental disorder", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foetal death", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "OZCAN G, ET AL.. 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{ "abstract": "Clozapine is a dibenzodiazepine antipsychotic used for resistant schizophrenia, which is known to be associated with side effects such as agranulocytosis, seizures, weight gain, and less commonly myocarditis/ cardiomyopathy. We present a case of a 20-year-old female who presented with chest pain, shortness of breath, and cough. She was later found to have clozapine-induced pericardial effusion that resolved after discontinuation of clozapine therapy. Our case discloses the importance to consider clozapine in the differential diagnosis of pericardial effusion as discontinuation of the drug leads to resolution of effusion, with no need for further treatment.", "affiliations": "Internal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.;Internal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.;Psychiatry, Bronson Health, Kalamazoo, USA.;Cardiology, Ascension Borgess Hospital, Kalamazoo, USA.", "authors": "Bath\|Anandbir S\|AS\|;Garg\|Abhinav\|A\|;Gajare\|Nilanjan\|N\|;Gupta\|Vishal\|V\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.4890", "fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4890CardiologyInternal MedicinePsychiatryPericardial Effusion: Rare Adverse Effect of Clozapine Muacevic Alexander Adler John R Bath Anandbir S 1Garg Abhinav 1Gajare Nilanjan 2Gupta Vishal 3\n1 \nInternal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA \n2 \nPsychiatry, Bronson Health, Kalamazoo, USA \n3 \nCardiology, Ascension Borgess Hospital, Kalamazoo, USA \nAnandbir S. Bath [email protected] 6 2019 6 2019 11 6 e489028 5 2019 11 6 2019 Copyright © 2019, Bath et al.2019Bath et al.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.This article is available from https://www.cureus.com/articles/20472-pericardial-effusion-rare-adverse-effect-of-clozapineClozapine is a dibenzodiazepine antipsychotic used for resistant schizophrenia, which is known to be associated with side effects such as agranulocytosis, seizures, weight gain, and less commonly myocarditis/ cardiomyopathy. We present a case of a 20-year-old female who presented with chest pain, shortness of breath, and cough. She was later found to have clozapine-induced pericardial effusion that resolved after discontinuation of clozapine therapy. Our case discloses the importance to consider clozapine in the differential diagnosis of pericardial effusion as discontinuation of the drug leads to resolution of effusion, with no need for further treatment.\n\npericardial effusionclozapineschizophreniaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nClozapine is a dibenzodiazepine antipsychotic used in cases of schizophrenia, which are partially or fully resistant to conventional antipsychotic therapy. Clozapine is well known to be associated with side effects such as agranulocytosis, seizures, weight gain, insulin resistance, and less commonly myocarditis/cardiomyopathy [1]. Herein, a case of clozapine-induced pericardial effusion is presented, a rare side effect with only a few published case reports.\n\nCase presentation\nA 20-year-old female presented to the emergency department with ongoing complaints of chest pain, shortness of breath, and productive cough for one week. Chest pain was sudden in onset and sharp in character. No variation with respiratory movements was noted. Medical history was significant for resistant schizophrenia on clozapine therapy. The patient denied any history of recent travel or illicit drug use. On physical examination, the patient was found to be tachycardic and tachypneic. No jugular venous distension was noted. Cardiac auscultation revealed regular S1 and S2 with no murmurs, rubs, or gallops. Laboratory investigations were found to be significant for leukocytosis with elevated C-reactive protein (CRP) of 217.9 mg/dL (reference range: 0-0.9 mg/dL) and erythrocyte sedimentation rate (ESR) of 97 mm/h (reference range: 0-29 mm/h). The respiratory infectious disease panel was negative for any viral pathogen and was pneumococcal and legionella antigen. There was no elevation noted in the procalcitonin. Rheumatological workup was also negative to delineate a cause for the effusion. CT chest revealed left lower lobe pneumonia with large pericardial effusion. The patient was started on the appropriate treatment for her community-acquired pneumonia, for which she completed seven days of therapy. Meanwhile, transthoracic echocardiogram further characterized the effusion as moderate circumferential pericardial effusion (Figure 1).\n\nFigure 1 Arrow showing circumferential pericardial effusion in parasternal short axis view of transthoracic echocardiogram\nThere was no evidence of tamponade physiology. Upon consultation with the patient’s psychiatrist, clozapine was stopped, as it was thought to be the cause for the patient’s non-resolving pericardial effusion. Following the discontinuation of the drug, there was a gradual improvement in the respiratory status with follow-up transthoracic echocardiogram after three months revealing a reduction in the size of pericardial effusion (Figure 2).\n\nFigure 2 Follow-up transthoracic echocardiogram (parasternal short axis view) after three months upon discontinuation of clozapine showing resolution of the pericardial effusion\nCRP and ESR also trended down. The patient was discharged to home with discontinuation of clozapine in a stable and improved condition.\n\nDiscussion\nClozapine is an atypical antipsychotic used for resistant schizophrenia. It is used when patients have failed two different antipsychotics [2]. Though being more effective than typical antipsychotics, it is also associated with a hefty side effect profile, which includes agranulocytosis, seizures, central nervous system depression, myopericarditis, and cardiomyopathy. Cardiac toxicity from clozapine can be fatal as there have been reported cases of sudden cardiac death attributed to myocarditis or tamponade from pericardial effusion [3].\n\nPolyserositis from clozapine can lead to pleural effusion, pericardial effusion, and ascites. There have been well-documented case reports of clozapine causing myocarditis and cardiomyopathy but only a few reported cases of clozapine-induced pericardial effusion. Pericardial effusion is a rare (< 1:10,000) and serious adverse effect of clozapine [4].\n\nThere is no well-documented pathophysiology behind its cardiac side effects. Postmortem myocardial biopsy in a few cases revealed eosinophilic infiltrates with myocytolysis. Peripheral eosinophilia and increased levels of IgE have also been noted, indicating the role of IgE-mediated type I hypersensitivity reaction. It can also be viewed as an acute drug reaction as pleuropericardial effusions often occur within one or two weeks of initiation of clozapine therapy [1].\n\nClozapine can cause pericardial effusion as early as one week after the start of treatment. The cases of delayed cardiac manifestations appearing up to months to years after the initiation of clozapine therapy have also been reported [5-7]. In our case, the patient has been taking clozapine for the past 10 months before developing significant cardiac manifestations.\n\nThe presentation of patients can range from mild viral illness to sudden death from cardiac tamponade. Patients usually have a fever with shortness of breath and pleuritic chest pain. Common physical exam findings include tachycardia and tachypnea associated with muffled heart sounds depending on the size of effusion. Troponin elevation can be seen in the scenario of myocardial injury. Inflammatory markers such as CRP and ESR are usually elevated. Suspicion for clozapine-induced pericardial effusion should be high in patients who have been on clozapine for a long time.\n\nSince pericardial effusion is not well documented as an adverse effect, clozapine is usually overlooked as a possible etiology. Baseline ECG and echocardiography should be performed in patients with previous cardiac history who are started on clozapine therapy. All other causes such as viral infection or rheumatological conditions should be ruled out. Patients should follow-up with cardiology if diagnosed with pericardial effusion. Repeat transthoracic echocardiogram after three months of discontinuation of clozapine is recommended to ensure remission [8]. In our case, inflammatory markers CRP and ESR down trended within one week of discontinuation of clozapine therapy, and the repeat transthoracic echocardiogram after three months revealed decreased pericardial effusion.\n\nMultiple case reports have shown that discontinuing clozapine therapy resulted in a decrease in the size of effusion [6,9]. No further treatment is indicated if clozapine is being considered as the most likely cause in the absence of definitive etiology. Follow-up ECG at three months is recommended although no official guidelines exist. There is a lack of evidence to formulate the clinical guidelines regarding clozapine rechallenge. A study showed successful rechallenge outcomes; depending upon the adverse effect clozapine was discontinued for [10].\n\nConclusions\nPericardial effusion from clozapine therapy is a rare adverse effect. The timing of cardiac manifestations and initiation of treatment is variable; discontinuation of clozapine results in improvement of symptoms and resolution of pericardial effusion. No further treatment is indicated, but a follow-up echocardiogram is recommended.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Myocarditis and cardiomyopathy associated with clozapine Lancet Kilian JG Kerr K Lawrence C Celermajer DS 1841 1845 354 1999 10584719 \n2 Treatment-resistant schizophrenia-the role of clozapine Curr Med Res Opin Meltzer Meltzer HY HY 1 20 14 1997 9524789 \n3 Clozapine and incidence of myocarditis and sudden death-long term Australian experience Int J Cardiol Khan AA Ashraf A Baker D 136 139 238 2017 28343762 \n4 Clozapine rechallenge following clozapine-induced pericarditis J Clin Psychiatry Crews MP Dhillon GS MacCabe JH 959 71 2010 20667298 \n5 Clozapine-induced pericardial effusion J Clin Psychopharmacol Dauner DG DeRemer CE Haburchak D 455 456 28 2008 18626276 \n6 Clozapine and pericarditis with pericardial effusion Am J Psychiatry Murko A Clarke S Black DW 494 159 2002 \n7 Clozapine-induced pericarditis Afr J Psychiatry Markovic J Momcilov-Popin T Mitrovic D Ivanovic-Kovacevic S Sekuli S Stojsic-Milosavljevic A 236 238 14 2011 \n8 Monitoring the safe use of clozapine CNS Drugs Berk M Fitzsimons J Lambert T 117 127 21 2007 17284094 \n9 Polyserositis associated with clozapine treatment Am J Psychiatry Daly JM Goldberg RJ Braman SS 1274 1275 149 1992 \n10 Clozapine rechallenge after major adverse effects: clinical guidelines based on 259 cases Am J Ther Manu P Lapitskaya Y Shaikh A Nielsen J 218 223 25 2018\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "11(6)", "journal": "Cureus", "keywords": "clozapine; pericardial effusion; schizophrenia", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e4890", "pmc": null, "pmid": "31423370", "pubdate": "2019-06-12", "publication_types": "D002363:Case Reports", "references": "10584719;11870026;1503144;17284094;18626276;20667298;21863209;28343762;29505490;9524789", "title": "Pericardial Effusion: Rare Adverse Effect of Clozapine.", "title_normalized": "pericardial effusion rare adverse effect of clozapine" }	[ { "companynumb": "US-ACCORD-153075", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLOZAPINE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "202873", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "SCHIZOPHRENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLOZAPINE." } ], "patientagegroup": null, "patientonsetage": "20", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pericardial effusion", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "BATH AS, GARG A, GAJARE N, GUPTA V. PERICARDIAL EFFUSION: RARE ADVERSE EFFECT OF CLOZAPINE. CUREUS. 2019 JUN 12?11(6):E4890.", "literaturereference_normalized": "pericardial effusion rare adverse effect of clozapine", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190829", "receivedate": "20190829", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16753852, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" } ]
{ "abstract": "Tumor lysis syndrome(TLS)induced by chemotherapy for solid tumors is rare. We report a case of a 59-year-old woman with breast cancer who developed TLS. She underwent surgery to treat breast cancer in 1992. 19 years after surgery, however, she was diagnosed with multiple bone metastases(disease free interval, 13 years and 3 months). In March 2011, gemcitabine regimen was initiated(1,250mg/m2, 14 days followed by a 7-day rest period)because of worsening of multiple bone metastases. The patient was immediately admitted and treated for suspected TLS when she presented at our hospital with symptoms such as depressed level of consciousness, serious anemia, hypercalcemia, hyperuricemia, and liver/renal dysfunction on day 16 of the first line of regimen. Rasburicase was found to be effective for hyperuricemia.", "affiliations": "Dept. of Breast Oncology, Aichi Cancer Center Hospital.", "authors": "Kawaguchi Ushio\|Aya\|A\|;Hattori\|Masaya\|M\|;Kohno\|Norio\|N\|;Kaise\|Hiroshi\|H\|;Iwata\|Hiroji\|H\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "40(11)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001943:Breast Neoplasms; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008875:Middle Aged; D012008:Recurrence; D015275:Tumor Lysis Syndrome", "nlm_unique_id": "7810034", "other_id": null, "pages": "1529-32", "pmc": null, "pmid": "24231708", "pubdate": "2013-11", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Gemcitabine-induced tumor lysis syndrome caused by recurrent breast cancer in a patient without hemodialysis.", "title_normalized": "gemcitabine induced tumor lysis syndrome caused by recurrent breast cancer in a patient without hemodialysis" }	[ { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-113568", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "78433", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1250 MG/M^2 14 DAYS FOLLOWED BY A 7-DAY REST PERIOD", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO BONE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201103", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE" } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tumour lysis syndrome", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Renal impairment", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypercalcaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic function abnormal", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hyperuricaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KAWAGUCHI USHIO A, HATTORI M, KOHNO N, KAISE H, IWATA H. GEMCITABINE-INDUCED TUMOR LYSIS SYNDROME CAUSED BY RECURRENT BREAST CANCER IN A PATIENT WITHOUT HEMODIALYSIS. JPN J CANCER CHEMOTHER. 2013;NOV;40(11):1529-32", "literaturereference_normalized": "gemcitabine induced tumor lysis syndrome caused by recurrent breast cancer in a patient without hemodialysis", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20170525", "receivedate": "20160404", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12233625, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" } ]
{ "abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of white matter due to the opportunistic reactivation of John Cunningham virus in an immunocompromised patient. PML is associated with many immune-mediated diseases, lymphoproliferative conditions, and immunosuppressive agents. In this case report, we present a 79-year-old female patient diagnosed with rheumatoid arthritis who developed posterior fossa PML while on rituximab. She presented with subacute cerebellar ataxia, dysarthria, and nystagmus, and her brain MRI showed right pontine and pontocerebellar lesion with diffusion restriction and heterogenous enhancement highly characteristic of PML. Though many cases of PML with rituximab were reported in the literature, our case describes a rare type of PML affecting the posterior fossa in an HIV-negative patient on rituximab.", "affiliations": "Radiology, Creighton University Medical Center, Omaha, USA.;Neurology, Creighton University Medical Center, Omaha, USA.;Family Medicine, Creighton University Medical Center, Omaha, USA.;Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA.;Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA.", "authors": "Guduru\|Mounika\|M\|;Bendi\|Venkata Sunil\|VS\|;Bebawy\|Mariana S\|MS\|;Bande\|Dinesh\|D\|;Matta\|Abhishek\|A\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.10888", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.10888\nNeurology\nInfectious Disease\nRheumatology\nPosterior Fossa Progressive Multifocal Leukoencephalopathy Secondary to Rituximab\nMuacevic Alexander Adler John R Guduru Mounika 1 Bendi Venkata Sunil 2 Bebawy Mariana S 3 Bande Dinesh 4 Matta Abhishek 4 \n1 \nRadiology, Creighton University Medical Center, Omaha, USA \n\n2 \nNeurology, Creighton University Medical Center, Omaha, USA \n\n3 \nFamily Medicine, Creighton University Medical Center, Omaha, USA \n\n4 \nInternal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA \n\nAbhishek Matta [email protected]\n10 10 2020 \n10 2020 \n12 10 e108886 9 2020 9 10 2020 Copyright © 2020, Guduru et al.2020Guduru et al.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.This article is available from https://www.cureus.com/articles/22347-posterior-fossa-progressive-multifocal-leukoencephalopathy-secondary-to-rituximabProgressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of white matter due to the opportunistic reactivation of John Cunningham virus in an immunocompromised patient. PML is associated with many immune-mediated diseases, lymphoproliferative conditions, and immunosuppressive agents. In this case report, we present a 79-year-old female patient diagnosed with rheumatoid arthritis who developed posterior fossa PML while on rituximab. She presented with subacute cerebellar ataxia, dysarthria, and nystagmus, and her brain MRI showed right pontine and pontocerebellar lesion with diffusion restriction and heterogenous enhancement highly characteristic of PML. Though many cases of PML with rituximab were reported in the literature, our case describes a rare type of PML affecting the posterior fossa in an HIV-negative patient on rituximab.\n\npmlposterior fossaprogressive multifocal leukoencephalopathyrheumatoid arthritisrituximabThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nProgressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of cerebral white matter. It is due to the reactivation of John Cunningham (JC) polyomavirus in an immunocompromised patient [1,2]. JC virus primary infection often occurs during childhood or early adolescence, but the virus stays dormant in body tissues (central nervous system, kidneys, epithelium, kidneys, bone marrow, and lymph nodes) for long periods in immunocompetent individuals. Several studies in the literature reported that up to 50% of adults may be seropositive for the JC virus [3]. However, an intact immune system suppresses viral activation. In an immunocompromised state, the virus becomes reactivated, resulting in disease [4].\n\nImmunocompromised states such as HIV infection, leukemia, lymphomas, and different malignancies are well known to be associated with PML. Several reported cases in the literature show a strong association of PML with some immunosuppressants such as natalizumab, fingolimod, dimethyl fumarate, and rituximab [4-6]. Rituximab is an anti-CD20 monoclonal antibody used in the treatment of many lymphoproliferative conditions and immune-mediated diseases such as non-Hodgkin's lymphoma, neuromyelitis optica, psoriasis, and rheumatoid arthritis [7]. The drug acts against CD20+ cells with various mechanisms of action such as antibody-dependent cytotoxicity, cell-mediated cytotoxicity, apoptosis, and direct sensitization of cells to chemotherapy [8].\n\nCase presentation\nA 79-year-old woman with a known history of rheumatoid arthritis on long-term prednisone (5 mg daily) and rituximab (1,000 mg every six months) presented to the emergency room with multiple falls, gait difficulty, slurred speech, and confusion. She had a past medical history of hypertension and left hemispheric ischemic stroke for which she was on clopidogrel daily. On hospital admission, her vital signs were stable, and her physical examination revealed right spastic hemiparesis (a known residual from her old cerebrovascular insult), axial and appendicular ataxia, slurred dysarthria, and vertical nystagmus. Computed tomography (CT) scan of the brain showed a right pontine and right cerebellar hypodense irregular lesion without significant surrounding edema or mass effect and left parietal cortical and subcortical encephalomalacia, likely sequelae of an old vascular insult (Figure 1).\n\nFigure 1 Brain CT axial (a) and coronal (b) sections showing a right cerebellar hypodense lesion with no significant surrounding edema or mass effect and left cortical and subcortical parietal encephalomalacia (on coronal section).\nMagnetic resonance imaging (MRI) with gadolinium of the brain and posterior fossa revealed the right pontine lesion (at the brachium pontis) as involving the right cerebellar white matter. The lesion was isointense on T1 and hyperintense on T2 and FLAIR (fluid-attenuated inversion recovery) sequences. The outer borders of the right pontocerebellar lesion were more defined than the inner border, and there was minimal surrounding edema, with no mass effect on the adjacent fourth ventricle. The lesions showed diffusion restriction on diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps. The contrast study showed heterogenous leading edge enhancement at the right pontocerebellar lesion (Figure 2). A smaller T2 and FLAIR hyperintense lesion was also noted in the left middle cerebellar peduncle, extending to the left cerebellar hemisphere with heterogeneous enhancement. These radiological features, along with the clinical features in a rituximab-treated immunocompromised patient, are highly suggestive of PML.\n\nFigure 2 MRI of the brain with contrast showing an irregular right pontine isointense lesion on T1 (a), hyperintense signal on T2 (c), and FLAIR (d) sequences, with the extension of the lesion to the right cerebellar hemisphere showing minimal edema adjacent to the fourth ventricle. The lesion shows restriction on DWI (e) and ADC map (f) and heterogeneous enhancement at the margins (b, g, and h). Another T2 hyperintense smaller lesion is demonstrated at the left middle cerebellar peduncle and left cerebellar hemisphere (c) with heterogeneous enhancement (h).\nFLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted images; ADC, apparent diffusion coefficient\n\nHer routine chemistry panel was unremarkable except for mild anemia, slightly elevated creatinine level, and hyperglycemia (Table 1).\n\nTable 1 Routine laboratory tests\nRBC, red blood cells; WBC, white blood cells; HIV, human immunodeficiency virus; HbsAg, hepatitis B surface antigen; HCV, hepatitis C virus\n\nLaboratory test \tAdmission 1 \tReference range \t\nHemoglobin \t11.5 \t13-15 g/dL \t\nRBC \t3.8 \t4.6-6.8 x 106/mcL \t\nWBC \t6.4 \t3.6-10.3 x 103/mcL \t\nPlatelets \t197 \t140-420 x 103/mcL \t\nBlood glucose \t119 \t70-100 mg/dL \t\nSodium \t139 \t135-145 mmol/L \t\nPotassium \t4.3 \t3.7-5.1 mmol/L \t\nChloride \t107 \t96-110 mmol/L \t\nBicarbonate \t22 \t22-32 mmol/L \t\nKetone screen \tNegative\t \t\nBlood urea \t17 \t6-24 mg/dL \t\nCreatinine \t1.36 \t0.6-1.3 mg/dL \t\nHIV \tNegative\t \t\nHbsAg \tNegative\t \t\nAnti-HCV \tNegative\t \t\nLumbar puncture with cerebrospinal fluid (CSF) studies and treatment options were discussed with the patient. However, the patient and her family decided to adopt a palliative approach, and the patient was discharged from the hospital to a nursing home where she died within a month.\n\nDiscussion\nIn general, the incidence of PML in HIV-negative patients receiving rituximab is about 1 in every 32,000 patients [4]. Rituximab is a typical monoclonal antibody used for the treatment of many immune-mediated disorders and lymphoproliferative conditions. Despite its efficacy, it has been reported to be associated with severe adverse events particularly PML. PML is estimated to occur in around 6% of patients receiving rituximab [9], and since 1990, many case reports and case series have been published reporting the occurrence of PML with rituximab usage [7]. The patient presented in this article represents a rare case of posterior fossa PML who was on rituximab for rheumatoid arthritis. PML requires a high index of suspicion for diagnosis, and clinicians should always be on alert to include it in the differential diagnosis in immunocompromised patients, particularly those on monoclonal antibody therapy. PML is diagnosed based on clinical, radiological, and laboratory testing. Clinically, the most common three presenting symptoms are hemiparesis, visual dysfunction, and disturbed mental state [6]. However, some patients may present with posterior fossa symptoms such as ataxia, slurred dysarthria, and nystagmus [6], which are also notable in our patient. Radiologically, PML appears as white matter demyelinating single or less often as multiple lesions that predominantly affect the supratentorial structures. The lesions are characteristically large subcortical with ill-defined inner borders and well-defined outer borders that show a restriction on diffusion sequences. The lesions enhance on contrast administration typically in an open-ring pattern. However, heterogeneous patterns of enhancement were reported [10]. CSF analysis in PML might show mildly elevated proteins and white blood cells, and a high viral load. The most accurate diagnostic test of PML is a brain biopsy of the suspected lesion.\n\nAlthough many cases of PML have been reported to develop in the context of rituximab therapy, the exact pathophysiological mechanism of rituximab-associated PML remains elusive. It is proposed that the rituximab-induced B-cell depletion, change in cytokine nature, and altered T-lymphocyte activity lead to reactivation of the JC virus [11]. Hematopoietic progenitor cells in the bone marrow are thought to be the site of viral latency, and when they get mobilized to the blood and central nervous system under the effect of monoclonal antibodies, they result in the hematogenous spread of the virus to the brain, activation, and development of PML [12]. As with natalizumab, the risk of PML development in patients receiving rituximab depends on the JC virus titer, the previous use of immunosuppressant medications, and the duration of use of the monoclonal antibody drug [5]. Additionally, low CD4b increases the risk of rituximab-associated PML [13]. The patient reported in this article has been on oral steroids and rituximab for years, increasing her risk of PML. As PML can be fatal, patients receiving rituximab should be meticulously monitored. Regular follow-up of CD4b is essential, and abrupt discontinuation of rituximab is fundamental to reduce mortality if PML is suspected [4]. The FDA has granted Orphan Drug designation to NT-I7 (efineptakin alfa) for the treatment of PML. Plasma exchange to remove the circulating drug as well as stopping the offending drug represent the treatment of choice for these cases [6].\n\nConclusions\nAs PML can be fatal, patients receiving rituximab should be meticulously monitored. Regular follow-up of CD4b is essential, and abrupt discontinuation of rituximab is fundamental to reduce mortality if PML is suspected. Although there is no definitive evidence that FDA approved the medication for PML to date, plasma exchange to remove the circulating drug as well as stopping the offending drug represent the treatment of choice for these cases.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Progressive multifocal leukoencephalopathy in autoimmune diseases Joint Bone Spine Palazzo E Yahia SA 351 355 79 2012 22281228 \n2 Progressive multifocal leukoencephalopathy: current treatment options and future perspectives Ther Adv Neurol Disord Pavlovic D Patera AC Nyberg F Gerber M Liu M 255 273 8 2015 26600871 \n3 Asymptomatic reactivation of JC virus in patients treated with natalizumab N Engl J Med Chen Y Bord E Tompkins T e t al 1067 1074 361 2009 19741227 \n4 Progressive multifocal leukoencephalopathy Neurol Clin Grebenciucova E Berger JR 739 750 36 2018 30366552 \n5 [Neuropathology of natalizumab-associated progressive multifocal leukoencephalopathy] Brain Nerve Kanda T 891 901 67 2015 26160817 \n6 Progressive multifocal leukoencephalopathy and monoclonal antibodies: a review Cancer Control Bohra C Sokol L Dalia S 1073274817729901 24 2017 28975841 \n7 Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis Arch Neurol Clifford DB Ances B Costello C 1156 1164 68 2011 21555606 \n8 Rituximab-associated infections Semin Hematol Gea-Banacloche JC 187 198 47 2010 20350666 \n9 Neuromyelitis optica spectrum disorders in Iran Mult Scler Relat Disord Eskandarieh S Nedjat S Azimi AR Moghadasi AN Sahraian MA 209 212 18 2017 29141812 \n10 Imaging manifestations of progressive multifocal leukoencephalopathy Clin Radiol Shah R Bag AK Chapman PR Curé JK 431 439 65 2010 20451009 \n11 Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project Blood Carson KR Evens AM Richey EA 4834 4840 113 2009 19264918 \n12 The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34 hematopoietic progenitor cells in humans Blood Zohren F Toutzaris D Klärner V Hartung HP Kieseier B Haas R 3893 3895 111 2008 18235044 \n13 Immunotherapy: past, present and future Nat Med Waldmann TA 269 277 9 2003 12612576\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(10)", "journal": "Cureus", "keywords": "pml; posterior fossa; progressive multifocal leukoencephalopathy; rheumatoid arthritis; rituximab", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e10888", "pmc": null, "pmid": "33178540", "pubdate": "2020-10-10", "publication_types": "D002363:Case Reports", "references": "30366552;28975841;26600871;19264918;22281228;19741227;21555606;20350666;18235044;29141812;26160817;12612576;20451009", "title": "Posterior Fossa Progressive Multifocal Leukoencephalopathy Secondary to Rituximab.", "title_normalized": "posterior fossa progressive multifocal leukoencephalopathy secondary to rituximab" }	[ { "companynumb": "US-ROCHE-2716407", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RHEUMATOID ARTHRITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DAILY", "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": "CLOPIDOGREL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "103705", "drugbatchnumb": "UNKNOWN", "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": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RITUXIMAB." } ], "patientagegroup": null, "patientonsetage": "79", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Progressive multifocal leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "GUDURU M, BENDI VS, BEBAWY M, BANDE D AND MATTA A. 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{ "abstract": "We present a case of a 43-year-old female patient with clinical stage IIIB (T3N2M0) anaplastic lymphoma kinase (ALK)-positive adenocarcinoma of the lung. Surgery was not performed initially because of multiple mediastinal lymph nodes invasion, although the mass was technically resected. With the assessment of upfront multidisciplinary consultation, administration of neoadjuvant crizotinib was selected to induce the downstaging and facilitate the subsequent surgical treatment. After 10 weeks of neoadjuvant crizotinib treatment, a partial response was achieved and the tumor could be radically resected. There were no sever toxic effects and treatment-related surgical delay during the whole neoadjuvant crizotinib therapy. The patient then successfully underwent video-assisted single port thoracoscopic right upper lobectomy and lymphadenectomy. Concurrent chemotherapy and radiotherapy were applied postoperatively. Perioperative targeted therapy demonstrated good curative effect in this case, and no recurrence was observed at the clinic 8 months after surgery. In this case, the safety and effectiveness of neoadjuvant crizotinib and subsequent surgery are preliminarily proved. We here intend to investigate the optimal setting of neoadjuvant targeted therapy combined with minimally invasive surgery and postoperative adjuvant therapy, inspire more potential targeted treatment based schedules and to apply these strategies in treating patients with locally advanced mutant-positive non-small cell lung cancer (NSCLC).", "affiliations": "Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China.", "authors": "Tian\|Yu\|Y\|;Huang\|Jia\|J\|;Li\|Chongwu\|C\|;Jiang\|Long\|L\|;Lin\|Hao\|H\|;Lu\|Peiji\|P\|;Luo\|Qingquan\|Q\|;Yang\|Guocai\|G\|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/atm-20-3927", "fulltext": "\n==== Front\nAnn Transl Med\nAnn Transl Med\nATM\nAnnals of Translational Medicine\n2305-5839\n2305-5847\nAME Publishing Company\n\natm-08-12-770\n10.21037/atm-20-3927\nCase Report\nPerioperative crizotinib in a patient with stage IIIB ALK-positive non-small cell lung cancer: a case report\nTian Yu 1#\nHuang Jia 1#\nLi Chongwu 1#\nJiang Long 1\nLin Hao 1\nLu Peiji 1\nLuo Qingquan 1\nYang Guocai 2\n1 Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;\n2 Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China\n# These authors contributed equally to this work.\n\nCorrespondence to: Guocai Yang. Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road Lincheng New District, Zhoushan, China. Email: [email protected].\n6 2020\n6 2020\n8 12 77017 4 2020\n11 6 2020\n2020 Annals of Translational Medicine. All rights reserved.\n2020\nAnnals of Translational Medicine.\nWe present a case of a 43-year-old female patient with clinical stage IIIB (T3N2M0) anaplastic lymphoma kinase (ALK)-positive adenocarcinoma of the lung. Surgery was not performed initially because of multiple mediastinal lymph nodes invasion, although the mass was technically resected. With the assessment of upfront multidisciplinary consultation, administration of neoadjuvant crizotinib was selected to induce the downstaging and facilitate the subsequent surgical treatment. After 10 weeks of neoadjuvant crizotinib treatment, a partial response was achieved and the tumor could be radically resected. There were no sever toxic effects and treatment-related surgical delay during the whole neoadjuvant crizotinib therapy. The patient then successfully underwent video-assisted single port thoracoscopic right upper lobectomy and lymphadenectomy. Concurrent chemotherapy and radiotherapy were applied postoperatively. Perioperative targeted therapy demonstrated good curative effect in this case, and no recurrence was observed at the clinic 8 months after surgery. In this case, the safety and effectiveness of neoadjuvant crizotinib and subsequent surgery are preliminarily proved. We here intend to investigate the optimal setting of neoadjuvant targeted therapy combined with minimally invasive surgery and postoperative adjuvant therapy, inspire more potential targeted treatment based schedules and to apply these strategies in treating patients with locally advanced mutant-positive non-small cell lung cancer (NSCLC).\n\nKeywords:\n\nNon-small cell lung cancer (NSCLC)\nstage IIIB\nanaplastic lymphoma kinase-positive (ALK-positive)\nneoadjuvant therapy\ncase report\n==== Body\nIntroduction\n\nLocally advanced non-small cell lung cancer (NSCLC) has always been recognized as a highly heterogeneous clinical issue (1). Concurrent chemoradiotherapy and surgery along with chemotherapy or chemoradiotherapy, as the two main treatment modalities, have been offered for patients with locally advanced disease. Although neoadjuvant chemoradiotherapy has been recommended as one of the clinical practices based on current National Comprehensive Cancer Network guidelines, a multimodality regimen for this malignant disease is still heterogeneous, and the prognosis remains unsatisfactory (2). In previous research, neoadjuvant therapy prior to surgical resection has been demonstrated to provide favorable tumor shrinkage and disease-free survival (DFS) for patients with locally advanced NSCLC (3-5).\n\nThe anaplastic lymphoma kinase (ALK) gene rearrangement is one of the significant driver mutations that can be detected in 4% to 6% of NSCLC patients (6). Enormous progress in efficacy and long-term survival has been achieved by applying ALK receptor tyrosine kinase inhibitors (TKIs) in advanced NSCLC (7). Crizotinib, as a typical ALK-TKI drug, was proven to be superior to combined chemotherapy in the first-line setting for advanced ALK-positive NSCLC by the PROFILE 1014 trial (8), with an improved objective response rate (ORR) (74% vs. 45%) and progression-free survival (PFS) (10.9 vs. 7 months). Furthermore, crizotinib has shown a more rapid 6-week response compared to the 12-week response of chemotherapy (9). However, research focusing on applying ALK-targeted treatment in locally advanced NSCLC or neoadjuvant therapy has rarely been reported, and the scant trials and studies that are available are limited in offering reliable evidence due their small sample sizes.\n\nThus, definite conclusions concerning the efficacy and optimal settings of neoadjuvant ALK-TKIs urgently need to be found. Here, we present a patient with stage IIIB ALK-positive NSCLC who obtained significant response to perioperative crizotinib treatment. Clinicopathological features of the patient are described in this article in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-3927).\n\nCase presentation\n\nA 43-year-old female patient was admitted with dry cough and a suspicious right upper lobe mass complicated by obstructive pneumonia. The patient represented maternal history of breast cancer. Personal history was negative for smoking and neoplastic diseases. Contrast-enhanced computed tomography (CT) scan (November 27, 2018) showed a 65.0 mm × 61.5 mm mass and obstructive symptoms, together with multiple enlarged hilar and mediastinal lymph nodes (Figure 1). The significant serum tumor markers included carcinoembryonic antigen (157.25 ng/mL), cancer antigen-125 (81.3 U/mL), and circulating cytokeratin 19 fragments (CYFRA21-1; 19.03 ng/mL). Positron emission tomography-CT (PET-CT) was performed revealing a high level of 18-fluorodeoxyglucose (FDG) uptake in the right upper lobe mass and right upper paratracheal nodes (2R) (Figure 2), which was highly indicative of malignant disease and lymph node (2R) metastasis with no signs of distant metastasis. A CT-guided percutaneous biopsy in the right lung neoplasm was performed. Pathological analysis showed a poorly differentiated adenocarcinoma. Immunohistochemistry revealed positive staining of cytokeratin (CK), CD56, and thyroid transcription factor-1 (TTF-1), and napsin A was partially positive. Gene mutation test was positive for ALK gene rearrangement. The patient was diagnosed with clinical stage IIIB (T3N2M0) pulmonary adenocarcinoma with hilar and mediastinal lymph node metastasis.\n\nFigure 1 Prior to neoadjuvant immunotherapy, computed tomography (CT) images of the chest in November 27, 2018 indicated a 65.0 mm × 61.5 mm mass (★ marked) in the right upper pulmonary lobe, together with enlarged hilar and mediastinal lymph nodes (★ marked).\n\nFigure 2 Positron emission tomography-computed tomography (PET-CT) images confirmed lung cancer in the right upper lobe (6.5 cm × 5.9 cm × 6.2 cm; SUV, 17.8) and mediastinal lymph node (2R) metastasis (1.6 cm; SUV, 10.4).\n\nThe patient preferred surgical treatment, and the primary tumor and involved lymph nodes were technically resectable. With the assessment of upfront multidisciplinary consultation, neoadjuvant crizotinib administration was selected to induce the downstaging and facilitate the subsequent surgical treatment. The patient proceeded to accept neoadjuvant targeted therapy with crizotinib (2×250 mg per day) from December 20, 2018 to March 4, 2019. Side effects were limited to grade 1 hepatic damage and mild edema of the lower limbs. Chest CT scan (March 10, 2019) after treatment showed that the lesion in the right upper lobe had obviously reduced to 29.3 mm × 28.3 mm, while the enlarged hilar and mediastinal lymph nodes had almost disappeared (Figure 3). Partial remission (PR) after neoadjuvant targeted therapy was achieved in the patient.\n\nFigure 3 Computed tomography (CT) scan after crizotinib immunotherapy demonstrating the therapeutic effect as partial remission (PR). Tumor shrinked (A and B) and enlarged lymph nodes almost disappeared (B).\n\nThe patient underwent right upper lobectomy with mediastinal lymph node dissection in single-port video-assisted thoracoscopic surgery, 2 weeks (March 22, 2019) after the last dose. Following an uneventful postoperative course, the patient was discharged on postoperative day 6. Postoperative pathological examination revealed changes of moderately-to-poorly differentiated acinar-predominant adenocarcinoma of the lung after targeted therapy. The resected residual tumor was 35 mm × 35 mm × 32 mm, and the right upper paratracheal (2R), right lower paratracheal (4R), and right interlobar (11R) lymph nodes were involved. Immunohistochemistry examination revealed the following: TTF-1 (+), napsin A (partly +), CD56 (+), and KI-67 (50%+). Postoperative staging was confirmed as ypT2N2M0 (stage IIIA).\n\nGiven his good recovery situation and the risk of recurrence, the patient received adjuvant concurrent chemo- and radiotherapy. Four cycles of pemetrexed (860 mg on day 1, every 4 weeks) and cisplatin (600 mg on day 1, every 4 weeks) were accepted. The postoperative radiotherapy was given at a dose of 1.8 Gy × 28 fx. During the combination therapy, the patient presented grade 1 hepatic damage which was relieved after symptomatic treatment. Treatment was completed by July 2019, and the compliance and tolerance of the patient appeared to be quite high (Figure 4). The patient was last followed up at the clinic 8 months after surgery (December 6, 2019), and no recurrence was observed (Figure 5).\n\nFigure 4 Timeline of diagnosis and treatment.\n\nFigure 5 Comparison of computed tomography (CT) scan after adjuvant chemoradiotherapy indicated no evidence of recurrence during the 8-month follow-up. Imagine of lung window (A) and imagine of vertical window (B).\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nDiscussion and conclusion\n\nSince ALK-TKI treatment was proven superior to chemotherapy for advanced ALK-positive NSCLC (9), the indication of ALK-TKI has tentatively been extended to the neoadjuvant therapy settings. In the case series report by Zhang et al. (4), crizotinib (250 mg twice per day) was administered to 11 patients with ALK-positive locally advanced NSCLC in the neoadjuvant setting. In total, 10 (90.9%) of 11 patients had a partial response, with the remaining patient experiencing stable disease response. Surgery was successfully performed on all patients after perioperative crizotinib, with 2 patients (18.2%) achieving pathologic complete response and 3 (27.3%) experiencing pathological node downstaging. Meanwhile, 6 patients had disease recurrence, and the median DFS time was 10.1 months (range, 5.3–20 months). Another case report showed that a patient with ALK-positive mediastinum-invasive NSCLC achieved radiological major response and pathological partial response after neoadjuvant crizotinib (10), with the DFS lasting 44 months as of publication. Previous trials demonstrate that neoadjuvant administration of crizotinib might be a promising therapy in providing an opportunity for resection and prolonged DFS for locally advanced ALK-positive NSCLC patients. The SAKULA trial was a multicenter single-arm phase II study aimed at assessing the efficacy and safety of neoadjuvant therapy with ceritinib followed by surgery in patients with ALK-positive resectable locally advanced NSCLC, with its preliminary results being reported in the 2019 World Conference on Lung Cancer . The ORR was 100% in the all 7 enrolled patients, and 6 out of 7 patients completed the full cycle of treatment and accepted surgery, with complete (R0) resection being achieved in 5 of them. Among the 7 evaluable patients, 4 patients achieved major pathologic response (57%, 95% CI: 18% to 90%) and 2 patients achieved pathologic complete response. Adverse events occurred in all the patients leading to 7 cases of dose interruption and 5 cases of dose reduction. The results revealed the efficacy of neoadjuvant ceritinib, but the optimal dose arrangement and further observation of safety require continued study.\n\nIn the case presented here, the patient achieved PR and pathological tumor downstaging in response to the neoadjuvant crizotinib, which suggests that locally advanced ALK-positive NSCLC patients may also benefit from minimally invasive surgery after the induction of targeted therapy. The administration of perioperative crizotinib provided a safe and efficacious chance for resection without increasing the difficulty and complications of the surgery. However, the duration of crizotinib therapy is still open to discussion as it concerns its optimal regimen. Considering that the effect of postoperative crizotinib remains unknown, we applied conventional chemotherapy and radiotherapy to achieve a better prognosis. Moreover, since the second-generation ALK inhibitors such as alectinib and brigatinib have been shown to be more effective than crizotinib in advanced NSCLC (11,12), their tentative application in the neoadjuvant setting is expected.\n\nIn conclusion, this is the first report of an ALK-positive stage IIIB NSCLC patient receiving neoadjuvant ALK-TKI treatment and radical minimally invasive surgery. This case demonstrated the safety and efficacy of crizotinib combined with minimally invasive surgery for the adjuvant setting. Further research focusing on neoadjuvant targeted therapy in locally advanced NSCLC can be expected to provide more substantive evidence and clarify the optimal regimen.\n\nAcknowledgments\n\nFunding: None.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nOpen Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-3927\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3927). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Rigas JR Kelly K Current treatment paradigms for locally advanced non-small cell lung cancer. J Thorac Oncol 2007;2 Suppl 2 :S77-85. 10.1097/01.JTO.0000269735.21209.bc 17589303\n2 Yeh J Marrone KA Forde PM Neoadjuvant and consolidation immuno-oncology therapy in stage III non-small cell lung cancer. J Thorac Dis 2018;10 :S451-S459. 10.21037/jtd.2018.01.109 29593890\n3 Forde PM Chaft JE Smith KN Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378 :1976-86. 10.1056/NEJMoa1716078 29658848\n4 Zhang C Li SL Nie Q Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement. J Thorac Oncol 2019;14 :726-31. 10.1016/j.jtho.2018.10.161 30408570\n5 Perez-Gracia JL Sanmamed MF Melero I Neoadjuvant immunotherapy in non-small cell lung cancer: the sooner the better? Transl Lung Cancer Res 2018;7 :S356-S357. 10.21037/tlcr.2018.10.12 30705854\n6 Kwak EL Bang YJ Camidge DR Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363 :1693-703. 10.1056/NEJMoa1006448 20979469\n7 Shaw AT Yeap BY Solomon BJ Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011;12 :1004-12. 10.1016/S1470-2045(11)70232-7 21933749\n8 Solomon BJ Mok T Kim DW First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371 :2167-77. 10.1056/NEJMoa1408440 25470694\n9 Shaw AT Kim DW Nakagawa K Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368 :2385-94. 10.1056/NEJMoa1214886 23724913\n10 Kilickap S Onder S Dizdar O Short-time use of crizotinib as neoadjuvant in ALK-positive non-small cell lung carcinoma can be a chance for resectability. Cancer Chemother Pharmacol 2019;83 :1195-6. 10.1007/s00280-019-03810-9 30863883\n11 Hida T Nokihara H Kondo M Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017;390 :29-39. 10.1016/S0140-6736(17)30565-2 28501140\n12 Camidge DR Kim HR Ahn MJ Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2018;379 :2027-39. 10.1056/NEJMoa1810171 30280657\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2305-5839", "issue": "8(12)", "journal": "Annals of translational medicine", "keywords": "Non-small cell lung cancer (NSCLC); anaplastic lymphoma kinase-positive (ALK-positive); case report; neoadjuvant therapy; stage IIIB", "medline_ta": "Ann Transl Med", "mesh_terms": null, "nlm_unique_id": "101617978", "other_id": null, "pages": "770", "pmc": null, "pmid": "32647695", "pubdate": "2020-06", "publication_types": "D002363:Case Reports", "references": "30863883;29658848;25470694;29593890;30280657;28501140;21933749;20979469;17589303;30408570;30705854;23724913", "title": "Perioperative crizotinib in a patient with stage IIIB ALK-positive non-small cell lung cancer: a case report.", "title_normalized": "perioperative crizotinib in a patient with stage iiib alk positive non small cell lung cancer a case report" }	[ { "companynumb": "CN-ACCORD-207125", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206774", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1, EVERY 4 WEEKS", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201904", "drugstartdateformat": "610", "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CISPLATIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "ON DAY 1, EVERY 4 WEEKS", "drugenddate": "201907", "drugenddateformat": "610", "drugindication": "LUNG ADENOCARCINOMA STAGE III", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201904", "drugstartdateformat": "610", "drugstructuredosagenumb": "860", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED." } ], "patientagegroup": null, "patientonsetage": "43", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Liver injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2019" } }, "primarysource": { "literaturereference": "TIAN Y, HUANG J, LI C, JIANG L, LIN H, LU P ET AL. PERIOPERATIVE CRIZOTINIB IN A PATIENT WITH STAGE IIIB ALK-POSITIVE NON-SMALL CELL LUNG CANCER: A CASE REPORT. ANNALS OF TRANSLATIONAL MEDICINE. 2020?8(12):ARTICLE NUMBER 770. DOI: 10.21037/ATM-20-3927.", "literaturereference_normalized": "perioperative crizotinib in a patient with stage iiib alk positive non small cell lung cancer a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20201105", "receivedate": "20201105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18466894, "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": "BACKGROUND Thrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response. CASE REPORT Three of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib. CONCLUSIONS Avatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.", "affiliations": "Department of Medical Oncology, Gabrail Cancer Center, Canton, OH, USA.;Department of Medical Oncology, Gabrail Cancer Center, Canton, OH, USA.", "authors": "Gabrail\|Nash\|N\|;Smith\|Carrie\|C\|", "chemical_list": "D007191:Indazoles; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013844:Thiazoles; D013876:Thiophenes; D000246:Adenosine Diphosphate Ribose; C533238:avatrombopag; D011065:Poly(ADP-ribose) Polymerases; C545685:niraparib", "country": "United States", "delete": false, "doi": "10.12659/AJCR.927008", "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\n33191394\n10.12659/AJCR.927008\n927008\nArticles\nAvatrombopag Optimizes Response to Niraparib by Managing Thrombocytopenia Associated with Poly-ADP Ribose Polymerase (PARP) Inhibition in Ovarian Cancer and Breast Cancer: A Case Series\nGabrail Nash ABCDEF Smith Carrie AB Department of Medical Oncology, Gabrail Cancer Center, Canton, OH, U.S.A.\nCorresponding Author: Nash Gabrail, 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 \n16 11 2020 \n21 e927008-1 e927008-10\n23 6 2020 18 9 2020 03 10 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Case series\n\nPatients:—\n\nFinal Diagnosis: Breast cancer • ovarian cancer\n\nSymptoms: Thrombocytopenia\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Oncology\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nThrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response.\n\nCase Reports:\nThree of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib.\n\nConclusions:\nAvatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.\n\nMeSH Keywords:\nBreast NeoplasmsOvarian NeoplasmsPoly(ADP-ribose) PolymerasesReceptors, ThrombopoietinThrombocytopenia\n==== Body\nBackground\nBy interfering with DNA repair mechanisms, such as the homologous recombination repair pathway [1,2], poly-ADP ribose polymerase (PARP) inhibitors have been shown to be effective in the maintenance treatment of advanced ovarian cancer [3–8] and in advanced breast cancer with germline BRCA1/2 mutations [9]. Clinical trials of niraparib indicate responses in patients with both germline and somatic BRCA mutations, with a smaller degree of benefit in BRCA-negative homologous recombination deficiency (HRD)-positive patients, and the least benefit in BRCA-negative HRD-negative patients [3,6,10]. Most recently, on April 29, 2020, niraparib was approved for first-line maintenance treatment of ovarian cancer following complete or partial response to platinum-based chemotherapy [10,11]. In an analysis of the NOVA trial, niraparib improved progression-free survival outcomes in a dose-related manner [12]. Moreover, the unique pharmacology of niraparib, including improved blood-brain-barrier penetrance over other PARP inhibitors, has been shown to induce intracranial response in animal models [13].\n\nAlthough niraparib has unique characteristics, its therapeutic efficacy may be limited by adverse events such as thrombocytopenia [14]. The FDA-approved labeling for niraparib advises interruption of niraparib therapy or dose reduction for management of thrombocytopenia, which may compromise efficacy [12,14]. Unfortunately, there are no medications currently approved for management of this potential treatment-limiting adverse event [14]. Although one agent, oprelvekin, was approved for the management of chemotherapy-induced thrombocytopenia, this agent has been discontinued [15]. Based on the mechanism of action of thrombopoietin (TPO) receptor agonists, these agents have the potential to treat thrombocytopenia associated with therapeutic agents for cancer, such as niraparib [16–18].\n\nTPO receptor agonists increase platelet levels by interacting with the TPO receptor on megakaryocytes, the endogenous target of thrombopoietin. Given that TPO receptor agonists increase platelet production, use of these agents may counteract or mitigate PARP-induced thrombocytopenia [16]. Approved TPO receptor agonists are avatrombopag, eltrombopag, and lusutrombopag, all of which are administered orally, as well as romiplostim, which is administered as a subcutaneous injection [17–20]. Unlike eltrombopag, avatrombopag does not require regular monitoring for liver test abnormalities during therapy, which can reduce the complexity of monitoring in highly comorbid patients with cancer receiving maintenance treatment with niraparib. In addition, use of avatrombopag offers flexibility in oral dosing. Unlike eltrombopag, avatrombopag can be taken with polyvalent cations such as calcium, magnesium, and iron [17,18]. As a result, based on its mechanism of action, safety, and flexible dosing, avatrombopag is a rational choice for the prevention and management of thrombocytopenia associated with niraparib therapy.\n\nThis case series reviewed the treatment of 2 patients with breast cancer and 4 patients with ovarian cancer. All patients received niraparib for the maintenance treatment of advanced breast cancer or advanced ovarian cancer in combination with avatrombopag to reduce the risk of thrombocytopenia and improve the dose-intensity of niraparib therapy. By optimizing the dose-intensity of therapy, avatrombopag has the potential to optimize treatment outcomes, consistent with the dose-response relationship observed in multiple clinical trials of niraparib [3,6,10]. In this case series, outcomes were evaluated prospectively over the course of treatment for breast or ovarian cancer in 6 patients.\n\nCase Reports\nCase 1: Breast cancer with brain metastases\nA patient with breast cancer, born in 1977, was diagnosed with ER-positive HER2-negative stage III breast cancer in August 2016. From September 2016 to January 2017, she received 4 cycles of doxorubicin and cyclophosphamide followed by maintenance letrozole from a different provider. By January 2019, she had progressive disease with brain metastases. She received radiosurgery (Gamma Knife®) and subsequently started abemaciclib, which she did not tolerate well. Before presenting in July 2019 for her fourth opinion, she had previously been seen at multiple other centers.\n\nFrom July 2019 to October 2019, she received talazoparib and experienced progressive disease in the brain with no response to therapy. Radiosurgery (Gamma Knife®) was not feasible and she declined whole-brain radiotherapy. The patient was then switched to a different PARP inhibitor, niraparib. Niraparib was chosen based on its ability to cross the blood-brain barrier and favorable results in regression of intracranial tumors in animal models [13]. The patient started treatment with niraparib 300 mg daily in November 2019, with CT-verified response in early January and late February 2020. This response was accompanied by clinical improvement, including successful discontinuation of steroids and absence of reported seizures between December 2019 and March 2020. As of her latest CT scan performed April 16, 2020, this patient has experienced complete intracranial response (Figure 1).\n\nUse of avatrombopag in this patient\nBefore starting therapy with avatrombopag, this patient experienced a dramatic drop in platelet count to 31 000/µL on January 8, 2020, shortly after initiating niraparib 300 mg daily on December 29, 2019. After starting treatment with avatrombopag 20 mg daily, the patient experienced a dramatic increase in platelet counts, which peaked at a supranormal level of 757 000/µL on January 23, 2020. As this patient was extremely responsive to avatrombopag, avatrombopag was held and reinitiated at a lower total weekly dose of 60 mg (20 mg administered on Monday, Wednesday, and Friday each week) starting on February 5, 2020. The patient was able to take niraparib at the maximal dose of 300 mg daily while receiving avatrombopag. Before initiating avatrombopag, niraparib 300 mg daily had previously caused profound thrombocytopenia. After initiating avatrombopag, platelet counts exceeded 250 000/µL on 3 of 5 occasions from February 5, 2020 to March 11, 2020. During this time, the patient received the maximal dose of niraparib (300 mg daily) in combination with avatrombopag 60 mg weekly (Figure 2).\n\nCase 2: Breast cancer with brain metastases\nA female patient born in 1976 was diagnosed with locally advanced estrogen receptor (ER)-positive HER2-negative breast cancer in February 2016. She initially received alternative medicine. In November 2017, she sought conventional medical treatment. She had stage IV disease with liver metastases and pleural effusion and was enrolled in a clinical trial of carboplatin in combination with paclitaxel and a checkpoint inhibitor. On the clinical trial, the patient achieved partial response, until she developed progressive disease in July 2018. She received treatment with fulvestrant, palbociclib, leuprolide, and exemestane from July 2018 until the onset of progressive disease with brain metastases in April 2019. She refused cranial radiotherapy and experienced no response with single-agent doxorubicin. On May 30, 2019, she was started on niraparib and achieved partial response in the brain, liver, and lungs.\n\nUse of avatrombopag in this patient\nFrom May 30, 2019 to March 16, 2020, the patient received weekly dose of niraparib ranging from 200 mg to 2100 mg, co-administered with avatrombopag weekly doses ranging from 140 mg weekly to 280 mg weekly. Of note, following an interruption in niraparib dosing the week of June 15, 2019, there were a total of 3 weeks in which avatrombopag was not administered (the weeks of July 29, 2019, August 26, 2019, and November 25, 2019). The gap in use of avatrombopag during July and August led to subsequent low platelet levels on of 140 000/µL on September 26, 2019 and 148 000/µL on October 21, 2019. These low platelet levels due to a gap in avatrombopag therapy led to 2 additional interruptions in niraparib therapy the weeks of November 25, 2019, and December 26, 2019. Despite the interruption of avatrombopag therapy, use of avatrombopag in this patient aided in escalating the dose of niraparib from 1800 mg weekly to 2000 mg weekly from August 29, 2019 to October 27, 2019. Most recently, the dose of avatrombopag was increased from 140 mg weekly to 280 mg weekly, resulting in a rebound in platelet counts from 48 000/µL on February 25, 2020 to 94 000/µL on March 2, 2020. The increase in avatrombopag dose also enabled escalation of the weekly dose of niraparib from 200 mg weekly to 1400 mg weekly as of March 16, 2020. On August 26, 2019 and on January 8, 2020, CT assessments indicated intracranial partial response (Figure 3). In addition to 2 standard-dose platelet transfusions, continuous administration of avatrombopag for all but 3 weeks during the dose titration helped enable administration of the optimal dose of niraparib in this patient.\n\nCase 3: Ovarian cancer\nA patient with stage IV ovarian cancer, born in 1959, was diagnosed in October 2018. She received carboplatin, paclitaxel, and bevacizumab from November 2018 to February 2019. After experiencing partial response to primary treatment, she received maintenance niraparib therapy. On her last CT scan, January 26, 2020, she was found to have stable disease. Her CA-125 levels indicate response to treatment.\n\nUse of avatrombopag in this patient\nBefore receiving avatrombopag, this patient was initiated on a maximal dose of niraparib of 2100 mg weekly starting on March 18, 2019, which rapidly led to a profound reduction in platelet counts, as low as 36 000/µL. Following 2 interruptions of niraparib therapy the weeks of March 25, 2019 and April 29, 2019, CA-125 levels increased from 33 units/mL to 57 units/mL. When platelet counts had recovered by May 8, 2019, the patient was again initiated on niraparib at a reduced weekly dose of 1400 mg, which gradually increased to 1900 mg weekly by October 15, 2019. Although platelet counts were initially stable during dose escalation, shortly after the dose of niraparib was escalated to 2000 mg weekly on October 19, 2019, the patient’s platelet count dropped below 100 000/µL shortly afterward on October 29, 2019. As a result, the patient was prescribed avatrombopag at a dose of 20 mg daily (140 mg weekly) to stabilize platelet counts. Initiation of avatrombopag enabled further niraparib dose escalation to 2100 mg weekly on December 15, 2019. Notably, the patient’s last platelet count was 219 000/µL on March 17, 2020 on the same dose of niraparib that had previously caused a precipitous decline in platelet counts prior to receiving avatrombopag. Additionally, CA-125 levels in this patient have more than halved since initiating treatment with avatrombopag, falling from 69 units/mL to 32 units/mL. This reduction in CA-125 levels occurred concurrently with dose escalation of niraparib to 2000 mg/week and then 2100 mg/week, which was enabled by concurrent administration of avatrombopag (Figure 4).\n\nCase 4: Ovarian cancer\nA female patient born in 1954 was diagnosed with stage II ovarian cancer concurrent with uterine cancer and fallopian tube cancer in July 2017. She received debulking surgery followed by 6 cycles of carboplatin and docetaxel from August 2017 to December 2017. In August 2019, she developed recurrence in the liver and peritoneum. Following recurrence, from August 2019 to December 2019, she received carboplatin, paclitaxel, and bevacizumab, followed by maintenance therapy with bevacizumab plus niraparib. A recent CT scan indicated stable disease.\n\nUse of avatrombopag in this patient\nIn this patient, administration of avatrombopag 20 mg daily concurrently with initiation of niraparib 300 mg daily may have reduced the severity of platelet count reduction, to 63 000/µL by February 20, 2020. The use of avatrombopag 40 mg daily has enabled the patient to tolerate niraparib 300 mg daily, with a platelet count of 155 000/µL measured on March 19, 2020, 1 week after starting niraparib. CA-125 levels were stable in this patient while using niraparib in combination with avatrombopag.\n\nCase 5: Ovarian cancer\nA female patient born in 1966 was diagnosed with stage III ovarian cancer in October 2018. She received 6 cycles of carboplatin, paclitaxel, and bevacizumab from November 2018 to April 2019 followed by niraparib maintenance therapy. She declined dual maintenance therapy with bevacizumab and niraparib. Her CA-125 levels showed a rise when niraparib maintenance was interrupted, and a subsequent decline when niraparib therapy was reintroduced and the dose was escalated.\n\nUse of avatrombopag in this patient\nBefore starting avatrombopag, the patient experienced 3 episodes of platelet count declines in association with niraparib use from April 2019 to August 2019 (platelet counts were 1000/µL on May 20 and May 28, 2019, 10 000/µL on July 31, 2019, and 65 000/µL on August 28, 2019). After starting avatrombopag at a weekly dose of 140 mg, the patient was able to tolerate an increase in her weekly niraparib dose from 500 mg to 900 mg on December 2, 2019 and a further increase to 1000 mg weekly on March 18, 2020. On February 5, 2019, the dose of avatrombopag increased from 140 mg weekly to 280 mg weekly. Despite continued up-titration in the dose of niraparib, platelet counts continued to rise. CA-125 levels fell from 43 U/mL on February 5, 2020 to 37 U/mL by March 4, 2020 concurrent with continuous use of niraparib and avatrombopag in this patient.\n\nCase 6: Ovarian cancer\nA patient born in 1944 was diagnosed with stage III ovarian cancer in March 2019. From March 2019 to May 2019, she received 4 cycles of carboplatin, paclitaxel, and bevacizumab, followed by debulking surgery in June 2019. Following disease progression, she received 4 cycles of carboplatin and paclitaxel until September 2019, followed by rucaparib maintenance. CA-125 levels in this patient had normalized since surgical intervention and have remained stable throughout treatment. As of March 2020, she was disease-free.\n\nUse of avatrombopag in this patient\nIn this patient, niraparib therapy was initiated at a dose of 700 mg weekly on December 4, 2019, which was gradually increased to 2100 mg weekly by January 7, 2020. With upward dose titration, platelet counts fell from a peak of 199 000/µL on December 11, 2019 to 106 000/µL by December 26, 2019. As a result of this drop in platelet counts, avatrombopag was also initiated on December 26, 2019 at a daily dose of 20 mg (140 mg weekly). As a result of avatrombopag coadministration, the patient experienced an increase in platelet counts to 163 000/µL on January 7, 2020. To support further dose escalation and platelet count stabilization on January 7, 2020, the daily dose of avatrombopag was escalated to 40 mg daily (280 mg weekly) and the niraparib dose was escalated to the maximal dose of 2100 mg weekly. Although 2 troughs in platelet levels occurred despite avatrombopag therapy (47 000/µL on January 29, 2020 and 28 000/µL on March 4, 2020), these troughs were managed through niraparib dose reduction initially to 1400 mg weekly on January 29, 2020, and then to 700 mg weekly by March 11, 2020. Although dose reductions were necessary to maintain platelet counts above 100 000/µL, this patient has been able to continue niraparib therapy, which may not have been possible in the absence of avatrombopag therapy.\n\nResults\nThree of 6 patients were able to sustain treatment with the maximum dose of niraparib (300 mg daily) for at least 3 continuous weeks. Continuous administration of avatrombopag mitigated thrombocytopenia and enabled dose escalation of niraparib to induce CT-confirmed response in 2 patients with breast cancer (cases 1 and 2). Reductions in CA-125 levels were observed in association with niraparib therapy enabled by avatrombopag therapy in 2 of 4 patients with ovarian cancer (cases 3 and 5). The remaining 2 patients had stable CA-125 levels (cases 4 and 6). One of these patients (case 6) has experienced complete response and was disease-free as of March 2020. One patient with breast cancer who experienced profound thrombocytopenia (31 000/µL) on niraparib attained supranormal platelet counts (757 000/µL) within 3 weeks of initiating avatrombopag 20 mg daily and was transitioned to a reduced dose (20 mg 3 times weekly), which enabled continued therapy with niraparib and continued response (Table 1).\n\nDiscussion\nUse of niraparib is limited by potential adverse events, including thrombocytopenia [14], which can lead to dose interruption or treatment discontinuation, which may reduce efficacy [12,14]. With a lack of approved medications for management of thrombocytopenia, there is a need for new therapeutic options [14,15]. As demonstrated in this case series, the TPO receptor agonist avatrombopag can counteract thrombocytopenia by interacting with the TPO receptor on megakaryocytes, the endogenous target of thrombopoietin [16–18]. In this case series of 2 patients with breast cancer and 4 patients with ovarian cancer, concurrent administration of the TPO receptor agonist avatrombopag mitigated thrombocytopenia and enabled both niraparib dose reescalation and improved clinical response.\n\nIn 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. Notably, in 1 patient with metastatic breast cancer, niraparib induced intracranial response, while previous use of talazoparib had not. This observation is confirmatory of preclinical findings with niraparib indicating superior blood-brain-barrier penetrance over other PARP inhibitors [13].\n\nTo reduce the risk of adverse events with niraparib, including thrombocytopenia, the starting dose of niraparib may be adjusted based on baseline bodyweight and platelet count. Specifically, patients with a baseline bodyweight <77 kg or with a baseline platelet count <150 00/µL may receive a reduced starting dose of 200 mg of niraparib daily, rather than a starting dose of 300 mg daily. In the PRIMA trial evaluating niraparib in the first-line maintenance setting of ovarian cancer, this strategy was introduced as a protocol amendment, and was shown to reduce the risk of thrombocytopenia from 52.4% with fixed starting dose niraparib to 33.7% with individualized starting dose niraparib. However, the initial dose adjustment of niraparib does not eliminate the issue of thrombocytopenia, as 14.8% of patients receiving individualized starting dose niraparib in PRIMA experienced thrombocytopenia of grade 3 severity or higher. Based on this case series, the risk of developing treatment-limiting thrombocytopenia may be further reduced through the use of avatrombopag in appropriate patients [19,20].\n\nIn patients with ovarian cancer, prior to avatrombopag initiation, increases in CA-125 levels in association with niraparib dose interruption occurred as a result of suboptimal niraparib dosing in association with thrombocytopenia. Additionally, in 2 patients with ovarian cancer, CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. This result indicates a potential for improved clinical outcomes in association with niraparib dose optimization enabled by avatrombopag therapy. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.\n\nConclusions\nResponses in this small series of patients indicate a role for avatrombopag in optimizing the dose of niraparib in patients receiving maintenance treatment for ovarian cancer and breast cancer. In this case series, the adverse event profile of niraparib did not differ from those noted for avatrombopag in trials supporting its indication for use in immune thrombocytopenia. One potential limitation of this case series is the fact that thrombocytopenia induced by PARP inhibition might not share the same bone marrow suppression effect observed with chemotherapy-induced thrombocytopenia. Avatrombopag should be further investigated in thrombocytopenia induced by niraparib in a trial assessing bone marrow for megakaryocyte count over the course of niraparib therapy. These preliminary results, presented in the form of a case series, demonstrate the need for a large prospective trial to confirm our findings.\n\nEditorial support in the form of manuscript writing, styling, and submission was provided by BioCentric, Inc. (Collingswood, NJ), and funded by Dova Pharmaceuticals (Durham, NC).\n\nDepartment and Institution where work was done\n\nDepartment of Medical Oncology, Gabrail Cancer Center, Canton, OH, U.S.A.\n\nFigure 1. Case 1, change in brain CT scan in a patient with breast cancer and brain metastases.\n\nFigure 2. Case 1, platelet count, niraparib dose, and avatrombopag dose over time.\n\nFigure 3. Case 2, change in brain CT scan in a patient with ovarian cancer.\n\nFigure 4. Case 3, platelet count, niraparib dose, and avatrombopag dose over time.\n\nTable 1. Outcomes in patients receiving avatrombopag to optimize therapeutic outcomes with niraparib therapy in breast cancer and ovarian cancer.\n\n\tTherapeutic doses used\tSustained maximal dose of niraparib* (Y/N)\tBiomarkers confirming clinical response\tKey notes on case\t\nCase 1 (breast cancer with brain metastases)\tAvatrombopag: 0–140 mg/week\nNiraparib: 0–2100 mg/week\tY\tCT-confirmed intracranial response and successful discontinuation of steroids and absence of reported seizures after intracranial response enabled by niraparib and avatrombopag\tUse of niraparib in this patient initially led to profound thrombocytopenia (31,000/µL), which was rapidly transformed to a supranormal platelet count (757,000/µL) when the patient received avatrombopag 20 mg daily. Dosing of avatrombopag 20 mg two to three times weekly (total weekly dose: 40 mg to 60 mg) enabled continued therapy with niraparib and clinical response\t\nCase 2 (breast cancer with brain metastases)\tAvatrombopag: 140–280 mg/week\nNiraparib: 0–2100 mg/week\tN\tCT-confirmed intracranial partial response confirmed on 2 occasions\tContinuous administration of avatrombopag for all but 3 weeks enabled titration to the maximal dose of niraparib, enabling intracranial partial response. Of note, a period when avatrombopag was interrupted led to a reduction in platelet counts in subsequent months\t\nCase 3 (ovarian cancer)\tAvatrombopag: 140 mg/week\nNiraparib: 0–2100 mg/week\tY\tReduction in CA-125 levels in association with treatment with niraparib enabled by avatrombopag therapy\tThe patient has been able to receive the maximal dose of niraparib while receiving avatrombopag. Notably, the maximal dose of niraparib caused profound thrombocytopenia (36,000/µL) when it was administered without avatrombopag. CA-125 levels increased upon niraparib dose interruption and increased upon niraparib dose escalation enabled by avatrombopag therapy\t\nCase 4 (ovarian cancer)\tAvatrombopag: 140–280 mg/week\nNiraparib: 0–2100 mg/week\tY\tCA-125 levels were stable during continued dosing of niraparib and avatrombopag\tUse of avatrombopag enabled the patient to tolerate a maximal dose of niraparib. CA-125 levels were stable during continued dosing of niraparib and avatrombopag\t\nCase 5 (ovarian cancer)\tAvatrombopag: 140–280 mg/week\nNiraparib: 0–2100 mg/week\tN\tDrop in CA-125 levels in association with continued dosing of niraparib and avatrombopag\tUse of avatrombopag enabled the patient to tolerate a weekly dose of 500 mg of niraparib, which was later escalated to 1000 mg of niraparib. A reduction in CA-125 levels was observed with niraparib dose optimization\t\nCase 6 (ovarian cancer)\tAvatrombopag: 0–280 mg/week\nNiraparib: 0–2100 mg/week\tN\tCA-125 levels were stable during continued dosing of niraparib and avatrombopag. The patient experienced complete response and is disease-free as of March 2020\tWhile receiving concurrent avatrombopag, the patient was able to maintain platelet counts above 100,000/µL while on niraparib with some niraparib dose reductions. Avatrombopag therapy enabled this patient to tolerate niraparib, which may not have been possible in the absence of avatrombopag\t\n* Total weekly dose of treatments administered daily;\n\n** defined as 3 or more consecutive weeks receiving niraparib 300 mg daily.\n==== Refs\nReferences:\n1. Sonnenblick A de Azambuja E Azim HA Jr Piccart M An update on PARP inhibitors – moving to the adjuvant setting Nat Rev Clin Oncol 2015 12 1 27 41 25286972 \n2. Weil MK Chen AP PARP inhibitor treatment in ovarian and breast cancer Curr Probl Cancer 2011 35 1 7 50 21300207 \n3. Mirza MR Monk BJ Herrstedt J Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer N Engl J Med 2016 375 22 2154 64 27717299 \n4. González-Martín A Pothuri B Vergote I Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2019 381 25 2391 402 31562799 \n5. Moore K Colombo N Scambia G Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2018 379 26 2495 505 30345884 \n6. Moore KN Secord AA Geller MA Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): A multicentre, open-label, single-arm, phase 2 trial [published correction appears in Lancet Oncol, 2019; 20(5): e242] Lancet Oncol 2019 20 5 636 48 30948273 \n7. Pujade-Lauraine E Ledermann JA Selle F Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol, 2017; 18(9): e510] Lancet Oncol 2017 18 9 1274 84 28754483 \n8. Coleman RL Oza AM Lorusso D Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet, 2017; 390(10106): 1948] Lancet 2017 390 10106 1949 61 28916367 \n9. Litton JK Rugo HS Ettl J Talazoparib in patients with advanced breast cancer and a germline BRCA mutation N Engl J Med 2018 379 8 753 –. doi: 10.1056/NEJMoa1802905 30110579 \n10. González-Martín A Pothuri B Vergote I Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2019 381 25 2391 402 31562799 \n11. FDA FDA approves niraparib for first-line maintenance of advanced ovarian cancer 2020 https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer \n12. Wang J Zhang Z Mirza MR The exposure-response relationship of niraparib in patients with gBRCAmut and non-gBRCAmut: Results from the ENGOT-OV16/NOVA trial ESMO 2017 Congress 9 8–12 2017 Madrid, Spain https://oncologypro.esmo.org/meeting-resources/esmo-2017-congress/The-Exposure-Response-Relationship-of-Niraparib-in-Patients-with-gBRCAmut-and-Non-gBRCAmut-Results-from-the-ENGOT-OV16-NOVA-Trial \n13. Sun K Mikule K Wang Z A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models Oncotarget 2018 9 98 37080 96 30647846 \n14. ZEJULA (niraparib) [package insert] Research Triangle Park, NC GlaxoSmithKline 2020 \n15. FDA FDA Drug Shortages https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Oprelvekin%20(Neumega%C2%AE)%20Lyophilized%20Powder%20for%20Injection%20Rx&st=d&tab=tabs-4 \n16. Zufferey A Kapur R Semple JW Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP) J Clin Med 2017 6 2 16 \n17. DOPTELET (avatrombopag) [package insert] Durham, NC Dova Pharmaceuticals Inc 2019 https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210238s001lbl.pdf \n18. PROMACTA (eltrombopag) [package insert] East Hanover, NJ Novartis Pharmaceuticals Corporation 2018 https://www.accessdata.fda.gov/drug-satfda_docs/label/2018/022291s021lbl.pdf \n19. Berek JS Matulonis UA Peen U Safety and dose modification for patients receiving niraparib Ann Oncol 2018 29 8 1784 92 29767688 \n20. González-Martín A Pothuri B Vergote I Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2019 381 25 2391 402 31562799\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": "D000246:Adenosine Diphosphate Ribose; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D007191:Indazoles; D010051:Ovarian Neoplasms; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D013844:Thiazoles; D013876:Thiophenes; D013921:Thrombocytopenia", "nlm_unique_id": "101489566", "other_id": null, "pages": "e927008", "pmc": null, "pmid": "33191394", "pubdate": "2020-11-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28916367;30948273;27717299;29767688;30345884;21300207;28754483;25286972;30647846;31562799;30110579", "title": 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AVATROMBOPAG OPTIMIZES RESPONSE TO NIRAPARIB BY MANAGING THROMBOCYTOPENIA ASSOCIATED WITH POLY-ADP RIBOSE POLYMERASE (PARP) INHIBITION IN OVARIAN CANCER AND BREAST CANCER: A CASE SERIES. AMERICAN JOURNAL OF CASE REPORTS. 2020?4:3144", "literaturereference_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201203", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573179, "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" }, { "companynumb": "US-TOLMAR, INC.-21US025565", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUBCUTANEOUS INJECTION", "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELIGARD" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to central nervous system", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201904" } }, "primarysource": { "literaturereference": "GABRAIL N., SMITH C.. AVATROMBOPAG OPTIMIZES RESPONSE TO NIRAPARIB BY MANAGING THROMBOCYTOPENIA ASSOCIATED WITH POLY?ADP RIBOSE POLYMERASE (PARP) INHIBITION IN OVARIAN CANCER AND BREAST CANCER: A CASE SERIES. AMERICAN JOURNAL OF CASE REPORTS. 2020?21:1?10", "literaturereference_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210219", "receivedate": "20210219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18916310, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "US-MYLANLABS-2021M1015189", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GABRAIL N, SMITH C. AVATROMBOPAG OPTIMIZES RESPONSE TO NIRAPARIB BY MANAGING THROMBOCYTOPENIA ASSOCIATED WITH POLY?ADP RIBOSE POLYMERASE (PARP) INHIBITION IN OVARIAN CANCER AND BREAST CANCER: A CASE SERIES. AM?J?CASE?REP 2020?21:1?10.", "literaturereference_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210315", "receivedate": "20210315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19009600, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]
{ "abstract": "OBJECTIVE\nWhen we published the diagnostic criteria for \"ictal epileptic headache\" in 2012, we deliberately and consciously chose to adopt restrictive criteria that probably underestimate the phenomenon, rather than spread panic among patients and physicians who are reluctant to accept this entity.\n\n\nMETHODS\nHere we discuss four intriguing clinical cases to highlight why we believe, to this day, that it is necessary to follow these restrictive diagnostic criteria.\n\n\nCONCLUSIONS\nEEG is not recommended as a routine examination for children diagnosed with headache, but it is mandatory and must be carried out promptly in cases of prolonged headache that does not respond to antimigraine drugs, if epilepsy is suspected or has been diagnosed previously. This is not a marginal or irrelevant question because possible isolated, non-motor, ictal manifestations should be taken into account before declaring that an epileptic patient is \"seizure free\" so as to ensure that any decision taken to suspend anticonvulsant therapy is safe.", "affiliations": "Child Neurology, NESMOS Department, Chair of Pediatrics, Faculty of Medicine and Psychology, Sapienza University c/o Sant'Andrea Hospital, Via di Grottarossa, 1035-1039, 00189, Rome, Italy. Electronic address: [email protected].;Department of Pediatrics, University of Perugia, Perugia, Italy.;Neuropsychiatry Ward, Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\", Trieste, Italy.;Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, \"G. Gaslini\" Institute, Genoa, Italy.;Neuropsychiatry Ward, Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\", Trieste, Italy.;Neuropsychiatry Ward, Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\", Trieste, Italy.;Emergency Pediatric Department, \"Bambino Gesù\" Children's Hospital, IRCCS, Rome, Italy.;Child Neurology, NESMOS Department, Chair of Pediatrics, Faculty of Medicine and Psychology, Sapienza University c/o Sant'Andrea Hospital, Via di Grottarossa, 1035-1039, 00189, Rome, Italy.;Neurology Clinic, Department of Neuroscience, Sant'Anna Hospital, Como, Italy.", "authors": "Parisi\|Pasquale\|P\|;Verrotti\|Alberto\|A\|;Costa\|Paola\|P\|;Striano\|Pasquale\|P\|;Zanus\|Caterina\|C\|;Carrozzi\|Marco\|M\|;Raucci\|Umberto\|U\|;Villa\|Maria Pia\|MP\|;Belcastro\|Vincenzo\|V\|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1059-1311", "issue": "31()", "journal": "Seizure", "keywords": "Autonomic seizures; Autonomic status epilepticus; Epilepsy; Headache; Ictal epileptic headache; Migraine; Status migrainosus; Tension-type headache", "medline_ta": "Seizure", "mesh_terms": "D000293:Adolescent; D002648:Child; D003937:Diagnosis, Differential; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006261:Headache; D006801:Humans; D008297:Male", "nlm_unique_id": "9306979", "other_id": null, "pages": "56-63", "pmc": null, "pmid": "26362378", "pubdate": "2015-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Diagnostic criteria currently proposed for \"ictal epileptic headache\": Perspectives on strengths, weaknesses and pitfalls.", "title_normalized": "diagnostic criteria currently proposed for ictal epileptic headache perspectives on strengths weaknesses and pitfalls" }	[ { "companynumb": "IT-JNJFOC-20150918532", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "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": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": "3", "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pallor", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PARISI P, VERROTTI A, COSTA P, STRIANO P, ZANUS C, CARROZZI M, ET AL. DIAGNOSTIC CRITERIA CURRENTLY PROPOSED FOR ^ICTAL EPILEPTIC HEADACHE^: PERSPECTIVES ON STRENGTHS, WEAKNESSES AND PITFALLS. SEIZURE 2015?31:56-63.", "literaturereference_normalized": "diagnostic criteria currently proposed for ictal epileptic headache perspectives on strengths weaknesses and pitfalls", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20151007", "receivedate": "20151007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11604812, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]
{ "abstract": "This study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV).\n\n\n\nWe analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy.\n\n\n\nA total of 141 patients (median age 39 (IQR 33-45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3-3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time.\n\n\n\nPH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV.", "affiliations": "Division of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Department of Medicine, Division of Respirology, University Health Network, Toronto, Ontario, Canada.;Department of Pediatrics, Division of Cardiology, The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.", "authors": "Van De Bruaene\|Alexander\|A\|0000-0002-0469-8640;Toh\|Norihisa\|N\|;Hickey\|Edward J\|EJ\|;Benson\|Lee\|L\|;Horlick\|Eric\|E\|;Granton\|John T\|JT\|;Williams\|William G\|WG\|;Roche\|S Lucy\|SL\|", "chemical_list": "D020097:Natriuretic Peptide, Brain", "country": "England", "delete": false, "doi": "10.1136/heartjnl-2019-314756", "fulltext": null, "fulltext_license": null, "issn_linking": "1355-6037", "issue": "105(19)", "journal": "Heart (British Cardiac Society)", "keywords": "VAD; heart failure; pulmonary hypertension; systemic right ventricle; transposition of the great arteries", "medline_ta": "Heart", "mesh_terms": "D000328:Adult; D006328:Cardiac Catheterization; D004452:Echocardiography; D005260:Female; D016027:Heart Transplantation; D006352:Heart Ventricles; D006353:Heart-Assist Devices; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010101:Oxygen Consumption; D015995:Prevalence; D012189:Retrospective Studies; D014262:Tricuspid Valve Insufficiency; D018487:Ventricular Dysfunction, Left", "nlm_unique_id": "9602087", "other_id": null, "pages": "1471-1478", "pmc": null, "pmid": "31053610", "pubdate": "2019-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pulmonary hypertension in patients with a subaortic right ventricle: prevalence, impact and management.", "title_normalized": "pulmonary hypertension in patients with a subaortic right ventricle prevalence impact and management" }	[ { "companynumb": "BE-MYLANLABS-2020M1059904", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BOSENTAN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "205173", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOSENTAN." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DE BRUAENE A, TOH N, HICKEY EJ, BENSON L, HORLICK E, GRANTON JT, ET AL. PULMONARY HYPERTENSION IN PATIENTS WITH A SUBAORTIC RIGHT VENTRICLE: PREVALENCE, IMPACT AND MANAGEMENT. HEART 2019?105(19):1471-1478.", "literaturereference_normalized": "pulmonary hypertension in patients with a subaortic right ventricle prevalence impact and management", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200630", "receivedate": "20200630", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17964768, "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": "BE-ACTELION-A-CH2020-206730", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BOSENTAN" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021290", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY HYPERTENSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BOSENTAN." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ventricular assist device insertion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN DE BRUAENE A, TOH N, HICKEY EJ, BENSON L, HORLICK E, GRANTON JT, ET AL.. PULMONARY HYPERTENSION IN PATIENTS WITH A SUBAORTIC RIGHT VENTRICLE: PREVALENCE, IMPACT AND MANAGEMENT. HEART. 2019?105(19):1471?1478", "literaturereference_normalized": "pulmonary hypertension in patients with a subaortic right ventricle prevalence impact and management", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20200714", "receivedate": "20200714", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18018562, "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": "Tendon or muscle rupture is a rare complication of statins that could potentially be disabling and result in a significant burden to patients. The co-administration of statin and gemfibrozil should warrant prescribers' awareness of tendon-related complications of statin use, particularly in high-risk populations with poor renal function or musculoskeletal comorbidities.", "affiliations": "Division of Infectious Diseases Mayo Clinic Rochester Minnesota.;BronxCare Health System Bronx New York.;Parkview Medical Center Pueblo Colorado.;BronxCare Health System Bronx New York.;BronxCare Health System Bronx New York.", "authors": "Cano Cevallos\|Edison Jose\|EJ\|https://orcid.org/0000-0002-0154-2544;Shaikh\|Danial Haris\|DH\|;Gonzalez\|Jose\|J\|;Sanchez\|William\|W\|;Patel\|Madanmohan\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2387", "fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2387CCR32387Case ReportCase ReportsTendon rupture associated with concomitant simvastatin and gemfibrozil use: Biological and pharmacokinetic implications CANO CEVALLOS et al.Cano Cevallos Edison Jose https://orcid.org/0000-0002-0154-2544\n1\[email protected] Shaikh Danial Haris \n2\nGonzalez Jose \n3\nSanchez William \n2\nPatel Madanmohan \n2\n\n1 \nDivision of Infectious Diseases\nMayo Clinic\nRochester\nMinnesota\n\n2 \nBronxCare Health System\nBronx\nNew York\n\n3 \nParkview Medical Center\nPueblo\nColorado\n* Correspondence\n\nEdison Jose Cano Cevallos, Division of Infectious Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905.\n\nEmail: [email protected]\n28 8 2019 10 2019 7 10 10.1002/ccr3.v7.101919 1922 07 2 2019 18 7 2019 21 7 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nTendon or muscle rupture is a rare complication of statins that could potentially be disabling and result in a significant burden to patients. The co‐administration of statin and gemfibrozil should warrant prescribers’ awareness of tendon‐related complications of statin use, particularly in high‐risk populations with poor renal function or musculoskeletal comorbidities.\n\nadverse effectsgemfibrozilmuscle rupturestatintendon rupture source-schema-version-number2.0component-idccr32387cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:11.10.2019\n\n\nCano Cevallos \nEJ \n, \nShaikh \nDH \n, \nGonzalez \nJ \n, \nSanchez \nW \n, \nPatel \nM \n. Tendon rupture associated with concomitant simvastatin and gemfibrozil use: Biological and pharmacokinetic implications . Clin Case Rep . 2019 ;7 :1919 –1922 . 10.1002/ccr3.2387 \n\n\n\nWork carried at BronxCare Health System, 1650 Grand Concourse; Bronx, NY 10457. All the authors were affiliated with the above institution at the time the work was performed.\n==== Body\n1 INTRODUCTION\nStatins remain a widely used lipid‐lowering drug class. They have shown a reduction in all‐cause mortality, major vascular events, and revascularizations in people with and without cardiovascular disease.1, 2, 3 Combination with fibrates, such as gemfibrozil and fenofibrate, has shown even greater reductions in total cholesterol, LDL cholesterol, and triglycerides than either type of drug alone; however, this combination therapy is associated with an increased risk of hepatic dysfunction, renal insufficiency, and disorders of the musculoskeletal system.4 Muscle and tendon rupture has been described as a very rare complication of statin therapy, yet has not been reported in association with fibrates. We present a patient with normal kidney function and long‐standing use of simvastatin presenting with spontaneous myotendinous junction rupture of the plantaris muscle after recent initiation of gemfibrozil.\n\n2 CASE HISTORY/EXAMINATION\nA 53‐year‐old female presented to the emergency department complaining of sudden onset right calf pain. Her pain occurred after standing from a sitting position. It was intense, pressure‐like, nonradiating, and worsened by movement. The patient denied any history of direct or indirect trauma. Her medical comorbidities included hypertension, dyslipidemia, anemia, and right rotator cuff tear.\n\nHer home medications included simvastatin 10 mg daily, hydrochlorothiazide, amlodipine, benazepril, naproxen, ferrous sulfate, multivitamins, and calcium supplements. Three weeks ago, she was started on gemfibrozil 600 mg twice a day and had since reported worsening of her right shoulder pain, for which she did not seek medical attention.\n\nOn examination, she was awake, alert, oriented, and vital signs were within normal limits. The right lower extremity was bruised, tender, deformed, and warm in the calf area. Pain on palpation and passive movement was out of proportion to the apparent injury. The surgeon was called for assessment, and his impression was muscle rupture with suspected compartment syndrome due to intense pain and stiffness on examination. Pulses and sensations were preserved distally. Intracompartmental pressure measured on admission was 22 mm Hg, which would improve to <10 mm Hg in the following days.\n\n2.1 Differential diagnosis, investigations, and treatment\nOn laboratory (Table 1), kidney and liver tests were normal, serum creatinine kinase levels were 103, 167, and 180 units/L on days 1, 2, and 4, respectively. Serum aldolase values remained negative. Lipid panel was normal. Ultrasound of right lower extremity was negative for deep vein thrombosis and showed intermuscular hematoma with a possible muscle tear. Magnetic resonance imaging of the right lower extremity (Figures 1 and 2) showed an acute large hematoma within the posteromedial right lower leg, superficial to the soleus muscle and deep to the medial gastrocnemius, deemed secondary to rupture of the myotendinous junction of the plantaris muscle, with an otherwise intact musculature and no fracture.\n\nTable 1 Laboratory results\n\nLaboratory test\tValue\tNormal range\t\nWhite blood cells\t12.0 k/µL\t4.8‐10.8 k/µL\t\nNeutrophiles (%)\t78.6%\t40%‐70%\t\nBUN\t10 mg/dL\t6‐20 mg/dL\t\nSerum creatinine\t0.5 mg/dL\t0.5‐1.5 mg/dL\t\nEstimated GFR\t133 mL/min/1.73m2\n\t51‐120 mL/min/1.73m2\n\t\nC‐reactive protein\t<5 mg/dL\t<5 mg/dL\t\nCreatine kinase\t167 units/L\t20‐200 units/L\t\nAldolase\t4.6 units/L\t<8.1 units/L\t\nAST\t20 units/L\t9‐36 units/L\t\nALT\t15 units/L\t5‐40 units/L\t\nTotal cholesterol\t163 mg/dL\t162‐240 mg/dL\t\nHDL cholesterol\t43 mg/dL\t34‐82 mg/dL\t\nLDL cholesterol\t100 mg/dL\t<160 mg/dL\t\nTriglycerides\t102 mg/dL\t25‐150 mg/dL\t\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen.\n\nJohn Wiley & Sons, LtdFigure 1 Acute hematoma (*) within the posteromedial right lower leg measuring 5.0 × 1.9 cm transversely and approximately 15 cm craniocaudally, lying superficially to the soleus muscle and deep to the medial gastrocnemius, secondary to rupture of the myotendinous junction of the plantaris muscle\n\nFigure 2 Redemonstrated hematoma and mild edema‐like signal (arrow) noted within the medial gastrocnemius muscle adjacent to the hematoma probably representing a partial tear or strain of the medial gastrocnemius; otherwise intact musculature and no fracture\n\nThe patient was provided analgesics and strict limb elevation. A diagnosis of tendon rupture was made and an association to statin and fibrate combination was suspected, necessitating discontinuation of these medications. Pain improved notably in the following days. The orthopedic team deemed surgical intervention as not necessary and recommended evaluation for physical therapy with outpatient follow‐up. Discontinuation of gemfibrozil was ensured at the time of discharge.\n\n2.2 Outcome and follow‐up\nAt the 3‐month follow‐up with her primary care physician, she was able to walk with minimal support, had received 10 weeks of physical therapy and decided not to take any lipid‐lowering therapy but instead start a low‐fat diet and implement lifestyle changes. Her calculated 10‐year ASCVD risk was 2.6%.\n\n3 DISCUSSION\nLipid‐lowering medications can adversely induce myopathy, tendinopathy, and rhabdomyolysis secondary to their inhibitory effect on the conversion of hydroxymethyl glutaryl coenzyme A (HMG‐CoA) to mevalonic acid, a rate‐limiting step in the cholesterol synthesis pathway. This decreases the production of coenzyme Q10, an important element in the electron transport chain, ultimately impairing myocyte energy production. Mitochondrial dysfunction, genetic predisposition, and alterations in gene expression may also play a role in the pathogenic mechanisms.5\n\n\nTendons’ extracellular matrix consists mainly of type 1 collagen which is highly resistant to proteolytic cleavage. Statins promote an imbalance between the synthesis and degradation of matrix metalloproteinases, which can induce microdamage in muscles and tendons alike. They are also known to inhibit tendon cell proliferation, thus having a negative impact on tendon healing.6 Simvastatin use has also been shown to promote apoptosis in fibroblasts of patients with rheumatoid arthritis and induce arrest at the G1/S transition of the cell cycle, further suggesting an association between statin use and tendon disorders.7\n\n\nGemfibrozil is responsible for PPARα activation and is rarely (<1%) associated with myopathy or rhabdomyolysis. Skeletal muscle toxicity has been described in type I muscle fibers in rats and the proposed mechanism might include oxidative stress and tissue damage from elevated peroxisomal and mitochondrial β‐oxidation.8 Gemfibrozil inhibits the metabolism of all statins, including simvastatin, and has shown to increase plasma concentrations of simvastatin acid (the active form of simvastatin) in pharmacokinetic studies.9 Some studies reported an increased risk of muscle toxicity, as high as 1 to 5 percent when statins were co‐administered with Gemfibrozil.10, 11\n\n\nMyopathy secondary to statin use has been described in the presence of normal creatine kinase, as seen in this patient, with microscopic evidence of ragged red fibers, abnormally increased lipid stores and lack of fibers staining for cytochrome oxidase activity.12\n\n\nStudies have implicated atorvastatin as the most commonly involved statin, and diseases such as rheumatoid arthritis, systemic lupus erythematosus, gout, diabetes mellitus, hyperparathyroidism, and chronic kidney disease are inherent risk factors for tendon rupture.\n\nTendinopathy most often occurs within the first year of statin initiation and the Achilles tendon is usually the most frequent site of rupture. A pharmacovigilance study from France reported 30 possible cases of spontaneous tendon rupture attributed to the use of simvastatin.13 As of April 2018, the Food and Drug Administration adverse event reporting system (FAERS) database contained 280 reports of tendon rupture associated with simvastatin therapy, and one case of tendon rupture associated with gemfibrozil, since 1994.14 Despite a considerable number of cases in which simvastatin was involved, cases with concomitant use of fibrates, particularly gemfibrozil, remain unknown.\n\nFenofibrate appears to be safer than gemfibrozil because renal excretion of statins appears to be significantly inhibited by gemfibrozil but not by fenofibrate.15, 16 Meta‐analyses of randomized trials have found no increase in muscle or tendon‐related adverse events in patients taking fenofibrate plus a statin compared with a statin alone.17, 18 Studies have also failed to show an increase in the incidence of myopathy or tendinopathy in patients with combined hyperlipidemia who were prescribed pravastatin plus gemfibrozil.19\n\n\nAlthough myopathy and myositis are common adverse outcomes, tendon rupture remains a seldom reported entity of statin‐gemfibrozil combination use. Even more unusual is that our patient did not possess any comorbidities predisposing to tendon rupture and endured the injury in an uncommon location. This case represents a probable adverse drug reaction (Naranjo score of 7).20 She was on simvastatin therapy for about a year and had only recently been started on gemfibrozil with unchanged liver or kidney function. Her triglyceride level prior to starting gemfibrozil was unknown, however, when she presented to us her level was 102 mg/dL. To our knowledge, this is the first case of tendon rupture associated with gemfibrozil and simvastatin combination use.\n\nIn conclusion, we suggest that prescribers should be aware of the tendon‐related complications of statin use, especially with co‐administration of gemfibrozil, and particularly so in patients with comorbidities that are known to increase the risk. Routine musculoskeletal examination may be beneficial in statin‐treated patients on gemfibrozil, especially during the first year of combination therapy. The use of fenofibrate in patients who require combined therapy with a statin appears safe, whereas pravastatin appears to have little muscle/tendon toxicity when used in combination with gemfibrozil.\n\nCONFLICT OF INTEREST\nNo conflicts of interest have been declared.\n\nAUTHOR CONTRIBUTIONS\nEdison J. Cano: resident who admitted the patient and carried initial assessment and management. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. Danial H. Shaikh: resident who took care of the patient and carried subsequent management. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. Jose A. Gonzalez: resident who took care of the patient and carried subsequent management. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. William Sanchez: resident who carried follow‐up of the patient. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. Madanmohan Patel: attending on file that assessed and managed the patient. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission.\n==== Refs\nREFERENCES\n1 \n\nTaylor \nF \n, \nHuffman \nMD \n, \nMacedo \nAF \n, et al. Statins for the primary prevention of cardiovascular disease . Cochrane Database Syst Rev . 2013 ;1 :CD004816 \n10.1002/14651858.CD004816.pub5 \n\n2 \nCholesterol Treatment Trialists’ (CTT) Collaborators \n, \nMihaylova \nB \n, \nEmberson \nJ \n, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta‐analysis of individual data from 27 randomised trials . Lancet . 2012 ;380 :581 ‐590 .22607822 \n3 \nHeart Protection Study Collaborative Group \n. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high‐risk individuals: a randomised placebo‐controlled trial . Lancet . 2002 ;360 :7 ‐22 .12114036 \n4 \n\nChoi \nHD \n, \nShin \nWG \n, \nLee \nJ‐Y \n, \nKang \nBC \n. Safety and efficacy of fibrate‐statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta‐analysis . Vascul Pharmacol . 2015 ;65–66 :23 ‐30 .\n5 \n\nAuer \nJ \n, \nSinzinger \nH \n, \nFranklin \nB \n, \nBerent \nR \n. Muscle‐ and skeletal‐related side‐effects of statins: tip of the iceberg? \nEur J Prev Cardiol . 2016 ;23 :88 ‐110 .25230981 \n6 \n\nde Oliveira \nLP \n, \nVieira \nCP \n, \nGuerra \nF \n, \nde Almeida \nM \n, \nPimentel \nER \n. Statins induce biochemical changes in the Achilles tendon after chronic treatment . Toxicology . 2013 ;311 :162 ‐168 .23831763 \n7 \n\nYokota \nK \n, \nMiyoshi \nF \n, \nMiyazaki \nT \n, et al. High concentration simvastatin induces apoptosis in fibroblast‐like synoviocytes from patients with rheumatoid arthritis . J Rheumatol . 2008 ;35 :193 ‐200 .18203325 \n8 \n\nBurri \nL \n, \nHege Thoresen \nG \n, \nBerge \nRK \n. The role of PPARα activation in liver and muscle . PPAR Research . 2010 ;2010 :1 ‐11 .\n9 \n\nBackman \nJT \n, \nKyrklund \nC \n, \nKivistö \nKT \n, \nWang \nJS \n, \nNeuvonen \nPJ \n. Plasma concentrations of active simvastatin acid are increased by gemfibrozil . 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Available: https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e-8068-f564c31baa25/sheet/33a0f68e-845c-48e2-bc81-8141c6aaf772/state/analysis.\n15 \n\nPrueksaritanont \nT \n, \nZhao \nJJ \n, \nMa \nB \n, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins . J Pharmacol Exp Ther . 2002 ;301 (3 ):1042 ‐1051 .12023536 \n16 \n\nBallantyne \nCM \n, \nDavidson \nMH \n. Possible differences between fibrates in pharmacokinetic interactions with statins . Arch Intern Med . 2003 ;163 (19 ):2394 .14581261 \n17 \n\nGeng \nQ \n, \nRen \nJ \n, \nChen \nH \n, \nLee \nC \n, \nLiang \nW \n. Adverse events following statin‐fenofibrate therapy versus statin alone: A meta‐analysis of randomized controlled trials . Clin Exp Pharmacol Physiol . 2013 ;40 (3 ):219 ‐226 .23324122 \n18 \n\nGuo \nJ \n, \nMeng \nF \n, \nMa \nN \n, et al. Meta‐analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia . Am J Cardiol . 2012 ;110 :1296 ‐1301 .22840347 \n19 \n\nAthyros \nVG \n, \nPapageorgiou \nAA \n, \nHatzikonstandinou \nHA \n, et al. Safety and efficacy of long‐term statin‐fibrate combinations in patients with refractory familial combined hyperlipidemia . Am J Cardiol . 1997 ;80 (5 ):608 ‐613 .9294990 \n20 \n\nNaranjo \nCA \n, \nBusto \nU \n, \nSellers \nEM \n, et al. A method for estimating the probability of adverse drug reactions [Internet] . Clin Pharmacol Ther . 1981 ;30 (2 ):239 ‐245 .7249508\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2050-0904", "issue": "7(10)", "journal": "Clinical case reports", "keywords": "adverse effects; gemfibrozil; muscle rupture; statin; tendon rupture", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "1919-1922", "pmc": null, "pmid": "31624609", "pubdate": "2019-10", "publication_types": "D002363:Case Reports", "references": "12353945;18203325;10976543;7249508;23440795;22607822;25451563;20847941;23831763;12114036;9468088;18311771;23324122;14581261;25230981;22840347;12023536;2355431;9294990", "title": "Tendon rupture associated with concomitant simvastatin and gemfibrozil use: Biological and pharmacokinetic implications.", "title_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications" }	[ { "companynumb": "US-PFIZER INC-2019394901", 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. DOI: 10.1002/CCR3.2387. 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLINICAL CASE REPORTS. 2019.", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191026", "receivedate": "20190920", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16831875, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "US-AMNEAL PHARMACEUTICALS-2019-AMRX-01894", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMINS" }, 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null, "medicinalproduct": "BENAZEPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "NAPROXEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "AMLODIPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPPLEMENTATION THERAPY", "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": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Compartment syndrome", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Haematoma muscle", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tendon rupture", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANO CEVALLOS EJ, SHAIKH DH, GONZALEZ J, SANCHEZ W, PATEL M. TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLIN CASE REP. 2019?00:1-4", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190916", "receivedate": "20190916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16810275, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-CPL-001315", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": null, "drugadditional": null, "drugadministrationroute": null, 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"drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRON" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMFIBROZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "203266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MG TWICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "DYSLIPIDAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ROTATOR CUFF SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NAPROXEN." }, { "actiondrug": "1", "activesubstance": { 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"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": "HYDROCHLOROTHIAZIDE." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tendon rupture", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CANO CEVALLOS EJ, SHAIKH DH, GONZALEZ J, SANCHEZ W, PATEL M. TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLIN CASE REP. 2019 AUG 28?7(10):1919-1922.", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191026", "receivedate": "20191026", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16963865, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": 1, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-CIPLA LTD.-2019US06291", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MILLIGRAM, DAILY, FROM ABOUT A YEAR", "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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VITAMINS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPPLEMENTATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MULTIVITAMINS [VITAMINS NOS]" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPPLEMENTATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FERROUS SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPPLEMENTATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FERROUS SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "AMLODIPINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BENAZEPRIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "BENAZEPRIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMFIBROZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077836", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, BID, 3 WEEKS AGO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMFIBROZIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "NAPROXEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematoma muscle", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Musculoskeletal pain", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tendon rupture", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANO CEVALLOS EJ, SHAIKH DH, GONZALEZ J, SANCHEZ W, PATEL M. TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLINICAL CASE REPORTS. 2019. DOI: 10.1002/CCR3.2387.", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191216", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16804833, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]
{ "abstract": "Although patients with cancer and immunosuppression are at a risk of functional hyposplenism, how to detect it promptly remains unclear. Since hyposplenism allows erythrocytes with nuclear remnants (Howell-Jolly bodies [HJBs]) to appear in the peripheral blood, HJB detection by a routine microscopic examination may help identify patients with functional hyposplenism. This prospective study was thus performed to determine the underlying diseases in patients who presented with HJBs. Of 100 consecutive patients presenting with HJBs, 73 had a history of splenectomy. The remaining 27 had hematologic cancer (n = 6, 22%), non-hematologic cancer (n = 8, 30%), hepatic disorders (n = 4, 15%), premature neonates (n = 3, 11%), hemolytic anemia (n = 2, 7%), autoimmune disorders (n = 2, 7%) and miscellaneous diseases (n = 2, 7%), and their prior treatments included chemotherapy (n = 8, 30%), steroids (n = 7, 26%) and molecular-targeted therapy (n = 3, 11%). Among the 27 patients, 22 had computed tomography scans available: 3 (14%) had underlying diseases in the spleen, and the remaining 19 (86%) were all found to have a decreased splenic volume, including 11 (50%) with more than 50% of the ideal value. The present findings suggest that HJB detection identifies patients with potentially functional hyposplenism who should receive appropriate interventional treatment, such as vaccination and prophylactic antibiotics.", "affiliations": "Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Radiology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.;Department of Radiology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.;Department of Clinical Laboratory, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Clinical Laboratory, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan. [email protected].", "authors": "Nakagami\|Yuya\|Y\|;Uchino\|Kaori\|K\|;Okada\|Hiroaki\|H\|;Suzuki\|Kojiro\|K\|;Enomoto\|Megumi\|M\|;Mizuno\|Shohei\|S\|;Yamamoto\|Hidesuke\|H\|;Hanamura\|Ichiro\|I\|;Nakayama\|Takayuki\|T\|;Tani\|Hiroya\|H\|;Takami\|Akiyoshi\|A\|http://orcid.org/0000-0002-1822-9976", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1007/s12185-020-02925-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "112(4)", "journal": "International journal of hematology", "keywords": "Functional hyposplenism; Howell−Jolly body; Peripheral blood smear", "medline_ta": "Int J Hematol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004908:Erythrocyte Inclusions; D004912:Erythrocytes; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013158:Splenic Diseases; D055815:Young Adult", "nlm_unique_id": "9111627", "other_id": null, "pages": "544-552", "pmc": null, "pmid": "32572828", "pubdate": "2020-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Potential role of Howell-Jolly bodies in identifying functional hyposplenism: a prospective single-institute study.", "title_normalized": "potential role of howell jolly bodies in identifying functional hyposplenism a prospective single institute study" }	[ { "companynumb": "JP-BAXTER-2021BAX000778", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "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": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "012142", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADRIAMYCIN" }, { "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": "NON-HODGKIN^S LYMPHOMA", "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": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-HODGKIN^S LYMPHOMA", "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": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyposplenism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Spleen atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAKAGAMI Y, UCHINO K, OKADA H, SUZUKI K, ENOMOTO M, MIZUNO S, YAMAMOTO H, HANAMURA I, NAKAYAMA T, TANI H, TAKAMI A. POTENTIAL ROLE OF HOWELL?JOLLY BODIES IN IDENTIFYING FUNCTIONAL HYPOSPLENISM: A PROSPECTIVE SINGLE?INSTITUTE STUDY. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2020?112(4):544?552.", "literaturereference_normalized": "potential role of howell jolly bodies in identifying functional hyposplenism a prospective single institute study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210128", "receivedate": "20210115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18748958, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" }, { "companynumb": "JP-BAXTER-2021BAX000777", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOXORUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "ADRIAMYCIN" }, { "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": "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": "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": "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": "RITUXIMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "VINCRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "012142", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": null, "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": "ENDOXAN 1G" } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyposplenism", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Spleen atrophy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NAKAGAMI Y, UCHINO K, OKADA H, SUZUKI K, ENOMOTO M, MIZUNO S, YAMAMOTO H, HANAMURA I, NAKAYAMA T, TANI H, TAKAMI A. POTENTIAL ROLE OF HOWELL?JOLLY BODIES IN IDENTIFYING FUNCTIONAL HYPOSPLENISM: A PROSPECTIVE SINGLE?INSTITUTE STUDY. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2020?112(4):544?552.", "literaturereference_normalized": "potential role of howell jolly bodies in identifying functional hyposplenism a prospective single institute study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210128", "receivedate": "20210115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18748956, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" } ]
{ "abstract": "Depression constitutes the most frequent comorbid condition associated with rheumatoid arthritis (RA), with prevalence rates ranging from 14% to 48%. This wide range can be explained by several factors including subtypes of depression considered, instrument of measure (i.e. self-questionnaires versus clinical interview), threshold applied but also the overlap of symptoms between the two conditions. Despite being a frequent comorbid condition in RA, depressive states are repeatedly underdiagnosed and thus, often remain untreated. Consequences are dramatic as conclusive evidence show that depression deleteriously impacts just about all outcomes of RA, including disease activity, arthritis-related complications, level of pain, chance of remission, quality of life and mortality. Importantly, links between depression and RA appear to be bidirectional as if RA patients show increased prevalence of depression. Conversely, patients with depression compared to the general population have higher risk to develop RA. Among the factors explaining this strong association between depression and RA, recent advances have underlined the putative role of models based on the inflammatory hypothesis. Pro-inflammatory cytokines such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-18 are involved in RA pathogenesis, but also in depression. Furthermore, the connections between the central nervous system, the peripheral system and the immune system are now better understood. As a consequence of the strong comorbidity and the aggravate prognostic, the management of patient showing this dual diagnosis should be carefully monitor. The common physiopathology also opens the path to utilization of RA treatment in severe depression or treatment-resistant depression.", "affiliations": "Psychiatry department, University Hospital of Saint Etienne, Saint Etienne, France; INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, PSYR2 Team, Lyon, France.;Rheumatology department, University Hospital of Saint Etienne, Saint Etienne, France; Inserm U1059, Equipe LBTO, Université de Lyon, Saint-Étienne, France. Electronic address: [email protected].", "authors": "Fakra\|Eric\|E\|;Marotte\|Hubert\|H\|", "chemical_list": "D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha", "country": "France", "delete": false, "doi": "10.1016/j.jbspin.2021.105200", "fulltext": null, "fulltext_license": null, "issn_linking": "1297-319X", "issue": "88(5)", "journal": "Joint bone spine", "keywords": "Common characteristics; Depression; Inflammation; Rheumatoid arthritis", "medline_ta": "Joint Bone Spine", "mesh_terms": "D001172:Arthritis, Rheumatoid; D016207:Cytokines; D003863:Depression; D006801:Humans; D011788:Quality of Life; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "100938016", "other_id": null, "pages": "105200", "pmc": null, "pmid": "33932572", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Rheumatoid arthritis and depression.", "title_normalized": "rheumatoid arthritis and depression" }	[ { "companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2020-05197", "fulfillexpeditecriteria": "2", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204132", "drugbatchnumb": "UNKNOWN", "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": "DICLOFENAC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEFLUNOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "LEFLUNOMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "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": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KELLNER H. RHEUMATOID ARTHRITIS AND DEPRESSION. MMW-FORTSCHR-MED. 2009?151(51):49", "literaturereference_normalized": "rheumatoid arthritis and depression", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201013", "receivedate": "20201013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18375370, "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" } ]
{ "abstract": "Infliximab and adalimumab are widely used in the treatment of patients with ulcerative colitis (UC). There are few published data on the treatment persistence of infliximab and adalimumab in patients with UC.\n\n\n\nWe aimed to compare the treatment persistence rates of infliximab versus adalimumab as first- and second-line tumor necrosis factor antagonists (anti-TNF), to identify factors potentially associated with persistence, and to evaluate reasons for withdrawal in UC patients. We performed a retrospective, single-center cohort study of UC patients treated with infliximab or adalimumab for at least 6 months between June 2002 and May 2018.\n\n\n\nThe median (interquartile range [IQR]) duration of follow-up was 5.4 (3.2-8.3) years. For first-line anti-TNF agent, data on 160 patients with UC were analyzed. The mean (SD) duration of persistence was 3.4 (3.5) years and 2.1 (2.0) years in the infliximab and adalimumab subgroups, respectively (P = 0.24). Concomitant use of 5-aminosalicylate was associated with higher persistence of first-line anti-TNF treatment in the overall population (hazard ratio [HR] 0.5; 95% CI, 0.3-0.8; P = 0.002). For second-line anti-TNF agent, data on 43 patients were analyzed. The mean (SD) duration of persistence was 2.0 (1.7) years and 3.2 (3.1) years in the infliximab and adalimumab subgroups, respectively (P = 0.95). No factors were associated with persistence of second-line anti-TNF treatment.\n\n\n\nInfliximab and adalimumab showed similar levels of persistence as first- and second-line anti-TNF treatments. Concomitant use of 5-aminosalicylates was associated with higher persistence of first-line anti-TNF treatment.", "affiliations": "INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.;Clinical Research Support Facility PARC, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;Clinical Research Support Facility PARC, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.;INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.;Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan, Italy.;INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.", "authors": "Pouillon\|Lieven\|L\|;Baumann\|Cédric\|C\|;Rousseau\|Hélène\|H\|;Choukour\|Myriam\|M\|;Andrianjafy\|Charlotte\|C\|;Danese\|Silvio\|S\|;Peyrin-Biroulet\|Laurent\|L\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1093/ibd/izy322", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0998", "issue": "25(5)", "journal": "Inflammatory bowel diseases", "keywords": "adalimumab; clinical experience; infliximab; persistence; ulcerative colitis", "medline_ta": "Inflamm Bowel Dis", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D003093:Colitis, Ulcerative; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies", "nlm_unique_id": "9508162", "other_id": null, "pages": "945-954", "pmc": null, "pmid": "30329067", "pubdate": "2019-04-11", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Treatment Persistence of Infliximab Versus Adalimumab in Ulcerative Colitis: A 16-Year Single-Center Experience.", "title_normalized": "treatment persistence of infliximab versus adalimumab in ulcerative colitis a 16 year single center experience" }	[ { "companynumb": "FR-JNJFOC-20190819563", "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": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BAUMANN C, ROUSSEAU H, CHOUKOUR M, ANDRIANJAFY C, DANESE S, PEYRIN-BIROULET L, POUILLON L. TREATMENT PERSISTENCE OF INFLIXIMAB VERSUS ADALIMUMAB IN ULCERATIVE COLITIS: A 16-YEAR SINGLE-CENTER EXPERIENCE. INFLAMMATORY BOWEL DISEASES. 2019?25 (5):945-954.", "literaturereference_normalized": "treatment persistence of infliximab versus adalimumab in ulcerative colitis a 16 year single center experience", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20190822", "receivedate": "20190822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16729379, "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": "Sublingual buprenorphine/naloxone, a common treatment for opioid dependence, is frequently abused by intravenous injection. Inadvertent intra-arterial injection of buprenorphine/naloxone can produce acute ischemic insult to the hand due to gelatin embolism. Our purpose was to review a series of these patients in order to describe the clinical entity, review the outcomes, and propose a rational treatment algorithm.\n\n\n\nClinical records of all patients evaluated by the hand surgery team between 2011 and 2015 for ischemia of the hand after buprenorphine/naloxone injection were reviewed. Treatment, complications, and amount of tissue loss were recorded. Patients presenting within 48 hours of the injection were treated with intravenous heparin for 5 days, followed by oral aspirin and clopidogrel for 30 days. Those presenting after 48 hours were treated with aspirin and clopidogrel only.\n\n\n\nTen patients presented during the review period. Average follow-up time was 13 weeks. Eight had ischemia of the radial side of the hand, 1 of the ulnar side, and 1 had bilateral ischemia. Three patients were treated with intravenous heparin and 5 with oral agents. Two presented with dry gangrene and did not receive anticoagulation. All patients experienced tissue loss. There was no difference in outcome regardless of treatment.\n\n\n\nWith the increasing use of sublingual buprenorphine/naloxone in opioid dependency, ischemic hand injuries will be seen with greater frequency. Whereas outcomes did not vary with treatment modality in this series, further study is needed to determine the most effective treatment of these injuries.", "affiliations": "1 University of Kentucky, Lexington, USA.;1 University of Kentucky, Lexington, USA.;1 University of Kentucky, Lexington, USA.", "authors": "Wilson\|Ryan M\|RM\|;Elmaraghi\|Shady\|S\|;Rinker\|Brian D\|BD\|", "chemical_list": "D000069479:Buprenorphine, Naloxone Drug Combination; D005343:Fibrinolytic Agents; D009292:Narcotic Antagonists; D010975:Platelet Aggregation Inhibitors; D006493:Heparin; D000077144:Clopidogrel; D001241:Aspirin", "country": "United States", "delete": false, "doi": "10.1177/1558944716672198", "fulltext": null, "fulltext_license": null, "issn_linking": "1558-9447", "issue": "12(5)", "journal": "Hand (New York, N.Y.)", "keywords": "Suboxone; arterial injection; buprenorphine; drug injection; drug use; gangrene; hand; injection injury; ischemia; opioid abuse", "medline_ta": "Hand (N Y)", "mesh_terms": "D000328:Adult; D001241:Aspirin; D000069479:Buprenorphine, Naloxone Drug Combination; D000077144:Clopidogrel; D005260:Female; D005343:Fibrinolytic Agents; D006225:Hand; D006493:Heparin; D006801:Humans; D007269:Injections, Intra-Arterial; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "101264149", "other_id": null, "pages": "507-511", "pmc": null, "pmid": "28832211", "pubdate": "2017-09", "publication_types": "D016428:Journal Article", "references": "24857945;15945530;21466501;21565452;19368419;10432001;26179339;25221984;24680219;20403021;22048730;16284682", "title": "Ischemic Hand Complications From Intra-Arterial Injection of Sublingual Buprenorphine/Naloxone Among Patients With Opioid Dependency.", "title_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency" }	[ { "companynumb": "US-TEVA-2019-US-997368", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838574, "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": "US-OREXO US, INC.-ORE201810-000114", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598684, "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-LANNETT COMPANY, INC.-US-2019LAN000179", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16022874, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000112", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598704, "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-2019-US-997363", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry gangrene", "reactionmeddraversionpt": "21.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838634, "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": "US-MYLANLABS-2019M1000859", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15801537, "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": "US-OREXO US, INC.-ORE201810-000111", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598687, "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-MYLANLABS-2019M1000916", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15803508, "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": "US-TEVA-2019-US-997361", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838508, "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": "US-TEVA-2019-US-997365", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838628, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000181", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023188, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000110", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20181107", "receivedate": "20181107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15595448, "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-LANNETT COMPANY, INC.-US-2019LAN000186", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023598, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000116", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598686, "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-2019-US-997366", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838536, "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": "US-TEVA-2019-US-997364", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838629, "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": "US-OREXO US, INC.-ORE201810-000117", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598679, "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" }, { "companynumb": "US-MYLANLABS-2019M1000911", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry gangrene", "reactionmeddraversionpt": "21.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799849, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "US-MYLANLABS-2019M1000863", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190110", "receivedate": "20190110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15809142, "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": "US-MYLANLABS-2019M1000868", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190114", "receivedate": "20190114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15820422, "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": "US-TEVA-2019-US-997367", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838570, "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": "US-MYLANLABS-2019M1000922", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799950, "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": "US-MYLANLABS-2019M1000914", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15801590, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000183", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000119", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598680, "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-OREXO US, INC.-ORE201810-000113", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598705, "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-MYLANLABS-2019M1000904", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15801535, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000187", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000115", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598685, "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-2019-US-997371", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838571, "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": "US-OREXO US, INC.-ORE201810-000118", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598691, "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-2019-US-997362", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838631, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000184", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023661, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-LANNETT COMPANY, INC.-US-2019LAN000177", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16022621, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-MYLANLABS-2019M1000926", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799943, "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": "US-TEVA-2019-US-997369", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838573, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000180", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023353, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-LANNETT COMPANY, INC.-US-2019LAN000185", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023653, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-LANNETT COMPANY, INC.-US-2019LAN000182", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023833, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-MYLANLABS-2019M1000910", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799853, "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\nPriapism is a common concern in sickle cell disease. With a high frequency of recurrences and serious long-term sequela, a preventative, rather than traditionally reactive approach, needs to be taken in these patients. Reports have shown successful use of sildenafil as a prophylactic treatment but have failed to address adverse outcomes, including vasoocclusive pain crises, of chronic sildenafil therapy in sickle cell patients.\n\n\nOBJECTIVE\nWe wish to draw attention to the potential adverse outcomes of this therapy on the overall state of the patient's disease for consideration in future studies.\n\n\nMETHODS\nWe used sildenafil in a patient suffering from almost daily attacks of priapism.\n\n\nRESULTS\nSildenafil was successful in decreasing the frequency of priapism; however, our patient experienced an increased frequency of vasoocclusive crises, something not previously addressed.\n\n\nCONCLUSIONS\nFuture studies of sildenafil use in sickle cell disease need to assess the global state of the disease, not just the frequency of priapism.", "affiliations": "Florida State University College of Medicine, Tallahassee, FL 32114, USA. [email protected]", "authors": "Lane\|Andrew\|A\|;Deveras\|Ruby\|R\|", "chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate", "country": "Netherlands", "delete": false, "doi": "10.1111/j.1743-6109.2011.02440.x", "fulltext": null, "fulltext_license": null, "issn_linking": "1743-6095", "issue": "8(11)", "journal": "The journal of sexual medicine", "keywords": null, "medline_ta": "J Sex Med", "mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D006801:Humans; D008297:Male; D010410:Penile Erection; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011317:Priapism; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones", "nlm_unique_id": "101230693", "other_id": null, "pages": "3193-5", "pmc": null, "pmid": "21883942", "pubdate": "2011-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Potential risks of chronic sildenafil use for priapism in sickle cell disease.", "title_normalized": "potential risks of chronic sildenafil use for priapism in sickle cell disease" }	[ { "companynumb": "US-PFIZER INC-2011222763", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SILDENAFIL CITRATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "020895", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIAPISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILDENAFIL CITRATE." } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sickle cell anaemia with crisis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LANE, A.. POTENTIAL RISKS OF CHRONIC SILDENAFIL USE FOR PRIAPISM IN SICKLE CELL DISEASE. JOURNAL OF SEXUAL MEDICINE. 2011?8 (11):3193-3195", "literaturereference_normalized": "potential risks of chronic sildenafil use for priapism in sickle cell disease", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201103", "receivedate": "20110929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8161507, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]
{ "abstract": "Malakoplakia (from the Greek malakos, 'soft' and plakos 'plaque') is a granulomatous inflammatory condition, commonly presenting as a plaque in the genitourinary system, but has been shown to affect a wide variety of structures including the skin. Presentation is varied and a high degree of clinical suspicion is needed to make a diagnosis. We report a case of cutaneous malakoplakia presenting as an inguinal swelling in a 48-year-old kidney transplant patient with temporally associated graft dysfunction. New groin swelling in an immunosuppressed patient often prompts investigation centred on a malignant cause. While this is often appropriate, less common infectious and inflammatory causes should be considered. This case highlights the importance of thorough workup and investigation, including histopathology, in immunosuppressed cohorts and acts as a reminder that less common and more complex diagnoses warrant consideration in this group.", "affiliations": "School of Medicine, University of Glasgow, Glasgow, UK.;Department of Pathology, NHS Greater Glasgow and Clyde, Glasgow, UK.;Transplant Unit, NHS Greater Glasgow and Clyde, Glasgow, UK.;Department of Radiology, NHS Greater Glasgow and Clyde, Glasgow, UK.", "authors": "Macdonald\|Ross Andrew\|RA\|http://orcid.org/0000-0001-8655-9435;Moyes\|Colin\|C\|;Clancy\|Marc\|M\|;Douglas\|Peter\|P\|", "chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone", "country": "England", "delete": false, "doi": "10.1136/bcr-2018-227460", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(4)", "journal": "BMJ case reports", "keywords": "infectious diseases; pathology; renal transplantation", "medline_ta": "BMJ Case Rep", "mesh_terms": "D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D003251:Constriction, Pathologic; D003937:Diagnosis, Differential; D004487:Edema; D006119:Groin; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008287:Malacoplakia; D008297:Male; D008875:Middle Aged; D035583:Rare Diseases; D012867:Skin; D012871:Skin Diseases; D016896:Treatment Outcome; D014515:Ureteral Diseases", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31015237", "pubdate": "2019-04-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23793204;1084356;21393896;27935636;11393074;9036125;3570595;8029173;8842176;10084511;7036058;20137752;15753643;8655720;5013466;10901721;20101508;10982022;28566412;10503277;9557790;7770942;26793484;21965504;4130030;200843;25663335", "title": "Cutaneous malakoplakia presenting as a groin swelling and graft failure.", "title_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure" }	[ { "companynumb": "NVSC2019GB015927", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050791", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "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": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "65461", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "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": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hydronephrosis", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Complications of transplanted kidney", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REPORT. 2019?12(4)", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191029", "receivedate": "20191029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16971484, "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": "GB-STRIDES ARCOLAB LIMITED-2019SP010685", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "90055", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "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": "RENAL TRANSPLANT", "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": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "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": "TACROLIMUS" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mass", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P.. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REP. 2019?12(4):E227460", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191107", "receivedate": "20191101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16985136, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-ACCORD-129494", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "202555", "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": "MYCOPHENOLATE MOFETIL/MYCOPHENOLATE SODIUM/MYCOPHENOLIC ACID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "048", "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": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Swelling", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Genitourinary tract infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REPORTS. 2019?12(4):ARTICLE NUMBER E227460. DOI:10.1136/BCR-2018-227460.", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190528", "receivedate": "20190528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16360679, "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": "GB-VELOXIS PHARMACEUTICALS, INC.-2019VELGB1537", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transplant dysfunction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ureteric anastomosis complication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hydronephrosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REP. 2019?12(4):E227460", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190529", "receivedate": "20190529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16365381, "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": "GB-MYLANLABS-2019M1102131", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091248", "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": "MYCOPHENOLIC ACID." }, { "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": "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": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ-CASE-REP 2019?12:NO. 4.", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191031", "receivedate": "20191031", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16978563, "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 report a case of acute hepatic injury and acute renal failure secondary to rhabdomyolysis associated with fluvastatin-gemfibrozil combination therapy for hyperlipidemia.\n\n\nMETHODS\nA 56-year-old woman with a history of hyperlipidemia presented with fatigue, weakness in her lower extremities, and red-colored urine. One month prior, she had started combination therapy of fluvastatin 80 mg/day and gemfibrozil 1200 mg/day. On physical examination, she had a serious loss of motor function in the upper and lower extremities. Her laboratory tests revealed severe liver enzyme elevation and abnormal renal function. Abdominal ultrasound did not show hepatic cholestasis, renal parenchymal abnormality, or obstruction.\n\n\nCONCLUSIONS\nStatins and fibric acid derivatives have complementary effects on mixed hyperlipidemia. However, such combination therapy increases the risk of myopathy, which may result in life-threatening rhabdomyolysis. Several reports have suggested that combination fluvastatin-gemfibrozil therapy is both effective and safe in mixed lipid disorders. In our patient, severe rhabdomyolysis with serious hepatocellular injury was observed one month after the combination antihyperlipidemic therapy was started. Assessment with the Naranjo probability scale determined that an adverse drug reaction was probable. The mechanism of this combined toxicity is difficult to clarify, although in vivo and in vitro studies to date have reported considerable data concerning antihyperlipidemic drug interactions.\n\n\nCONCLUSIONS\nClinicians should carefully consider the risks and benefits of treating dyslipidemia with fluvastatin-gemfibrozil combination therapy.", "affiliations": "Nephrology Unit, Hacettepe University School of Medicine, Ankara, Turkey.", "authors": "Akoglu\|Hadim\|H\|;Yilmaz\|Rahmi\|R\|;Kirkpantur\|Alper\|A\|;Arici\|Mustafa\|M\|;Altun\|Bulent\|B\|;Turgan\|Cetin\|C\|", "chemical_list": "D000960:Hypolipidemic Agents", "country": "United States", "delete": false, "doi": "10.1345/aph.1H251", "fulltext": null, "fulltext_license": null, "issn_linking": "1060-0280", "issue": "41(1)", "journal": "The Annals of pharmacotherapy", "keywords": null, "medline_ta": "Ann Pharmacother", "mesh_terms": "D058186:Acute Kidney Injury; D056486:Chemical and Drug Induced Liver Injury; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents; D008107:Liver Diseases; D008875:Middle Aged; D009102:Multiple Organ Failure; D012206:Rhabdomyolysis", "nlm_unique_id": "9203131", "other_id": null, "pages": "143-7", "pmc": null, "pmid": "17148651", "pubdate": "2007-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Combined organ failure with combination antihyperlipidemic treatment: a case of hepatic injury and acute renal failure.", "title_normalized": "combined organ failure with combination antihyperlipidemic treatment a case of hepatic injury and acute renal failure" }	[ { "companynumb": "TR-PFIZER INC-2019227392", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUVASTATIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, DAILY (COMBINATION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUVASTATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMFIBROZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "018422", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG, DAILY (COMBINATION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMFIBROZIL." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatocellular injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AKOGLU, H.. COMBINED ORGAN FAILURE WITH COMBINATION ANTIHYPERLIPIDEMIC TREATMENT: A CASE OF HEPATIC INJURY AND ACUTE RENAL FAILURE. THE ANNALS OF PHARMACOTHERAPY. 2007?41(1):143-147", "literaturereference_normalized": "combined organ failure with combination antihyperlipidemic treatment a case of hepatic injury and acute renal failure", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190530", "receivedate": "20190529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16367871, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" } ]
{ "abstract": "We present the case of a 35-year-old man with thoracic back pain and stiffness, whose only medical history was cystic acne treated with repeated courses of retinoids. His thoracic spine was severely limited in range of movement and was found, on X-ray, to have unilateral hyperostosis typical of diffuse idiopathic skeletal hyperostosis (DISH)--an often asymptomatic condition rarely found in those under 50. Back stiffness in young patients with prolonged retinoid exposure should be investigated.", "affiliations": "Department of Rheumatology, Aintree University Hospital, Liverpool, UK.;Department of Rheumatology, Aintree University Hospital, Liverpool, UK.", "authors": "Zhao\|Sizheng\|S\|http://orcid.org/0000-0002-3558-7353;Goodson\|Nicola J\|NJ\|", "chemical_list": "D000700:Analgesics; D003879:Dermatologic Agents; D015474:Isotretinoin", "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": "D000152:Acne Vulgaris; D000328:Adult; D000700:Analgesics; D001416:Back Pain; D003879:Dermatologic Agents; D003937:Diagnosis, Differential; D004334:Drug Administration Schedule; D006801:Humans; D004057:Hyperostosis, Diffuse Idiopathic Skeletal; D015474:Isotretinoin; D008297:Male; D011859:Radiography; D013904:Thoracic Vertebrae", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26106176", "pubdate": "2015-06-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "18637435;935390;8167624;11368702;2645586;24843807;2970477;11679606;16013982", "title": "Diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne.", "title_normalized": "diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne" }	[ { "companynumb": "GB-AKORN PHARMACEUTICALS-2015AKN00514", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISOTRETINOIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "076485", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOWN-TITRATED TO 20 MG/D", "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": "ISOTRETINOIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISOTRETINOIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "076485", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "4 COURSES AT 500 ?G/KG/DAY FOR 6 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE CYSTIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISOTRETINOIN" } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Exostosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mood altered", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZHAO S, GOODSON NJ. DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS AND ISOTRETINOIN IN CYSTIC ACNE. BMJ CASE REP (DOI: 10.1136/BCR-2015-209775). 2015;ARTICLE NUMBER 209775", "literaturereference_normalized": "diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150922", "receivedate": "20150922", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11537788, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients.\nSeven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated.\nThe histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan.\nDecreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.", "affiliations": "Department of Neurosurgery, Fujita Health University, Japan.;Department of Neurosurgery, Chiba University, Japan.;Department of Neurosurgery, Nara Medical University, Japan.;Department of Neurosurgery, Kanazawa University, Japan.;Department of Neurosurgery, Nakamura Memorial Hospital, Japan.;Department of Neurosurgery, Sainte-Anne Hospital, Paris, France.;Department of Neurosurgery, Keio University School of Medicine, Japan.", "authors": "Muto\|Jun\|J\|;Matsutani\|Tomoo\|T\|;Matsuda\|Ryosuke\|R\|;Kinoshita\|Masashi\|M\|;Oikawa\|Mitsuteru\|M\|;Pallud\|Johan\|J\|0000-0002-1652-9844;Sasaki\|Hikaru\|H\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/nop/npz034", "fulltext": null, "fulltext_license": null, "issn_linking": "2054-2577", "issue": "7(1)", "journal": "Neuro-oncology practice", "keywords": "adverse events; hemodialysis patients; malignant glioma; temozolomide", "medline_ta": "Neurooncol Pract", "mesh_terms": null, "nlm_unique_id": "101640528", "other_id": null, "pages": "111-117", "pmc": null, "pmid": "32025326", "pubdate": "2020-01", "publication_types": "D016428:Journal Article", "references": "21874248;22578793;15756519;20805645;16969025;15758009;7016384;1739631;17929115;19506159", "title": "Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients.", "title_normalized": "temozolomide radiochemotherapy for high grade glioma patients with hemodialysis a case series of 7 patients" }	[ { "companynumb": "JP-ACCORD-172993", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "201528", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 DAYS TMZ (150 MG/M2) EVERY 28-DAY CYCLE, 3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia staphylococcal", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MUTO J, MATSUTANI T, MATSUDA R, KINOSHITA M, OIKAWA M, PALLUD J. ET. AL. TEMOZOLOMIDE RADIOCHEMOTHERAPY FOR HIGH-GRADE GLIOMA PATIENTS WITH HEMODIALYSIS: A CASE SERIES OF 7 PATIENTS. NEUROONCOL PRACT. 2020 JAN?7(1):111-117. 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{ "abstract": "Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib. Patients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected. Results: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R 2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7-16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8-1.6 m) vs. 4.3 m (95% CI: 3.3-5.3 m), p < 0.05]. Conclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.", "affiliations": "Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital and Institute, Beijing, China.;State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.;Department of Oncology, Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, China.;Department of Oncology, Xinqiao Hospital, Chongqing, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital and Institute, Beijing, China.;Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Department of Respiratory Medicine, Guigang City People's Hospital, Guigang, China.;Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China.;Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.;Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China.;Department of Party Affairs, The First Affiliated Hospital of University of South China, Hengyang, China.;Department of Oncology, Xinqiao Hospital, Chongqing, China.;Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China.;Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.;Department of Oncology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.;Department of Respiratory Medicine, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.;Department of Oncology, Haian People's Hospital, Nantong, China.;Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China.;Department of Thoracic Surgery, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China.;Department of Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, China.;Geneplus-Beijing, Beijing, China.;Geneplus-Beijing, Beijing, China.;Geneplus-Beijing, Beijing, China.;Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.", "authors": "Yuan\|Bo\|B\|;Zhao\|Jun\|J\|;Zhou\|Chengzhi\|C\|;Wang\|Xiumei\|X\|;Zhu\|Bo\|B\|;Zhuo\|Minglei\|M\|;Dong\|Xilin\|X\|;Feng\|Jiemei\|J\|;Yi\|Cuihua\|C\|;Yang\|Yunpeng\|Y\|;Zhang\|Hua\|H\|;Zhou\|Wangyan\|W\|;Chen\|Zhengtang\|Z\|;Yang\|Sheng\|S\|;Ai\|Xinghao\|X\|;Chen\|Kehe\|K\|;Cui\|Xuefan\|X\|;Liu\|Difa\|D\|;Shi\|Chunmei\|C\|;Wu\|Wei\|W\|;Zhang\|Yanjun\|Y\|;Chang\|Lianpeng\|L\|;Li\|Jin\|J\|;Chen\|Rongrong\|R\|;Yang\|Shuanying\|S\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fonc.2020.00729", "fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00729\nOncology\nOriginal Research\nCo-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib\nYuan Bo 1† Zhao Jun 2† Zhou Chengzhi 3 Wang Xiumei 4 Zhu Bo 5 Zhuo Minglei 2 Dong Xilin 1 Feng Jiemei 6 Yi Cuihua 7 Yang Yunpeng 8 Zhang Hua 9 Zhou Wangyan 10 Chen Zhengtang 5 Yang Sheng 11 Ai Xinghao 12 Chen Kehe 13 Cui Xuefan 14 Liu Difa 15 Shi Chunmei 11 Wu Wei 16 Zhang Yanjun 17 Chang Lianpeng 18 Li Jin 18 Chen Rongrong 18 Yang Shuanying 1* 1Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China\n2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital and Institute, Beijing, China\n3State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China\n4Department of Oncology, Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, China\n5Department of Oncology, Xinqiao Hospital, Chongqing, China\n6Department of Respiratory Medicine, Guigang City People's Hospital, Guigang, China\n7Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China\n8Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China\n9Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China\n10Department of Party Affairs, The First Affiliated Hospital of University of South China, Hengyang, China\n11Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China\n12Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China\n13Department of Oncology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China\n14Department of Respiratory Medicine, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China\n15Department of Oncology, Haian People's Hospital, Nantong, China\n16Department of Thoracic Surgery, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China\n17Department of Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, China\n18Geneplus-Beijing, Beijing, China\nEdited by: Ye Wang, Qingdao University Medical College, China\n\nReviewed by: Yuxiang Zhao, Biotrans Technology Co. LTD, China; Rossano Lattanzio, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy\n\nCorrespondence: Shuanying Yang [email protected] article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work and share first authorship\n\n\n12 5 2020 \n2020 \n10 72925 12 2019 16 4 2020 Copyright © 2020 Yuan, Zhao, Zhou, Wang, Zhu, Zhuo, Dong, Feng, Yi, Yang, Zhang, Zhou, Chen, Yang, Ai, Chen, Cui, Liu, Shi, Wu, Zhang, Chang, Li, Chen and Yang.2020Yuan, Zhao, Zhou, Wang, Zhu, Zhuo, Dong, Feng, Yi, Yang, Zhang, Zhou, Chen, Yang, Ai, Chen, Cui, Liu, Shi, Wu, Zhang, Chang, Li, Chen and YangThis 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.Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib.\n\nPatients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected.\n\nResults: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7–16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8–1.6 m) vs. 4.3 m (95% CI: 3.3–5.3 m), p < 0.05].\n\nConclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.\n\nnon-small cell lung cancerERBB2 exon 20 insertionco-occurring alterationsafatinibclonality statusNational Natural Science Foundation of China10.13039/501100001809Natural Science Foundation of Shaanxi Province10.13039/501100007128\n==== Body\nIntroduction\nAberrations in human epidermal growth factor receptor 2 (HER-2, ERBB2) have emerged as oncogenic drivers and therapeutic targets in 1–4% of non-small cell lung cancer (NSCLC) and up to 6% of EGFR/KRAS/ALK-negative lung adenocarcinoma (LUAD) (1, 2). Most of ERBB2 mutations is characterized by inframe insertion occurring at exon 20 in the protein kinase domain (3). Prior studies showed that pan-ERBB family inhibitor (afatinib, dacomitinib) (4, 5), ado-trastuzumab (T-DM1) (6) as well as some new agents such as poziotinib (7), pyrotinib (8) may elicit an objective response in patients with ERBB2 exon 20 insertion (ERBB2ex20ins); however, no therapy has been approved as a standard treatment yet.\n\nAfatinib has been demonstrated its suppressive effect on lung cancer cell lines with ERBB2ex20ins in vivo (9). Previous studies also revealed clinical outcomes of afatinib with a 13–19% objective response rate (ORR) and a disease control rate (DCR) around 70% in three separate cohorts (10–12); Nevertheless, there exists profound efficacy heterogeneity on them, such as patients with the same subtype displayed discordant benefits and duration of time.\n\nSeveral prior studies revealed that genetic co-alterations were independent variables associated with unfavorable prognosis of EGFR-TKIs (13, 14). However, because of its low frequency, researches focused on ERBB2ex20ins have generally been limited to insufficient number of cases from single institution and prevent making a broad assessment of co-existing alteration patterns of ERBB2ex20ins, which may reflect its genomic background heterogeneity and contribute to the variable responsiveness to the targeted therapy. Therefore, making a comprehensive analysis of concomitant mutation spectrum of ERBB2ex20ins in a large cohort and correlating its co-mutation status with prognosis are urgently warranted.\n\nMoreover, growing number of studies are paying attention to the clonality heterogeneity of targetable somatic alterations and adapting the cancer-treatment strategy to taking into account how a tumor evolves (15). It seems that therapy targeted clonal (“trunk”) mutations may be more effective than targeted subclonal (“branch”) ones (16, 17). Nevertheless, how the clonality status of driver aberrations modulates the efficacy of therapy is unclear.\n\nUsing the next-generation sequencing (NGS) method, we here described the co-occurring molecular spectrum of ERBB2ex20ins in a cohort of 112 NSCLC patients from 17 hospitals in China. We also compared our spectrum with the western population from Memorial Sloan Kettering Cancer Center (MSKCC) and investigated the impact of co-mutation status on the prognosis of them. Furthermore, we retrospectively assessed the efficacy and tried to identify efficacy predictive factors of afatinib in 18 patients with ERBB2ex20ins.\n\nMaterials and Methods\nPatient Cohort and Clinical Data Collection\nWe retrospectively screened 112 patients (from 17 hospitals) harboring ERBB2ex20ins in a College of American Pathologists (CAP) Laboratory (Geneplus-Beijing, Beijing, People's Republic of China) from July 2016 to December 2018. Samples of tumor tissue, plasma or effusion were analyzed by next-generation sequencing (NGS) assay using two versions (59 or 1,021 cancer-related genes) of capture-based targeted sequencing panel. Gene lists of two versions of sequencing panel are shown in Table S1. The sample type and panel for each patient are shown in Figure 1A. A total of 55 and 57 samples were sequenced using 1,021 or 59-gene panel, respectively. Clinicopathological features were abstracted from the accompanying pathology report submitted by the ordering physician. All patients provided written informed consent for our study. This study was approved by the institutional review board of The Second Affiliated Hospital of Xi'an Jiaotong University and all participating hospital.\n\nFigure 1 (A) Sample types and sequencing panel details of study design. (B) Pie chart visualizing eight specified insertion subtypes combined with insertion site. Multi, multiple alterations; Co-Amp, co-amplification; Co-SNV, co-single nucleotide variant. (C) Top 18 genes in the highest co-occurring frequency with ERBB2 exon 20 insertion (no relation to the total numbers analyzed). Only the genes with concurrent frequency over 5% are shown. The genes included in the 59-gene panel.\n\nThe sequencing data of the Memorial Sloan Kettering Cancer Center (MSKCC) Cohort was downloaded from an open-access database named the Cancer Genome Atlas Database, which is publicly available at http://www.cbioportal.org [MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017)] (18, 19). The data of overall survival (OS) was acquired from the cbioportal website directly. OS was measured from the date when the tumor specimen was collected to the date of death or last follow-up visit (20).\n\nResponse Evaluation\nThe clinical outcomes of 18 patients treated with afatinib were collected by each contributing doctor in charge and pooled for analysis. Patients were administered afatinib depending on their performance status and other comorbidities at a starting dose of 30, 40, or 50 mg daily. Best response evaluation was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1). The progression free survival (PFS) for afatinib treatment was defined as the time from the start of afatinib treatment to the date of disease progression or death.\n\nDNA Extraction\nCirculating DNA and Genomic DNA for genomic testing were isolated from 3 ml of plasma or effusion and FFPE samples, respectively. Peripheral blood lymphocytes (PBL) DNA were extracted for germline reference (Supplemental Online Methods).\n\nTarget Capture and Next-Generation Sequencing\nKAPA Library Preparation Kit (Kapa Biosystems, Wilmington, MA, USA) was applied to prepare Indexed Illumina NGS libraries from peripheral blood lymphocytes (PBL) DNA, and tumor DNA or plasma DNA according to the manufacturer's protocol. Capture probes were designed to cover coding sequences or hot exons of 59 or extended 1,021 genes that are frequently mutated in NSCLC and other common solid tumors (details of sequencing region for each gene are uploaded in Table S1). Libraries were hybridized to custom-designed biotinylated oligonucleotide probes (Integrated DNA Technologies, Iowa, IA, USA). DNA sequencing was performed on the HiSeq 3000 Sequencing System (Illumina, San Diego, CA) with 2 × 101 bp paired-end reads.\n\nSequencing Data Analysis\nTerminal adaptor sequences and low-quality data were removed from the raw data. The BWA (0.7.12-r1039) was employed to align clean reads to the reference human genome (hg19) (21). MuTect2 (3.4-46-gbc02625) and GATK was applied to call single nucleotide variants (SNVs) and small insertions and deletions (Indels), respectively. Somatic copy number variants (CNVs) were identified using CONTRA (2.0.8) (22). Moreover, we employed the NoahCare Tool Kit using NCfilter (software developed by self, version 1.5.0) for fastq data QC, NCbamInfo (version 0.2.0) for alignment QC, NCanno (version 0.1.1) for annotation with multiple databases, and NChot (version 0.1.0) for hotspot region variant review and recall. All final candidate variants were all manually verified using the Integrative Genomics Viewer (IGV) Browser.\n\nClonality Analysis\nThe subclonal architecture of all DNA samples were constructed by PyClone run with 20,000 interactions and default parameters (23). Variants were clustered as previously described (23), briefly, the copy number information of each SNV was used as input for PyClone analysis (24, 25), and the cancer cell fraction (CCF) was inferred. Variants located in the cluster with greatest mean CCF were defined as clonal, the rest were subclonal (23).\n\nStatistical Analysis\nAll statistical analyses were performed using SPSS version 19.0 (SPSS Company, Chicago, IL). Categorical and continuous variables were compared by Fisher's exact test and Kruskal-Wallis H-test, respectively. The Pearson correlation coefficient was applied to assess the linear correlation degree of co-occurring genes' frequency appearing in Our Cohort and MSKCC Cohort. The OS and PFS were estimated using the Kaplan-Meier method and compared with the log-rank test. A multi-variant regression model was calculated for HRs and 95% CIs. All statistical tests were two-sided, and p < 0.05 was defined as statistical significance.\n\nResult\nPatients With ERBB2 exon 20 Insertion\nOne hundred and twelve patients carrying ERBB2ex20ins were screened from July 2016 to December 2018 (Figure 1A). The clinical characteristics for these patients were summarized in Table 1. In all, patients were predominantly in the stage IV (80/112, 72%) and had the histology of adenocarcinoma (68%,76/112). There were slightly more female (54%; 60/112) than male (46%; 52/112), with a median age of 61.5 years (range: 28–87 years).\n\nTable 1 Clinical characteristics of patients with ERBB2 exon 20 insertion in different positions.\n\nCharacteristics\tA775ins (n = 79)\tG776indel (n = 19)\tP780ins (n = 14)\tSum\tP-value\t\nAge at initial diagnosis\t\n Median (range)\t62 (28–83)\t58 (29–87)\t64 (48–83)\t61.5 (28–87)\t0.425\t\n Unknown\t6\t0\t2\t8\t\t\nGender\t\n Female\t39 (49%)\t11(58%)\t10 (71%)\t60 (54%)\t0.287\t\n Male\t40 (51%)\t8 (42%)\t4 (29%)\t52 (46%)\t\t\nHistology\t\n NSCLC NOS\t14 (18%)\t3 (16%)\t1 (7%)\t18 (16%)\tnc\t\n Adenocarcinoma\t55 (70%)\t11(58%)\t10 (72%)\t76 (68%)\t\t\n Squamous carcinoma\t0\t0\t1(7%)\t1(1%)\t\t\n Unknown\t10 (12%)\t5 (26%)\t2 (14%)\t17 (15%)\t\t\nStage\t\n I–III\t15 (19%)\t2 (10%)\t2 (14%)\t19 (16%)\t0.850\t\n IV\t55 (70%)\t14 (74%)\t11 (79%)\t80 (72%)\t\t\n Unknown\t9 (11%)\t3 (16%)\t1 (7%)\t13 (12%)\t\t\nP-values are calculated with Fisher's exact test except for age using the Kruskal-Wallis H-test.\n\nins, insertion; indel, insertion and deletion; NSCLC NOS, non-small cell lung cancer not other specified; nc, not calculate.\n\nTotally, eight specific insertion types of ERBB2ex20ins were identified. Considering the fact that certain studies discussing the efficacy of targeted therapy for ERBB2ex20ins are always based on the different insertion sites, we classified them into three subtypes. The most common subtype was four amino acids insertion at codon 775 (A775ins; 70.5%), followed by insertion combined with deletion occurring at codon 776 (G776indel; 17.0%), and three amino acids insertion at codon 780 (P780ins; 12.5%). Multi-alterations were present in five patients, with two patients harboring concurrent ERBB2 amplification and three patients carrying ERBB2ex20ins with ERBB2 single nucleotide variant (SNV) referring to p.A775_G776insYVMA+ p.R897Q, p.P780_Y781insGSP+ p.G519R, and p.G776delinsAVGC+ p.G776A (Figure 1B).\n\nMoreover, insertion-subtype abundance was not significantly different among the sample types (p = 0.41; Table S2). It indicated that distinct sample type was not biased toward the detection of certain ERBB2 subtype.\n\nCo-occurring Genomic Profile of ERBB2 exon 20 Insertion\nSpectrum of Co-occurring Alterations and Characteristics in Different Insertion Sites\nOn the basis of 59 genes strongly associated with cancer, 80.4% (90/112) of patients had at least one additional alteration, with 48.9% (44/90) of them carrying one and 27.8% (25/90) carrying two. Three or more concomitant alterations were present at the rest of 23.3% (21/90) patients. TP53 was the most frequent gene co-mutant with ERBB2ex20ins, making up 66.1% (74/112) cases, with predominant alteration type of missense mutation (63.5%, 47/74), concentrating on exon 5, 8, 6, 7 (76.7%, 56/74; range: exon 4-exon 11) (Figure S1A, Table S3). The remaining prevalent co-occurring genes were LRP1B (18.2%, 10/55), EPHA5 (9.1%, 5/55), MLL3 (9.1%, 5/55), and RB1 (8.0%; 9/112) (no relation to the total numbers analyzed). FOXA1 appeared in 5.5% (3/55) of patients and became the most common co-mutant gene in the form of amplification (Figure 1C). Putative driver aberrations including EGFR (L858R or 19del), ROS1 fusions, ALK receptor tyrosine kinase gene (ALK) rearrangement, KRAS, BRAF (V600E) were not found in this cohort, probably mutually exclusive from ERBB2ex20ins.\n\nOf the pathway level, we classified the co-mutant genes according to the pathway involved. 86.7% (78/90) of patients, who carried at least one additional mutation, had the co-altered genes enriched in the cell cycle, followed by receptor tyrosine kinase/growth factor signaling (RTK) (15.2%) and DNA damage/repair (8.9%) (Figure 2B). Furthermore, some patients had co-mutant genes involved multiple important pathways simultaneously, while some patients had more than one co-mutant genes involving one single pathway (Table S4).\n\nFigure 2 A comprehensive comparison of the co-occurring profile between our cohort and MSKCC cohort for the frequency of (A) totally matched 28 genes (the genes included in the analysis were matched in both cohorts' panel with the frequency over 5%; the genes labeled are significantly different between the two cohorts). (B) Pathway enriched (Only genes included in 59-gene panel were analyzed; *the pathway significantly different between the two cohorts). RTK, receptor tyrosine kinase/growth factor signaling. (C) Kaplan–Meier curve showing the difference of median overall survival (OS) among patients harboring three different ERBB2 insertion subtypes. (D) Kaplan–Meier curve visualizing the effect of TP53 alteration on OS.\n\nWe also explored the co-occurring alteration feature among A775ins (n = 79), G776indel (n = 19), and P780ins (n = 14). No substantial discrepancy was observed among the three groups at either the co-occurring somatic alterations (only TP53 was included in the analysis) or pathway enriched, the clinical details were as well (Figures S2A,C, Table 1). The location and exon distribution of TP53 mutation were comparable in three insertion-site subtypes (Figures S1B–E); however, when considering TP53 mutation types, there was a tendency that G776indel may be less adept at co-occurring with TP53 missense mutations, with no statistically significant (p = 0.06; Figure S2B).\n\nSpectrum Comparison With the Western Population From the MSKCC Cohort\nNext, we compared our data with the findings previously reported by the MSKCC, which included 1,563 tumor specimens from patients with NSCLC. Totally 30 patients harboring ERBB2ex20ins involved in this cohort.\n\nOverall, both the proportion of three subtypes and the whole molecular co-occurring mutation spectrum (genes that co-altered at a frequency over 5% in each cohort) were similar between the two cohorts (R2 = 0.74, P < 0.01), although the co-mutant frequencies of certain genes were higher in the MSKCC cohort than in ours(Figure 2A, Table S5). Notably, these genes in slightly higher frequency were in the form of copy number variant (CNV) (Figure S2D), and it is probably caused by the low detection rate of CNV due to the mixed plasma samples in our samples.\n\nFor the pathway analysis, the enrichment of each pathway in our cohort was in accord with the MSKCC cohort, with a slightly higher frequency of cell-cycle pathway enriched in MSKCC cohort (36.7 vs. 17.9%, P = 0.044) on account of the higher frequency of CDKN2A alteration (Figure 2B, Table S4).\n\nImpact of Insertional-Site Subtypes and Co-occurring Mutational Status on OS\nBased on the complete overall survival (OS) from the MSKCC cohort, prognosis impact of ERBB2 insertion-site subtypes and genes co-occurring over 5 or more cases in either cohort were evaluated. Statistic descriptive of co-occurring genes included in the analysis were summarized in Figure S3A. There was a trend that patients harboring co-occurring genes enriched in cell-cycle pathway showed a worse survival, with no significantly statistic difference (p = 0.059; Figure S3B). However, worse overall survival was seen in patients with co-mutations in TP53 [median OS:14.5 m (95% CI:12.7–16.3 m) vs. 30.3 m (95% CI: not reached); log-rank test], while OS was not significantly different among three subtypes (p = 0.72, Figures 2C,D).\n\nPrior study revealed TP53 mutation in exons 5, 7, 8, and 9 sharing a better prognosis than other sites in the advanced NSCLC (26). In this regard, we investigate the prognosis value of co-occurring TP53 mutation in exons 5, 7, 8, and 9 and whether they can be even more relevant in a specific subgroup of patients with ERBB2ex20ins mutation (i.e., A775ins, G776indel, and P780ins subgroups) but found negative result (log rank, p = 0.095; Fisher exact test, p = 0.427; Figures S3C,D).\n\nClinical Outcomes of Afatinib for Patients Harboring ERBB2ex20ins\nAfatinib Treatment Efficacy Overview\nThe basic clinical and molecular characteristics of 18 patients treated with afatinib were summarized in Table 2. Nearly all of patients were in the advanced stage and 61.1% (12/18) of patients receiving afatinib as 2 line or more.\n\nTable 2 Clinical and molecular characteristics of patients treated with afatinib.\n\nCharacteristics\tNCB (n = 8)\tDCB (n = 10)\tSum (n = 18)\tP-value\t\nAge at initial diagnosis, years\t\n Median (range)\t56.5 (40–75)\t54 (29–69)\t55.5 (29.75)\t\t\n <65\t5\t9\t14 (77.8%)\t0.28\t\n ≥65\t3\t1\t4 (22.2%)\t\t\nGender\t\n Female\t5\t5\t10 (55.6%)\t0.66\t\n Male\t3\t5\t8 (44.4%)\t\t\nTobacco use\t\n Never\t5\t4\t9 (50.0%)\t0.15\t\n Former or current\t3\t2\t5 (27.8%)\t\t\n Unknown\t0\t4\t4 (22.2%)\t\t\nHistology\t\n Adenocarcinoma\t8\t10\t18 (100.0%)\t\t\nBrain metastasis\t\n Yes\t3\t4\t7 (38.9%)\t0.34\t\n No\t3\t6\t9 (50.0%)\t\t\n NA\t2\t0\t2 (11.1%)\t\t\nTumor stage\t\n IIIa\t1\t0\t1 (5.6%)\tnc\t\n IV\t6\t10\t16 (88.8%)\t\t\n Unknown\t1\t0\t1 (5.6%)\t\t\nNo. line of afatinib treatment\t\n 1\t3\t3\t6 (27.8%)\t1.00\t\n ≥2\t5\t7\t12 (61.1%)\t\t\nERBB2ex20ins subtypes\t\n A775 insertion\t6\t7\t13 (72.2%)\t1.00\t\n G776 indel\t1\t2\t3 (16.7%)\t\t\n P780 insertion\t1\t1\t2 (11.1%)\t\t\nConcurrent TP53 alteration\t\n Yes\t7\t6\t13 (72.2%)\t0.31\t\n No\t1\t4\t5 (27.8%)\t\t\nConcurrent TP53 missense mutation\t\n Yes\t6\t4\t10 (55.6%)\t0.19\t\n No\t2\t6\t8 (44.4%)\t\t\nDCB, durable clinical benefit; NCB, no durable benefit; nc, not calculate.\n\nOf the 18 patients, tumor remission data according to RECIST 1.1 criteria were available for 15 patients. Among them, 5 patients achieved PR (33.3%) and 4 patients achieved SD (26.7%). All PRs were, respectively, observed in 3 separate insertion subtypes, whereas the patients with PD only involved in the subtype of A775ins. The median time on treatment with afatinib was 3.7 months (95% CI: 2.1–5.3 m; range: 0.7–13.4 m). The median duration time for patients responding to afatinib was 4.5 months (95% CI: 3.6–5.4 m; range: 2.5 m−13.4 months). The response details and duration of response (DoR) of afatinib for each patient were showed in Figure 3A. One patient harboring G776delinsVC was treated for afatinib as first-line therapy with PR for over 13.4 months and didn't achieve disease progression until the last follow-up in this study. As for the rest of patients, 3 cases (16.7%) responding to afatinib had a DoR over 6 months.\n\nFigure 3 (A) Swimming plot visualizing the response details for afatinib in each patient (n = 18). (B) Kaplan-Meier comparing PFS for ERBB2ex20ins as clonal or subclonal variant (p-values determined by multi-variant regression analysis and HR with 95% CI are shown). (C) The distribution of ERBB2 clonality status between the DCB group and the NDB group. DCB, durable clinical benefit; NDB, no durable benefit.\n\nImpact of Clonality Status and Co-occurring Mutations of ERBB2ex20ins on Afatinib Treatment Outcome\nFor 18 patients treated with afatinib, we identified 54 somatic SNVs, 4 CNVs and 18 somatic indels in 18 samples, for an average of 4.3 somatic variants per sample. In this regard, we applied method PyClone to evaluate whether the ERBB2ex20ins carried by the patients were clonal or subclonal mutations.\n\nResult revealed that ERBB2ex20ins as subclonal variants was significantly associated with shorter PFS of afatinib [median PFS: 1.2 m (95% CI: 0.8–1.6 m) vs. 4.3 m (95% CI: 3.3–5.3 m), p < 0.01], while co-occurring TP53 mutation and insertion-site subtypes had no significant impact on the efficacy of afatinib. This result remained significant when adjusted for ERBB2 insertion subtypes, TP53 mutation, TP53 missense mutation and no. line of afatinib [HR: 0.025 (0.002–0.41); p = 0.01)] (Figure 3B, Table S6).\n\nNext, we divided the patients into durable clinical benefit (DCB) cohort and no durable benefit (NDB) cohort (The DCB was defined as the patients achieving PR or SD and having the duration of PFS for over 3 months; the NDB referred to the patients having the PFS <3 months). Clinical baseline parameters for two groups of patients are displayed in Table 2 and basically similar among each parameter. The variables including concurrent TP53 mutation and TP53 missense mutation were not significantly different between the two groups (data not show, Fisher's exact test, p > 0.05) except for the ERBB2ex20ins clonality status (Fisher exact test, p < 0.01; Figure 3C).\n\nDynamic Detection and Afatinib Resistance\nTo gain some insight into the potential mechanism upon afatinib resistance, we analyzed two patients conducting NGS at two time points in the course of afatinib treatment. The clinical characteristics and test details for two patients were summarized in Table S7. Both patients were non-smoking female. For the Patient#1, ERBB2 amplification [copy number (CN) = 3.1] occurred in the repeat biopsy sample upon the progression of afatinib. Similarly, the patient#2 also presented the ERBB2 amplification (CN = 2.74) which was undetected in the initial plasma sample after taking afatinib for half of a month, unfortunately, we did not examine the ERBB2 CN status at the time of progression on afatinib. Despite this, it can be speculated that ERBB2 amplification may represent a potential resistance mechanism of afatinib.\n\nDiscussion\nIn this study, we delineate the co-occurring alterations and common pathway involved addicted to ERBB2ex20ins in a representative NSCLC cohort of 112 patients and correlate co-mutation patterns with the prognosis of patients harboring ERBB2ex20ins. Moreover, to our knowledge, we present the first time to examine the impact of clonality status of oncogenic drivers in relation to the efficacy of targeted therapy.\n\nThe recent widespread use of NGS enables us to move researches from concentrating solely on the driver gene to the full view of genomic co-alterations, which may have prognostic implications. To date, somatic mutations in TP53 are the most prevalent co-mutation in EGFR-mutant lung adenocarcinoma (LUAD) with a frequency of 54.6–64.6% and several studies have identified TP53 co-alteration as a negative prognosis marker, with consistently predicting worse clinical outcomes receiving EGFR-TKI therapy (27). In our study, TP53 ranked as the most common accompanying somatic altered gene with a frequency of 66%; this frequency was slightly higher than the previously reported 51.6% (10), possibly due to the fewer proportion of female in our cohort (28). Our results showed that patients had a worse OS when co-occurring mutation in TP53, which is also validated in a previous study (29). Recently, the different prognosis value was recognized in distinct exons and alteration types of TP53 mutation and the results were inconsistent. Exons 5, 7, 8 and 9 were reported to share a better prognosis than other sites (26); it is worth mentioning that the study referred here sought to reveal the prognostic value of TP53 alterations in advanced NSCLC compared to most of studies limited to the early stage or EGFR-mutant background (30, 31). Unfortunately, TP53 mutations in exons 5, 7, 8, and 9 did not produce more favorable prognosis than other sites in the advanced NSCLC patients carrying ERBB2 mutation. Clinicopathological characteristics and treatment status should be well-defined to clearly investigate the prognosis impact of various TP53 exons. Moreover, there is a tendency that G776indel subtype may be less adept at co-occurring with TP53 missense mutations, however, whether this characteristic will have a beneficial effect on the prognosis for them remains to be explored. Interestingly, we found neither the co-mutant frequency of TP53 nor pathway enrichment was significantly different among three insertion subtypes, and the OS was comparable as well. For the clinical practice, we suppose that the co-occurring mutation status may have greater impact on the prognosis for this subset of patients than the insertion subtypes itself. Moving forward, the study highlighted multiple concurrent mutations besides ERBB2 insertion subtypes should be tested prospectively in order to provide better predictions of prognosis for them.\n\nIn order to systematically understand the co-mutation profile of ERBB2ex20ins, we cataloged co-altered genes based on existing biological pathway knowledge and the cell-cycle (86.7%), receptor tyrosine kinase/growth factor signaling (RTK) (15.2%) and DNA Damage/Repair (8.9%) showed predominance among all the involved pathways. Prior study found that cell-cycle and DNA-damage response pathway are involved in leptomeningeal metastasis of NSCLC (32). This finding was somehow inter-correspondent with the likely unfavorable prognosis for the patients with the co-occurring genes enriched in the cell-cycle pathway in our study, although the survival discrepancy was not significant maybe on account of the insufficient follow-up time or limited sub-group sample size. Unfortunately, we cannot collect the detailed metastasis status for each patient; however, for the patients treated with afatinib, we found seven in 16 of patients having brain metastasis. Moreover, a recent retrospective study found patients carrying ERBB2 mutations in lung cancer developed more brain metastases on treatment than patients with KRAS mutations [28 vs. 8%; hazard ratio (HR), 5.2; p < 0.001] and trended more than patients with EGFR mutations [28 vs. 16%; HR, 1.7; p = 0.06; (33)]. These findings may underline the central nervous system (CNS) surveillance practices in patients with ERBB2 alterations and the urgent need for the development of novel HER2-targeted agents with active efficacy in the CNS.\n\nThe co-occurring genomic spectrum of ERBB2ex20ins in our cohort of Chinese people had an overall strong concordance with the MSKCC cohort from the United States (R2 = 0.74, p < 0.01). In a retrospective study collated two cohorts of patients with ERBB2 alteration from the MSKCC and Guangdong General Hospital, they also found great consistency with each other in the aspect of the prevalence and baseline clinical parameters of patients possessing ERBB2 mutation (34). These findings, on the one hand, can be supporting evidence for U.S.-China collaborations in clinical trials to accelerate new drug development for this infrequent mutation; on the one hand, highlight the robustness of our results.\n\nAn important aspect of our study is that we found the clonality status of ERBB2ex20ins was an independent potential indicator for response to afatinib. It is well-known that there exists substantial intratumor heterogeneity and tumor evolves in a trunk-branch model. The “trunk” mutation (clonal mutation) was known as taking place in the early development of cancer and expected to present in every tumor subclone and region, whereas the mutation defined as “branch” would present in a certain fraction of tumor cells and regions (17). Thus, alterations closer to the clonal variant were associated with numerical greater variant allele frequency (VAF). Driver mutations in lung cancer can occur both clonally and subclonally (35). Rachiglio et al. (36) reported that patients harboring EGFR alteration in a lower VAF presented shorter PFS than not, to some extent, this reflecting the clonality status may affect the efficacy of TKIs. These lead us to speculate that other small molecule TKIs in other molecularly defined cohorts may be even more efficacious when targeting the driver mutation as the clonal variants. In this study, however, we should make this result conclusive with caution due to the limited sample size, further exploration in a large cohort named DARWIN trial (Deciphering Anti-tumor Response With intratumor Heterogeneity; Clinical Trials No. NCT02183883) is ongoing (37, 38).\n\nERBB2 amplification has been identified as a resistance mechanism induced upon treatment with erlotinib or gefitinib (39, 40) and was observed in 12% of tumor samples obtained from patients at resistance to EGFR TKI therapy (41); however, its role in afatinib resistance is unclear. Chuang et al. (42) reported a patient carrying ERBB2ex20ins, whose plasma samples were obtained upon progression on her initial chemotherapy, erlotinib and afatinib, and results showed that the ERBB2 copy number (CN) level increased over time. In our study, we also found two patients treated with afatinib acquired ERBB2 CN gain after taking afatinib for half of a month and upon gained resistance; notably, for the first patient, the biopsy from the initial lesion was taken, respectively, before and upon progression on afatinib, which makes the result more reliable. This makes us speculate that the patients carrying combined ERBB2 mutation and amplification may be less benefit from afatinib. Further basic research may explore this hypothesis.\n\nAdmittedly, our study exists several limitations. Firstly, the sequencing panel in the cohort is not uniform, which impeded us making the deep understanding of co-occurring landscape of ERBB2ex20ins, and we can only analyze co-mutant feature of TP53 among the three insertion-site subgroups. Large-panel NGS should be conducted uniformly in further studies when enrolling patients for the research. Another limitation is due to its retrospective nature, a small sample size of the study, selected bias and various imaging intervals are inevitable in the process of assessing the clinical outcomes of afatinib; nonetheless, the ORR and PFS of afatinib treatment was almost correlated well with prior studies. Furthermore, since we used single tumor sample taken at a one-time point in the disease course, we may not verify the true clonality status of each mutation; however, this single-point samples may be more likely to underestimate the true extent of heterogeneity within tumors rather than distinguishing clonal from subclonal variants. Importantly, although multifocal or repeated tumor biopsies is better for tracking the true evolution process of tumor development, single sampling may be easier to achieve in the clinical practice.\n\nIn summary, our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, highlighting the greater impact of the co-mutation patterns than insertion-site subtypes on the prognosis of this group of patients. Furthermore, our clinical outcome data for afatinib confirmed its certain efficacy for patients with ERBB2ex20ins and suggested the clonality status of ERBB2 mutation may be a potential indicator of response to afatinib.\n\nData Availability Statement\nThe original contributions presented in the study are publicly available. This data can be found here: European Variation Archive (EVA) (www.ebi.ac.uk/eva) (PRJEB37583).\n\nEthics Statement\nThe study involving human participants were reviewed and approved by the institutional review board of The Second Affiliated Hospital of Xi'an Jiaotong University and all participating hospitals (including Peking University Cancer Hospital and Institute, The First Affiliated Hospital of Guangzhou Medical University, Inner Mongolia Autonomous Region Cancer Hospital, Xinqiao Hospital, Guigang City People's Hospital, Qilu Hospital of Shandong University, Sun Yat-sen University Cancer Center, Shaanxi Provincial People's Hospital, The First Affiliated Hospital of University of South China, Fujian Medical University Union Hospital, Shanghai Chest Hospital, The People's Hospital of Guangxi Zhuang Autonomous Region, The First Affiliated Hospital with Nanjing Medical University, Haian People's Hospital, The First Hospital Affiliated to AMU (Southwest Hospital), Shaanxi Provincial Cancer Hospital).\n\nAuthor Contributions\nShuY, LC, BY, and JZ designed the study. BY, JZ, JL, and RC contributed to data analysis. BY and JZ prepared the manuscript of the study. CZ, XW, BZ, MZ, XD, JF, CY, YY, HZ, WZ, ZC, SheY, XA, KC, XC, DL, CS, WW, and YZ collected the samples and assembled the clinical data. All authors read and approved the final manuscript.\n\nConflict of Interest\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\nWe thank the Geneplus-Beijing Institute (Beijing, People's Republic of China) for technical support and bioinformatic analysis.\n\nFunding. This study was supported by the National Natural Science Foundation of China (Grant No. 81672300) and the Basic Research Plan of Natural Science of Shaanxi Province (Grant No. 2018ZDXM-SF-042).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.00729/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1. Arcila ME Chaft JE Nafa K Roy-Chowdhuri S Lau C Zaidinski M . Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas\n. Clin Cancer Res . (2012 ) 18 :4910 –8\n. 10.1158/1078-0432.CCR-12-0912 22761469 \n2. Mazieres J Peters S Lepage B Cortot AB Barlesi F Beau-Faller M . Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives\n. J Clin Oncol . 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J Thorac Oncol . (2017 ) 12 :833 –42\n. 10.1016/j.jtho.2017.01.023 \n28167203\n\n", "fulltext_license": "CC BY", "issn_linking": "2234-943X", "issue": "10()", "journal": "Frontiers in oncology", "keywords": "ERBB2 exon 20 insertion; afatinib; clonality status; co-occurring alterations; non-small cell lung cancer", "medline_ta": "Front Oncol", "mesh_terms": null, "nlm_unique_id": "101568867", "other_id": null, "pages": "729", "pmc": null, "pmid": "32477948", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "25584892;26545934;28445112;22461637;24633410;29686424;27075079;30596880;28167203;28838393;22474122;30089598;29106415;25003521;30857358;22761469;19451168;23610105;25877892;26852079;29596544;28481359;31406302;15753357;29068003;30685684;22588877;25899785;24434212;31469421;30096481;29989854;21353324;29030356;26530965;23550210;22956644;27780855;26598547;26899019;30425522", "title": "Co-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib.", "title_normalized": "co occurring alterations of erbb2 exon 20 insertion in non small cell lung cancer nsclc and the potential indicator of response to afatinib" }	[ { "companynumb": "CN-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-028577", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFATINIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILOTRIF" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFATINIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GENE MUTATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILOTRIF" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YANG S, YUAN B, ZHAO J, ZHOU C, WANG X, ZHU B, ET AL. CO-OCCURRING ALTERATIONS OF ERBB2 EXON 20 INSERTION IN NON-SMALL CELL LUNG CANCER (NSCLC) AND THE POTENTIAL INDICATOR OF RESPONSE TO AFATINIB. FRONTIERS IN ONCOLOGY. 2020 MAY 12?10:729.", "literaturereference_normalized": "co occurring alterations of erbb2 exon 20 insertion in non small cell lung cancer nsclc and the potential indicator of response to afatinib", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20200612", "receivedate": "20200612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17887042, "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": "CN-B.I. 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{ "abstract": "Medical assistance in dying (MAID) and similar right-to-die laws are becoming increasingly common in jurisdictions across North America and elsewhere. To be eligible for MAID in Canada, requesters must have a serious illness, intolerable suffering, and a reasonably foreseeable natural death. They must also undergo two assessments to confirm eligibility. Although a growing body of literature now exists to help clinicians understand and support patients around requests for assisted death, a dearth of literature exists on how best to support those patients who are deemed ineligible. Here, we report on a case series of three patients who attempted suicide after being found ineligible for MAID. Two patients were ineligible because they did not appear to have reasonably foreseeable natural death. The third patient was ineligible because of concerns around decisional capacity. All three cases had previous diagnoses of depressive disorders and mild cognitive impairment, and two cases had histories of suicide attempts. In at-risk patients, we speculate that the period surrounding a finding of MAID ineligibility may represent a period of particular vulnerability. Clinicians must be vigilant and prepared for the possibility of heightened risk, including risk of self-harm, after a finding of ineligibility for assisted death.", "affiliations": "Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: [email protected].;Ethics Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.;Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.;Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.", "authors": "Isenberg-Grzeda\|Elie\|E\|;Bean\|Sally\|S\|;Cohen\|Carole\|C\|;Selby\|Debbie\|D\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jpainsymman.2020.02.016", "fulltext": null, "fulltext_license": null, "issn_linking": "0885-3924", "issue": "60(1)", "journal": "Journal of pain and symptom management", "keywords": "Assisted death; attempted suicide; end-of-life care; palliative care; risk assessment; suicide", "medline_ta": "J Pain Symptom Manage", "mesh_terms": "D002170:Canada; D006801:Humans; D012106:Research; D017236:Suicide, Assisted; D013406:Suicide, Attempted", "nlm_unique_id": "8605836", "other_id": null, "pages": "158-163", "pmc": null, "pmid": "32105792", "pubdate": "2020-07", "publication_types": "D016428:Journal Article", "references": null, "title": "Suicide Attempt After Determination of Ineligibility for Assisted Death: A Case Series.", "title_normalized": "suicide attempt after determination of ineligibility for assisted death a case series" }	[ { "companynumb": "CA-PFIZER INC-2020366187", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DILTIAZEM" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "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": "DILTIAZEM." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "OINTMENT", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": 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{ "abstract": "Asparaginase plays an integral role in chemotherapy for acute lymphoblastic leukemia (ALL). We present a 69-year old woman with refractory ALL, who developed asparaginase-induced hepatotoxicity and cholangiopathy after starting intravenous PEG-L-asparaginase-based chemotherapy. The patient was ultimately treated with the combination of L-carnitine and vitamin B complex, resulting in normalization of liver enzymes levels. This case highlights the consideration of PEG-L asparaginase chemotherapy-induced liver steatosis, injury, and cholangiopathy as well as the role of L-carnitine and vitamin B complex as treatment.", "affiliations": "Internal Medicine, University of Minnesota Medical School, Minneapolis, USA.;Division of Gastroenterology, Hepatology, and Nutrition/Transplant Hepatology and Critical Care Medicine, University of Minnesota, Minneapolis, USA.;Gastroenterology and Hepatology, University of Minnesota, Minneapolis, USA.", "authors": "Lee\|Christina\|C\|;Leventhal\|Thomas M\|TM\|;Anugwom\|Chimaobi M\|CM\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.16917", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16917\nInternal Medicine\nGastroenterology\nOncology\nL-Asparaginase-Induced Hepatotoxicity Treated Successfully With L-Carnitine and Vitamin B Infusion\nMuacevic Alexander\nAdler John R\nLee Christina 1\nLeventhal Thomas M 2\nAnugwom Chimaobi M 3\n1 Internal Medicine, University of Minnesota Medical School, Minneapolis, USA\n2 Division of Gastroenterology, Hepatology, and Nutrition/Transplant Hepatology and Critical Care Medicine, University of Minnesota, Minneapolis, USA\n3 Gastroenterology and Hepatology, University of Minnesota, Minneapolis, USA\nChristina Lee [email protected]\n5 8 2021\n8 2021\n13 8 e1691731 7 2021\nCopyright © 2021, Lee et al.\n2021\nLee et al.\nhttps://creativecommons.org/licenses/by/3.0/ 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.\nThis article is available from https://www.cureus.com/articles/64764-l-asparaginase-induced-hepatotoxicity-treated-successfully-with-l-carnitine-and-vitamin-b-infusion\nAsparaginase plays an integral role in chemotherapy for acute lymphoblastic leukemia (ALL). We present a 69-year old woman with refractory ALL, who developed asparaginase-induced hepatotoxicity and cholangiopathy after starting intravenous PEG-L-asparaginase-based chemotherapy. The patient was ultimately treated with the combination of L-carnitine and vitamin B complex, resulting in normalization of liver enzymes levels. This case highlights the consideration of PEG-L asparaginase chemotherapy-induced liver steatosis, injury, and cholangiopathy as well as the role of L-carnitine and vitamin B complex as treatment.\n\nsevere hepatotoxicity\ndrug-induced hepatotoxicity\ncholangiopathy\nacute lymphocytic leukemia\nasparaginase\nl-carnitine\nvitamin b\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nDrug-induced liver injury is a complex and diverse syndrome that has been attributed to a variety of therapeutic and non-therapeutic agents [1]. The toxic effect of cancer chemotherapy on the liver ranges from sub-clinical disease to fatal cases of acute liver failure; and management of these toxicities are largely supportive [1]. Here, we describe a case of severe hepatic steatosis and cholangiopathy due to PEG-Asparaginase toxicity, with the resolution of liver injury after discontinuation of PEG-asparaginase use and concomitant treatment with an L-carnitine supplement and vitamin B complex.\n\nCase presentation\n\nA 69-year-old female was seen in hospital consultation for abdominal pain and altered mental status, after being admitted five days prior for a planned chemotherapy treatment.\n\nShe has a medical history of T-cell ALL, diagnosed six months prior to presentation. This diagnosis was made based on biopsies of her submandibular lymph nodes and subsequently, her bone marrow. She had undergone induction chemotherapy with the PETHEMA protocol (vincristine, prednisone, daunorubicin, asparaginase, and cyclophosphamide) two months after diagnosis, followed by Hyper-CVAD therapy (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone, Methotrexate, and Cytarabine) for persistent disease after induction. \n\nA month prior to her hospitalization, a repeat bone marrow biopsy demonstrated low-level but persistent lymphoblastic leukemia. Additional chemotherapies were attempted, but she was unable to tolerate treatment with Vincristine and Nelarabine secondary to adverse side effects, which ultimately lead to the scheduled hospitalization for augmented hyper-CVAD therapy with PEG-asparaginase. \n\nAt the time of evaluation, she reported mild nausea but denied vomiting, diarrhea, fever or chills. With ambient air her oxygen saturation was 98%, she was afebrile, but demonstrated tachycardia and tachypnea. Physical examination also elucidated scleral icterus as well as right upper quadrant and epigastric tenderness. Laboratory tests revealed an aspartate aminotransaminase (AST) of 45 U/L, alanine aminotransaminase (ALT) of 72 U/L, alkaline phosphatase (Alk phos) of 282 U/L and total bilirubin (TB) was 2.0 mg/dL. Lipase was elevated at 1687 U/L; greater than three times the upper limit of normal at our laboratory. She was diagnosed with probable drug-induced pancreatitis and drug-induced cholestatic liver injury. An extensive investigation was carried out to determine any other causes of liver injury and pancreatitis. Serological testing revealed that she was immune to Hepatitis B and Hepatitis A, and negative for Hepatitis C infection. An ultrasound of the abdomen revealed hepatic steatosis, absent gall bladder, and absence of ascites (Figure 1).\n\nFigure 1 Ultrasound of the liver\n\nAbdominal ultrasound showing hepatic steatosis, absence of a gall bladder, and no masses or ascites.\n\nTo further evaluate biliary disease, a magnetic resonance cholangiopancreatography (MRCP) was obtained, which showed interstitial edematous pancreatitis, bilateral pleural effusions, but absent intrahepatic or extrahepatic biliary dilatation or changes concerning for cholangitis (Figure 2).\n\nFigure 2 MRCP\n\nMagnetic resonance cholangiopancreatography (MRCP) with evidence of edematous pancreatitis (white arrows); the common bile duct as seen here is not dilated (white arrow head) and no other biliary abnormalities were noted. \n\nThere was a suspicion of PEG-Asparaginase as the cause of her symptoms and multi-organ injury given the presence of concomitant hepatitis and pancreatitis. Her symptoms of nausea, abdominal pain, and altered mental status improved with a low-fat diet, intravenous fluid resuscitation, and analgesia. She was concomitantly started on L-carnitine supplementation and Vitamin B complex for presumed Asparaginase-induced liver injury. As her liver enzymes and bilirubin continued to increase despite these interventions, a liver biopsy was performed. The pathology revealed severe hepatic steatosis and moderate cholestasis (Figure 3, Figure 4), and mild small duct injury/cholangiopathy (Figure 5); consistent with the limited literature description of histologic characterization of asparaginase hepatotoxicity. \n\nFigure 3 Liver biopsy with hematoxylin and eosin stain (100x)\n\nLiver biopsy with hematoxylin and eosin stain showing diffuse steatosis made up of mixed micro and macro-vesicular steatosis, together affecting up to 70%-75% of the parenchyma. Hepato-canalicular cholestasis also shown by the black arrow.\n\nFigure 4 Liver biopsy with Prussian blue staining (400x)\n\nLiver biopsy with Prussian blue staining (400x) showing significant hemosiderosis (stained bright blue). Bile pigments (cholestasis) also noted in the specimen (stained brown) and marked by black arrows. \n\nFigure 5 Liver biopsy with hematoxylin and eosin stain (400x)\n\nLiver biopsy with hematoxylin and eosin stain (400x) showing diffuse steatosis. Diseased bile duct (cholangiopathy) is demonstrated in this figure with the black arrow. Iron pigments also noted diffusely in the figure, and marked by the black arrowheads.\n\nThere was no evidence of leukemia, nodular regenerative hyperplasia, granulomas or significant fibrosis. Her liver enzymes, alkaline phosphatase, and bilirubin started to show improvement on day 10 of IV L-carnitine and continued toward normalization thereafter (Figure 6, Figure 7).\n\nFigure 6 Serum AST and ALT\n\nSerum aspartate aminotransferase and alanine aminotransferase are seen decreasing through the course of the patient's hospitalization.\n\nFigure 7 Serum alkaline phosphatase and total bilirubin\n\nSerum alkaline phosphatase and total bilirubin are seen decreasing through the course of the patient's hospitalization. \n\nSince discharge, the patient has had a bone marrow biopsy without ALL on morphology but 0.06% abnormal lymphoblasts on flow. In order to maintain remission while working on performance status, the patient was started on maintenance chemotherapy with POMP (6-Mercaptopurine, Vincristine, Methotrexate, Prednisone) and she continues to tolerate her current therapy. She is planning to be a part of a clinical trial with CAR-T (chimeric antigen receptor T cell) immunotherapy, once her performance status improves.\n\nDiscussion\n\nSince its introduction to the field of pediatric oncology in the 1960s, Asparaginase has been an integral part of chemotherapy regimens for treating ALL [2, 3]. It is isolated from pathogenic bacteria and is available as L-asparaginase; and PEG-asparaginase - a pegylated form made by adding a mono-methoxypolyethylene moiety [3]. Leukemic cells cannot synthesize L-asparagine and so depend on extracellular sources. Asparaginase catalyzes the breakdown of asparagine to aspartic acid and ammonia, denying the cancer cells of this vital amino acid [4]. It is not inconceivable that depletion of this extracellular amino acid may have deleterious effects on non-malignant human cells.\n\nThere is a myriad of adverse effects associated with asparaginase, which include varying severities of hypertriglyceridemia, acute pancreatitis, venous thrombosis, hypersensitivity reactions, neurologic dysfunctions as well as hepatotoxicity and bile duct injury [5-7].\n\nHepatotoxicity due to asparaginase use may present itself as a self-limiting mild elevation of liver enzymes and bilirubin and in rare cases, severe liver injury with associated death [8,9]. Although the complete mechanism of action is not clear, a putative mechanism is the depletion of asparagine and possibly arginine, with resultant impairment in protein synthesis and lipoprotein export, diminished mitochondrial beta-oxidation of fatty acids, and consequent rapid free fatty acid accumulation [10]. The macroscopic effect of this disorder of protein and lipid metabolism is severe hepatic steatosis, found in up to 90% of patients, with associated biliary injury and cholestasis as was seen in our patient [11]. The biopsy specimen revealed significant micro-vesicular and macro-vesicular steatosis with cholestasis and cholangiopathy.\n\nSpontaneous resolution of hepatitis will occur in most cases of asparaginase-induced liver injury, and treatment is largely supportive. However, the use of L-carnitine has been studied in the treatment of liver toxicity due to asparaginase, carbon tetrachloride, valproic acid, and arsenic [12-14]. The combination with vitamin B complex, as was used in our patient, has been documented to accelerate improvement and resolution of hepatitis, especially in severe cases. It is suggested that by acting as mitochondrial beta-oxidation cofactors, they augment fatty acid oxidation and reduce the severity of steatosis [14-16].\n\nAdditionally, our patient had a continued rise in her liver enzymes and bilirubin even after a few days of treatment. This delayed improvement in liver injury has been documented in the literature as well [9].\n\nConclusions\n\nWe believe that our patient sustained liver injury due to PEG-Asparaginase use, and this improved overtime after administration of L-carnitine and vitamin B complex. It is important to note, however, that the beneficial effects of the combination of L-carnitine and vitamin B complex infusions have not been studied in a randomized controlled trial and that this may be a normal course of L-asparaginase induced hepatotoxicity, and therefore the resolution of liver injury cannot be fully ascribed to these medications and can only be inferred. It is nevertheless plausible to commence this combination treatment regimen in patients with severe asparaginase-induced liver injury.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Hepatotoxicity of chemotherapy Semin Oncol Floyd J Mirza I Sachs B Perry MC 50 67 33 2006 16473644\n2 Toxic and antineoplastic effects of L-asparaginase. Study of mice with lymphoma and normal monkeys and report on a child with leukemia Cancer Dolowy WC Henson D Cornet J Sellin H 1813 1819 19 1966 4959138\n3 L-asparaginase in the treatment of patients with acute lymphoblastic leukemia J Pharmacol Pharmacother Egler RA Ahuja SP Matloub Y 62 71 7 2016 27440950\n4 Amino acid requirements in vitro of human leukemic cells Cancer Res Onuma T Waligunda J Holland JF 1640 1644 31 1971 https://cancerres-aacrjournals-org.ezp1.lib.umn.edu/content/canres/31/11/1640.full.pdf 5287343\n5 Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open-Cancer Horizons roundtable discussion ESMO Open Burke PW Hoelzer D Park JH Schmiegelow K Douer D 0 5 2020\n6 Tolerability and toxicity of pegaspargase in adults 40 years and older with acute lymphoblastic leukemia Leuk Lymphoma Daley RJ Rajeeve S Kabel CC 176 184 62 2021 32985296\n7 Asparaginase toxicities: identification and management in patients with acute lymphoblastic leukemia Clin J Oncol Nurs Thu Huynh V Bergeron S 0 59 21 2017\n8 Fatal liver failure in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase Digestion Bodmer M Sulz M Stadlmann S Droll A Terracciano L Krähenbühl S 28 32 74 2006 16988508\n9 L-carnitine and vitamin B complex for PEG-L-asparaginase-induced hepatotoxicity ACG Case Rep J Arora S Klair J Bellizzi AM Tanaka T 0 6 2019\n10 Hepatic lipidosis associated with L-asparaginase treatment Proc Soc Exp Biol Med Gross MA Speer RJ Hill JM 733 736 130 1969 5773660\n11 Histopathological features of L-asparaginase-induced liver disease Semin Liver Dis Sahoo S Hart J 295 299 23 2003 14523682\n12 Protective effect of L-carnitine and coenzyme Q10 on CCl₄-induced liver injury in rats Sci Pharm Ali SA Faddah L Abdel-Baky A Bayoumi A 881 896 78 2010 21179323\n13 Acetyl-l-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats Environ Toxicol Pharmacol Bodaghi-Namileh V Sepand MR Omidi A Aghsami M Seyednejad SA Kasirzadeh S Sabzevari O 11 20 58 2018 29278859\n14 Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: a case report and review of the literature J Oncol Pharm Pract Blackman A Boutin A Shimanovsky A Baker WJ Forcello N 393 397 24 2018 28523950\n15 Successful treatment of pegaspargase-induced acute hepatotoxicity with vitamin B complex and L-carnitine Proc (Bayl Univ Med Cent) Lu G Karur V Herrington JD Walker MG 46 47 29 2016 26722167\n16 Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors Leuk Lymphoma Al-Nawakil C Willems L Mauprivez C 1670 1674 55 2014 24090500\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(8)", "journal": "Cureus", "keywords": "acute lymphocytic leukemia; asparaginase; cholangiopathy; drug-induced hepatotoxicity; l-carnitine; severe hepatotoxicity; vitamin b", 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"drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TN UNSPECIFIED" }, { "actiondrug": "5", "activesubstance": null, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "TN UNSPECIFIED" }, { "actiondrug": "5", "activesubstance": null, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "TN UNSPECIFIED" }, { "actiondrug": "5", "activesubstance": null, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "TN UNSPECIFIED" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cholestatic liver injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatic steatosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Biliary tract disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20210101" } }, "primarysource": { "literaturereference": "Lee C, Leventhal TM, Anugwom CM. L-Asparaginase-Induced Hepatotoxicity Treated Successfully With L-Carnitine and Vitamin B Infusion. Cureus. 2021;13:8", "literaturereference_normalized": "l asparaginase induced hepatotoxicity treated successfully with l carnitine and vitamin b infusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211002", "receivedate": "20211002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19909710, "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" } ]
{ "abstract": "BACKGROUND\nSteroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower hypercortisolism in patients with Cushing's syndrome (CS). Cortisol normalization is not reached in all patients taking these medications.\n\n\nOBJECTIVE\nTo test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS.\n\n\nMETHODS\nFifty-four CS patients (46 women; mean [±SD] age, 39.7±12.7; 83% with Cushing's disease [CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms (SNPs) were analysed: rs6410 (CYP11B1 gene), rs1799998 and rs4546 (CYP11B2 gene), and rs6163 (CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated.\n\n\nRESULTS\nNormalization of urinary free cortisol (UFC) was achieved in 50% of patients after 5 months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/AA (OR 0.25 [95%CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range (IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/AC carriers (4 [4.57] months vs 5.2 [6.1] months; P=.026).\n\n\nCONCLUSIONS\nA polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents.", "affiliations": "Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.;Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.", "authors": "Valassi\|Elena\|E\|http://orcid.org/0000-0002-3864-0105;Aulinas\|Anna\|A\|;Glad\|Camilla Am\|CA\|;Johannsson\|Gudmundur\|G\|;Ragnarsson\|Oskar\|O\|;Webb\|Susan M\|SM\|", "chemical_list": "D013256:Steroids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D007654:Ketoconazole; D008797:Metyrapone", "country": "England", "delete": false, "doi": "10.1111/cen.13414", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-0664", "issue": "87(5)", "journal": "Clinical endocrinology", "keywords": "Cushing's syndrome; ketoconazole; metyrapone; polymorphisms", "medline_ta": "Clin Endocrinol (Oxf)", "mesh_terms": "D000328:Adult; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D007654:Ketoconazole; D008297:Male; D008797:Metyrapone; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013254:Steroid 17-alpha-Hydroxylase; D013256:Steroids", "nlm_unique_id": "0346653", "other_id": null, "pages": "433-439", "pmc": null, "pmid": "28665508", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome.", "title_normalized": "a polymorphism in the cyp17a1 gene influences the therapeutic response to steroidogenesis inhibitors in cushing s syndrome" }	[ { "companynumb": "ES-JNJFOC-20171128990", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETOCONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019927", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "48", "drugcumulativedosageunit": "002", "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CUSHING^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETOCONAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METYRAPONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "120", "drugcumulativedosageunit": "002", "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CUSHING^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METYRAPONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hirsutism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VALASSI E, AULINAS A, GLAD CA, JOHANNSSON G, RAGNARSSON O, WEBB SM. A POLYMORPHISM IN THE CYP17A1 GENE INFLUENCES THE THERAPEUTIC RESPONSE TO STEROIDOGENESIS INHIBITORS IN CUSHING^S SYNDROME. CLINICAL ENDOCRINOLOGY NOV?2017?87 (5):433?439.", "literaturereference_normalized": "a polymorphism in the cyp17a1 gene influences the therapeutic response to steroidogenesis inhibitors in cushing s syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20180727", "receivedate": "20180727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15207133, "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" } ]
{ "abstract": "BACKGROUND\nWilson disease (WD) is an autosomal recessive hereditary disease in which the patient usually has a reduced risk of developing cancer. In particular, with the exception of hepatocellular carcinoma and cholangiocarcinoma, the incidence of cancer is significantly lower in WD patients compared with the general population. This case study presents a rare case of WD complicated with primary breast cancer.\nA 40-year-old woman who was diagnosed with WD at 25 years of age found a lump in her left breast. She has a family history of cancer.\nUltrasound and mammography results were highly suggestive of a malignant lesion. After core needle biopsy, it was confirmed that she had invasive breast cancer.\n\n\nMETHODS\nA modified radical mastectomy was performed for the left breast. As the tumor was defined as a stage IIa triple negative breast cancer, the patient would have been recommended epirubicin/cyclophosphamide + docetaxel for 8 cycles if WD was not a comorbidity. As the patient had cirrhosis and abnormal liver function, she was given paclitaxel weekly for 6 cycles instead.\n\n\nRESULTS\nThe patient showed good tolerance, and has not had a recurrence in 2 years.\n\n\nCONCLUSIONS\nWe reviewed the literature for studies of patients with WD complicated with cancers, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received chemotherapy even with liver dysfunction, which suggests that patients with WD can be safely treated with paclitaxel chemotherapy under close surveillance.", "affiliations": "Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospital.;Department of Anesthesia, Armed Police Corps Hospital in Shanxi Province, Xiaodian District, Taiyuan, Shanxi Province, P. R. China.;Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospital.", "authors": "Li\|Dong\|D\|;Wang\|Jun\|J\|;Gao\|Jinnan\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000015266", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31083157MD-D-18-0748510.1097/MD.0000000000015266152665750Research ArticleClinical Case ReportPrimary breast cancer in a patient with Wilson disease A case reportLi Dong PhD, MDaWang Jun MDbGao Jinnan PhD, MDa∗NA. a Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospitalb Department of Anesthesia, Armed Police Corps Hospital in Shanxi Province, Xiaodian District, Taiyuan, Shanxi Province, P. R. China.∗ Correspondence: Jinnan Gao, Department of Breast Surgery, Shanxi academy of Medical Sciences Shanxi Dayi Hospital, No. 99, Longcheng Street, Taiyuan, Shanxi Province, 030032, P. R. China (e-mail: [email protected]).5 2019 13 5 2019 98 19 e1526629 10 2018 3 3 2019 15 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 License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nWilson disease (WD) is an autosomal recessive hereditary disease in which the patient usually has a reduced risk of developing cancer. In particular, with the exception of hepatocellular carcinoma and cholangiocarcinoma, the incidence of cancer is significantly lower in WD patients compared with the general population. This case study presents a rare case of WD complicated with primary breast cancer.\n\nPatient concerns:\nA 40-year-old woman who was diagnosed with WD at 25 years of age found a lump in her left breast. She has a family history of cancer.\n\nDiagnoses:\nUltrasound and mammography results were highly suggestive of a malignant lesion. After core needle biopsy, it was confirmed that she had invasive breast cancer.\n\nInterventions:\nA modified radical mastectomy was performed for the left breast. As the tumor was defined as a stage IIa triple negative breast cancer, the patient would have been recommended epirubicin/cyclophosphamide + docetaxel for 8 cycles if WD was not a comorbidity. As the patient had cirrhosis and abnormal liver function, she was given paclitaxel weekly for 6 cycles instead.\n\nOutcomes:\nThe patient showed good tolerance, and has not had a recurrence in 2 years.\n\nLessons:\nWe reviewed the literature for studies of patients with WD complicated with cancers, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received chemotherapy even with liver dysfunction, which suggests that patients with WD can be safely treated with paclitaxel chemotherapy under close surveillance.\n\nKeywords\nbreast cancerchemotherapyWilson diseaseOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nWilson disease (WD)[1] is a copper metabolism disorder that is caused by a mutation of the gene encoding the copper-transporting P-type ATPase (ATP7B) protein. The clinical manifestations generally include liver cirrhosis, abnormal liver function, extrapyramidal effects, and corneal ring pigmentation such as Kayser-Fleischer (K-F) rings. The patients have increased levels of urinary copper but decreased levels of serum copper and ceruloplasmin (CER). WD complicated with another malignancy is very rare; in fact, WD patients have a significantly lower incidence rate of liver tumors compared with non-WD patients suffering from the same level of liver cirrhosis.[2] Extrahepatic tumors are even rarer among WD patients; we have found only 1 case of WD complicated with colon cancer[3] and 2 cases of WD complicated with acute lymphoblastic leukemia.[4,5] To date, there has been no report of WD complicated with breast cancer. In this paper, we reported the diagnosis and treatment of a patient with WD complicated with breast cancer.\n\n2 Case presentation\nA woman, aged 40, went to see a doctor because of “a lump felt on the left breast more than half a month ago.” A color Doppler ultrasound revealed: a hypoechoic nodule of about 2.0 × 1.3 cm in the outer upper quadrant of the left breast, with a clear boundary, irregular shape, and visible dotted blood flow signals; and enlarged lymph nodes of 2.3 × 0.8 cm in the left subaxillary region, with poor corticomedullary differentiation. A mammography revealed that both breasts had compact mammary glands, with an irregular and isodense mass of 2.0 × 1.5 cm in the outer upper quadrant of the left breast; the mass had an obscure boundary and inhomogeneous interior echoes with no abnormal calcification found and was classified as BI-RADS 4c. The outpatient clinic carried out a puncture biopsy, and the clinicopathological analysis confirmed that it was an invasive breast cancer. The patient suffered from abdominal distension, swollen legs, glossolalia, and limb jitters 15 years ago, and her CER level was determined to be 0.81 mg/dL; slit-lamp examination revealed the presence of a K-F ring (2+) and abdominal ultrasonography revealed liver cirrhosis. She was diagnosed with WD and received sodium dimercaptosulphonate decoppering treatment (the patient was allergic to penicillamine). With remarkably improved clinical symptoms, she received decoppering treatment on a regular basis thereafter. In 2003, she received a splenectomy due to splenomegaly and hypersplenism. The patient was allergic to penicillin and cephalosporin antibiotics and did not smoke or drink alcohol. She gave birth at the age of 37 without breastfeeding and her menstruation was normal. The patient had a sister who was diagnosed with breast cancer at 42, a maternal aunt who was diagnosed with lung cancer, and a maternal grandmother who was diagnosed with renal carcinoma. No one else in her family was diagnosed with cancer or WD.\n\nPhysical examination on admission showed a blood pressure of 126/88 mmHg and a pulse of 83 times/min. She had clear consciousness, spoke fluently, and both eyeballs moved freely without diplopia or nystagmus in any direction. Her limb muscle strength, muscular tension, and tendon reflex were normal. Both upper limbs had a slight postural tremor. The body skin and sclera did not have any obvious yellow staining. Her abdomen was flat and her liver size was normal; the spleen had been resected, shifting dullness (–) was detected, and both lower limbs were not swollen. A 2.0 cm hard enclosed lump was felt in the outer upper quadrant of left breast, with an unclear boundary and poor mobility. A soft swollen lymph node can be felt in the left subaxillary region. Laboratory examination showed a negative hepatitis virus index, hemoglobin levels of 110.4 g/L, blood albumin levels of 38.2 g/L, prealbumin levels of 183.6 mg/L, total bilirubin of 5.8 μmol/L, aspartate aminotransferase levels of 28.9 IU/L, alanine transaminase levels of 56.9 IU/L, total bile acid of 23.1 μmol/L, normal blood coagulation, urinary copper excretion of 840.5 μg within 24 hours, serum copper, serum zinc, copper/zinc. A modified radical mastectomy for the left breast was performed under general anesthesia and the postoperative pathology showed a left breast invasive ductal carcinoma of grade II (7 points) accompanied by massive necrosis in the central area. The size of the lump was 3 × 2 × 1.5 cm and did not involve vascular nerves. No cancer cells were found in the nipple or the incisal edge of the base. Axillary examination revealed no cancer metastasis in 30 lymph nodes (0/30) and immunohistochemical analysis showed that the carcinoma was ER(–), PR(–), HER-2(–), and showed positive Ki67 staining in 40% of the tumor cells. The patient was ultimately diagnosed with triple negative left breast cancer pT2N0M0, stage IIa. Paclitaxel was offered as a chemotherapy regime after operation (80 mg/m2 weekly), which the patient tolerated well, with just degree II abnormal liver function and degree I to II bone marrow suppression.\n\n3 Discussion and conclusions\nCopper is a trace element essential for the normal metabolism of human cells, acting as an activator for several enzymes as well as an essential component of antioxidant enzymes such as superoxide dismutase and monoamine oxidase. The total copper content in the body of an adult is normally about 50 to 150 mg, of which 5% to 10% exists in the blood. During blood circulation, about 95% of the copper is combined with CER and a small proportion is combined with albumin and histidine.\n\nHepatolenticular degeneration is also called Wilson disease,[1] so named because it was officially established in 1921 by Wilson, an English neuropathist. The incidence rate is estimated to be 1/30,000. WD is a type of autosomal recessive hereditary disease caused by a mutation of the gene encoding the ATP7B protein, which is the main regulator of the hepatic metabolism of copper in the body. Its pathophysiological basis is that the hereditary defect leads to the dysfunction of copper excretion by lysosomes in the liver cells and the decrease of CER synthesized by the liver. As a result, large amounts of copper accumulate in the liver and serum copper is loosely combined with albumin, entering into the systemic circulation. In this way, copper is deposited in the brain, liver, cornea, and other tissues, giving rise to diseases such as liver cirrhosis, liver function abnormalities, vertebral body symptoms, and corneal pigmentation such as K-F rings, as well as increasing levels of urinary copper and decreasing levels of serum copper and CER.\n\nThe relationship between serum copper and malignancies is still unclear. Studies have shown that cancer patients usually have high levels of copper in their serum[6–8] and tissue specimens.[9] Some scholars believe that copper is an inducing factor for malignancies because it can suppress the activity of glutathione peroxidase and make cells vulnerable to attack by free radicals. The overload of copper might raise the incidence rate of malignancies by causing P53 mutations,[10] increasing the possibility of BRAF mutations,[11] and promoting tumor angiogenesis.[12,13] However, others think that the rise of serum copper is not an inducing factor but the result of malignancies with mechanisms that may lead to the rise of serum copper. Under the anaerobic conditions of tumors, several enzymes that rely on copper are suppressed in the body, reflexively prompting the copper in other body parts to be metabolized and released into the blood to maintain the activity of essential enzymes, resulting in an increase in the level of copper in the blood. The increase of sialyltransferases on the surface of tumor cells suppresses CER decomposition and causes the rise of CER and copper in the blood. Currently, many studies have shown that serum copper reduction is used as a strategy to treat cancer. Some studies pointed out that copper chelation with tetrathiomolybdate can lower the chances of cancer recurrence and metastasis,[14–19] possibly due to the reduction of endothelial progenitor cells and inhibition of the generation of tumor microvasculature.\n\nClinically, there is a very low incidence rate of WD complicated with other malignancies. According to previous reports, complicating malignancies of WD mainly include hepatocellular carcinoma and cholangiocarcinoma (the probability of malignant pathological change is remarkably low relative to non-WD patients complicated with the same level of liver cirrhosis[2]) and other types of malignancies are even rarer. Although breast cancer is the most common malignancy in women, there has been no report of WD complicated with breast cancer. To our knowledge, this is the first case report on WD complicated with breast cancer.\n\nIn the report on WD complicated with colon cancer, the authors considered that constant chelation therapy might cause damage to the colonic mucosa, which is a possible factor to precipitate malignant change.[3] However, it is obvious that the incidence of breast cancer has no direct connection to this. We speculate that the decreased level of serum copper and CER in WD patients as well as the adoption of chelation decoppering treatment reduces the incidence rate of cancers and, therefore, the tumor incidence in WD patients is very low. As for the patient featured in our study, she bears many high-risk factors for breast cancer (advanced maternal age, no breastfeeding, history of malignancy in the family, etc.). We believe that she may be subjected to an even higher risk of tumor incidence if she had not contracted WD and accepted decoppering treatment.\n\nThere are scarcely any reports regarding chemotherapy risk assessment in WD patients. We could only find 1 case report about chemotherapy for a WD patient complicated with leukemia, where the authors pointed out that full consideration of serious therapy-related toxicity should be taken when treating WD patients with chemotherapy, which mainly includes hepatotoxicity and bone marrow suppression, and that the chemotherapeutic dosage should be reduced when necessary.[4] Since some researchers noted that the ATP7B mutation might result in drug resistance of tumor cells to platinum-based chemotherapy,[20] we adopted taxanes for chemotherapy. The treatment scheme was weekly therapy with paclitaxel, starting from 50% of the conventional chemotherapeutic dose, which was gradually increased to the standard dose (80 mg/m2 weekly) while keeping a close watch on the patient's liver function. According to clinical observation, the patient had good tolerance, with only degree II abnormal liver function and degree I to II bone marrow suppression (reduced glutathione was used as a liver protection drug during this process).\n\nIn summary, we reported a case of WD complicated with breast cancer, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received weekly chemotherapy with paclitaxel for 6 cycles after the operation and we will continue to keep a close watch on the patient.\n\nAuthor contributions\nConceptualization: Dong Li.\n\nSupervision: Jinnan Gao.\n\nWriting – original draft: Dong Li.\n\nWriting – review & editing: Jun Wang, Jinnan Gao.\n\nAbbreviations: ATP7B = copper-transporting P-type ATPase, CER = ceruloplasmin, ER = estrogen receptor, HER-2 = human epidermal growth factor receptor 2, K-F ring = Kayser-Fleischer ring, PR = progesterone receptor, WD = Wilson disease.\n\nThe patient has provide informed consent for publication of the case and we could provide this information if requested.\n\nThis paper was supported by a grant from the 136 Startup Project of Shanxi province (2019XY010).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] EASL . Clinical practice guidelines: Wilson's disease . J Hepatol \n2012 ;56 :671–85 .22340672 \n[2] Pfeiffenberger J Mogler C Gotthardt DN \nHepatobiliary malignancies in Wilson disease . Liver Int \n2015 ;35 :1615–22 .25369181 \n[3] Lee SY Kim IH Yoo SH \nA case of colonic adenocarcinoma in a patient with Wilson's disease . Gut liver \n2013 ;7 :500–3 .23898395 \n[4] Maeda S Matsubara H Hiejima E \nAcute lymphoblastic leukemia in a girl with Wilson's disease . Pediatr Int \n2014 ;56 :626–9 .25252055 \n[5] Yuce A Kocak N Yetgin S \nAcute lymphoblastic leukemia in a child with Wilson disease . Turk J Pediatr \n2000 ;42 :256–7 .11105631 \n[6] Gupta SK Shukla VK Vaidya MP \nSerum trace elements and Cu/Zn ratio in breast cancer patients . J Surg Oncol \n1991 ;46 :178–81 .2011029 \n[7] Kuo HW Chen SF Wu CC \nSerum and tissue trace elements in patients with breast cancer in Taiwan . Biol Trace Elem Res \n2002 ;89 :1–1 .12413046 \n[8] Zowczak M Iskra M Torlinski L \nAnalysis of serum copper and zinc concentrations in cancer patients . Biol Trace Elem Res \n2001 ;82 :1–8 .11697759 \n[9] Geraki K Farquharson MJ Bradley DA \nConcentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study . Phys Med Biol \n2002 ;47 :2327–39 .12164590 \n[10] Formigari A Gregianin E Irato P \nThe effect of zinc and the role of p53 in copper-induced cellular stress responses . J Appl Toxicol \n2013 ;33 :527–36 .23401182 \n[11] Brady DC Crowe MS Turski ML \nCopper is required for oncogenic BRAF signaling and tumorigenesis . Nature \n2014 ;509 :492–6 .24717435 \n[12] Finney L Vogt S Fukai T \nCopper and angiogenesis: unravelling a relationship key to cancer progression . Clin Exp Pharmacol Physiol \n2009 ;36 :88–94 .18505439 \n[13] Antoniades V Sioga A Dietrich EM \nIs copper chelation an effective anti-angiogenic strategy for cancer treatment? \nMed Hypotheses \n2013 ;81 :1159–63 .24210000 \n[14] Brewer GJ Merajver SD \nCancer therapy with tetrathiomolybdate: antiangiogenesis by lowering body copper--a review . Integr Cancer Ther \n2002 ;1 :327–37 .14664727 \n[15] Khan G Merajver S \nCopper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm . Expert Opin Investig Drugs \n2009 ;18 :541–8 .\n[16] Brewer GJ \nCopper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer . Curr Cancer Drug Targets \n2005 ;5 :195–202 .15892619 \n[17] Chan N Willis A Kornhauser N \nInfluencing the tumor microenvironment: a Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases . Clin Cancer Res \n2017 ;23 :666–76 .27769988 \n[18] Jain S Cohen J Ward MM \nTetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse . Ann Oncol \n2013 ;24 :1491–8 .23406736 \n[19] Goodman VL Brewer GJ Merajver SD \nControl of copper status for cancer therapy . Curr Cancer Drug Targets \n2005 ;5 :543–9 .16305350 \n[20] Kanzaki A Toi M Neamati N \nCopper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma . Jpn J Cancer Res \n2002 ;93 :70–7 .11802810\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0025-7974", "issue": "98(19)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D003937:Diagnosis, Differential; D005260:Female; D006527:Hepatolenticular Degeneration; D006801:Humans", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e15266", "pmc": null, "pmid": "31083157", "pubdate": "2019-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Primary breast cancer in a patient with Wilson disease: A case report.", "title_normalized": "primary breast cancer in a patient with wilson disease a case report" }	[ { "companynumb": "CN-PFIZER INC-2019246702", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "076131", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80MG/M2, CYCLE (WEEKLY, 6 CYCLE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER STAGE II", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PACLITAXEL." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic function abnormal", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone marrow failure", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LI, D.. PRIMARY BREAST CANCER IN A PATIENT WITH WILSON DISEASE: A CASE REPORT.. MEDICINE. 2019?98(19)", "literaturereference_normalized": "primary breast cancer in a patient with wilson disease a case report", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20190621", "receivedate": "20190613", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16427744, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190711" } ]
{ "abstract": "Wilms tumor, or nephroblastoma, is the most common malignant tumor of the urinary tract in children, but is rarely found in adults. Here, we report the first case of a female patient with a Wilms tumor, diagnosed during pregnancy, who underwent radical nephrectomy and adjuvant chemotherapy before and after delivering a healthy child. Generally, treatment should follow the guidelines established for the pediatric setting.", "affiliations": "Department of Urology, Technische Universität München, Klinikum rechts der Isar, Munich, Germany. [email protected]", "authors": "Maurer\|T\|T\|;Zorn\|C\|C\|;Klein\|E\|E\|;Weirich\|G\|G\|;Beer\|A J\|AJ\|;Gschwend\|J E\|JE\|;Zantl\|N\|N\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000241685", "fulltext": null, "fulltext_license": null, "issn_linking": "0042-1138", "issue": "83(3)", "journal": "Urologia internationalis", "keywords": null, "medline_ta": "Urol Int", "mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D009396:Wilms Tumor", "nlm_unique_id": "0417373", "other_id": null, "pages": "364-7", "pmc": null, "pmid": "19829043", "pubdate": "2009", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Multimodal tumor therapy in a 31-year-old pregnant woman with Wilms tumor.", "title_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor" }	[ { "companynumb": "DE-RECORDATI RARE DISEASES INC.-DKLU1060502", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "050682", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "45", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Alopecia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "ZANTL N. MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009 OCT?83(3):364-367.", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537678, "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": "DE-AUROBINDO-AUR-APL-2020-011554", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NEEDED", "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": "6", "activesubstance": { "activesubstancename": "GRANISETRON" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204238", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NEEDED", "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": "GRANISETRON" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM/SQ. METER, CYCLICAL (1.5 MG/M2, WEEKLY (MAXIMUM 2 MG; 22 WEEKS GESTATION) )", "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": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BISACODYL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NEEDED", "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": "BISACODYL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NEEDED", "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": "PARACETAMOL" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "45 MICROGRAM/KILOGRAM, CYCLICAL ((MAXIMUM 2 MG, EVERY 3 WEEKS FROM 22 WEEKS GESTATION) )", "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": "45", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "2.4", "reaction": [ { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAURER T. MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009?83(3):364-367", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17519466, "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": "DE-RECORDATI RARE DISEASES-DKLU1060504", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "050682", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL CONDITION AFFECTING FOETUS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "45", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "2.4", "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZANTL N. MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009 OCT?83(3):364-367.", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17538962, "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": "DE-MYLANLABS-2020M1029046", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, PRN (UNK, AS NEEDED)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIEMETIC SUPPORTIVE CARE", "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": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG/M2, WEEKLY (MAXIMUM 2 MG; 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MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009?83(3):364-367", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200424", "receivedate": "20200331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17603885, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" }, { "companynumb": "DE-PFIZER INC-2020074686", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": "3", "drugadministrationroute": 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"patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "2.4", "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia neonatal", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAURER, T.. MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009?83 (3):10.1159/000241685", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200325", "receivedate": "20200225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17458251, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "DE-MYLANLABS-2020M1034175", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, 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"medicinalproduct": "DACTINOMYCIN" } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Maternal exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MAURER, T.. MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS.. 2009?83 (3):364-367", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200331", "receivedate": "20200331", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17607943, "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": "Pyoderma gangrenosum is a sterile inflammatory disease of unknown etiology characterized by recurrent cutaneous ulcers. It can occur in extracutaneous locations, especially at operative sites, and has been reported following gynecologic surgery. This report is the first case of pyoderma gangrenosum as a remote complication of pelvic surgery with associated ureteral stricture. It demonstrates the diagnostic challenge of this rare disease and the importance of broadening the differential diagnosis when apparent infections do not respond to treatment to minimize the morbidity of ineffective antibiotic and surgical interventions.", "affiliations": "Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA.;Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd #3, Atlanta, GA, 30322, USA.;Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA.", "authors": "Walton\|Eric\|E\|;Wolner\|Zachary\|Z\|;Hammett\|Jessica\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.eucr.2021.101826", "fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00266-7\n10.1016/j.eucr.2021.101826\n101826\nInflammation and Infection\nVaginal cuff pyoderma gangrenosum with associated ureteral stricture: A case report\nWalton Eric [email protected]\na∗\nWolner Zachary b\nHammett Jessica a\na Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA\nb Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd #3, Atlanta, GA, 30322, USA\n∗ Corresponding author. Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA. [email protected]\n28 8 2021\n11 2021\n28 8 2021\n39 1018263 8 2021\n24 8 2021\n26 8 2021\n© 2021 The Authors. Published by Elsevier Inc.\n2021\n\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/).\nPyoderma gangrenosum is a sterile inflammatory disease of unknown etiology characterized by recurrent cutaneous ulcers. It can occur in extracutaneous locations, especially at operative sites, and has been reported following gynecologic surgery. This report is the first case of pyoderma gangrenosum as a remote complication of pelvic surgery with associated ureteral stricture. It demonstrates the diagnostic challenge of this rare disease and the importance of broadening the differential diagnosis when apparent infections do not respond to treatment to minimize the morbidity of ineffective antibiotic and surgical interventions.\n\nKeywords\n\nPyoderma gangrenosum\nVaginal cuff\nPelvic surgery\nUreteral stricture\n==== Body\npmc1 Introduction\n\nPyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis characterized by recurrent cutaneous ulceration; it is often associated with inflammatory bowel disease, rhematic disorders, or neoplasms.1 Although rare, there are gynecologic reports of PG.2,3 To the best of our knowledge, this report is the first case of PG arising as a remote complication of pelvic surgery that also involves adjacent urologic organs.\n\n2 Case presentation\n\nA sixty-year-old woman with surgical history pertinent for vaginal hysterectomy twenty years ago and sacrospinous ligament suspension fifteen years ago presented to the urology clinic for evaluation of vaginal discharge associated with right hydronephrosis. Symptoms began ten months prior to presentation when she developed dyspareunia followed by vaginal bleeding and discharge. She then developed low-grade fevers, chills, fatigue, poor appetite, weight loss, and weakness. No dysuria, gross hematuria, flank pain, or suprapubic pain.\n\nA gynecologist performed a pelvic exam and removed a right vaginal suture that appeared infected. She subsequently completed three courses of oral antibiotics without resolution of symptoms. Nine months after symptom onset, vaginal culture grew Bacteroides and MRI was obtained showing new-onset hydronephrosis associated with fluid collection at vaginal cuff (Fig. 1). Renal function was normal. Oral levofloxacin and metronidazole were started and switched to intravenous due to side effects. She then developed scattered skin lesions.Fig. 1 MRI depicting right hydroureteronephrosis associated with right vaginal cuff fluid collection.\n\nFig. 1\n\nMedical history includes hypertension, hyperlipidemia, hypothyroidism, mood disorder, and psoriasis treated with ixekizumab (humanized IgG4 monoclonal antibody specific for interleukin 17A). No personal or family history of inflammatory bowel disease, rheumatoid arthritis, or malignancy. She is a G5P4A1 with all spontaneous vaginal deliveries. She is a non-smoker.\n\nPhysical exam revealed scattered violaceous papules across her face and multiple pustular nodules of the distal extremities concerning for septic emboli (Fig. 2). Dried purulent discharge was noted on otherwise normal genitalia. Pelvic exam revealed an open vaginal cuff with intact perineum and copious purulent material.Fig. 2 Representative lesions on face and distal extremities at time of presentation to urology clinic.\n\nFig. 2\n\nThe patient was admitted with concern for subacute bacterial endocarditis. Vaginal and blood cultures were negative. Finger lesions underwent incision and drainage; wound cultures were negative. Cystoscopy with right retrograde pyelogram showed a draining vaginal cuff fluid collection, bladder inflammation, and right hydroureteronephrosis to the level of the bladder. Three vaginal cuff sutures (appearance most consistent with braided polyester) were removed. Vaginal cuff tissue cultures were negative. Additional soft tissue lesions developed despite broad antibiotic coverage. Echocardiography and autoimmune studies were unremarkable. Dermatology was consulted and expressed high suspicion for PG given history and exhaustive negative infectious work-up. Punch biopsy was performed demonstrating a neutrophilic infiltrate supportive of the diagnosis. The patient was initiated on cyclosporine with rapid response of skin lesions.\n\nOne month later, she had persistent vaginal discharge and right hydronephrosis with normal renal function despite overall good response to cyclosporine. Repeat cystoscopy with right retrograde pyelogram demonstrated vaginal cuff inflammation, severe hydroureteronephrosis, and distal ureteral stricture that was stented (Fig. 3). The patient was transitioned to adalimumab for long-term management. Her ureteral stricture is currently managed with ureteral stent exchanges. When her PG is adequately controlled and her vaginal cuff has healed, she will undergo ureteroneocystostomy.Fig. 3 Right hydroureteronephrosis to the level of the bladder with severe distal ureteral stricture associated with severe vaginal inflammation.\n\nFig. 3\n\n3 Discussion\n\nOnset of PG typically occurs in the third to sixth decade of life with a higher incidence in women. This rare disorder usually presents on the lower extremities as painful pustules that rapidly enlarge into ulcers with violaceous undermined borders, however, it can occur in other cutaneous or extracutaneous location. Etiology of PG is unknown but involves aberrant autoimmune response to unspecified antigen(s). With no definitive diagnostic criteria, it is a diagnosis of exclusion. Differential diagnosis includes vascular occlusive disease, vasculitis, malignancy, infectious diseases, tissue injury, and drug reactions. Diagnosis is supported by response to treatment, typically systemic corticosteroids or cyclosporine.1\n\nGynecologic reports of PG are rare. One report describes chronic ulceration of the vagina following cervical cone biopsy.2 Another case occurred in the vaginal vault as a late complication (post-op day 92) of vaginal hysterectomy.3 More commonly post-operative PG arises at surgical incisions during the immediate post-operative period, with breast and abdomen being the most common sites.4 In post-operative PG, trauma upregulates neutrophils at the site of ulceration. The role of suture material is unknown. It has been theorized that higher reactivity material (eg., silk) with epidermal puncture is more likely to elicit PG, however, no prospective data exists to support this theory and many cases occur after low reactivity absorbable subcuticular sutures are employed.4 Similarly, one case report found no difference in PG lesions created by seven different suture types.5 In this case braided polyester, a low reactivity non-absorbable suture, was identified. Furthermore, post-operative PG has a lower association with system disease (34 vs 50%) compared with classic PG; most patients with post-operative PG receive antibiotics and undergo wound debridement prior to diagnosis.4\n\nThe case presented here demonstrates the challenge of diagnosing PG in extracutaneous locations, especially by clinicians unfamiliar with this rare disease. It highlights the importance of considering alternative etiologies when seemingly infectious problems do not respond to antibiotic therapy. Furthermore, the remote history of pelvic surgery suggests foreign bodies can serve as a source of pathergy in PG beyond the acute peri-operative period. Involvement of adjacent urologic organs in this case add an additional layer of complexity. Ureteral stricture secondary to inflammation from PG has created a treatment conundrum where only additional operative trauma during ureteroneocystostomy can definitively resolve the consequence of the initial disease process.\n\n4 Conclusion\n\nThis case is the first report of PG of the vaginal cuff arising in a patient with a remote history of pelvic surgery; the involvement of adjacent urologic organs is also distinctive. It demonstrates the diagnostic challenge of this rare disease and underlies the importance of maintaining a broad differential diagnosis when apparent surgical infections do not respond to treatment. Early consultation of a dermatologist if concerned for PG can minimize the morbidity of repetitive antibiotic and surgical interventions that do not effectively treat this disease.\n\nConsent\n\nInformed consent was obtained from the patient to include case details in this written report.\n==== Refs\nReferences\n\n1 Wollina U. Pyoderma gangrenosum--a review Orphanet J Rare Dis. Apr 2 2007 19 10.1186/1750-1172-2-19\n2 Lilford R.J. Tindall V.R. Batchelor A.G. Post-surgical pyoderma gangrenosum of the vaginal vault associated with ulcerative colitis and Behçet's disease; a case report Eur J Obstet Gynecol Reprod Biol. Apr 31 1 1989 93 94 10.1016/0028-2243(89)90030-0\n3 Güth U. Wagner S. Huang D.J. Hess T.H. Pyoderma gangrenosum of the vaginal vault after vaginal hysterectomy: only the correct diagnosis of a rare entity can prevent long-term morbidity Arch Gynecol Obstet 288 1 Jul 2013 79 82 10.1007/s00404-012-2692-9 23283595\n4 Tolkachjov S.N. Fahy A.S. Cerci F.B. Wetter D.A. Cha S.S. Camilleri M.J. Postoperative pyoderma gangrenosum: a clinical review of published cases Mayo Clin Proc. 09 91 9 2016 1267 1279 10.1016/j.mayocp.2016.05.001\n5 Kratzsch D. Ziemer M. Milkova L. Wagner J.A. Simon J.C. Kendler M. 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{ "abstract": "Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.", "affiliations": "Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA [email protected].;Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.", "authors": "Below\|Samantha\|S\|http://orcid.org/0000-0001-8707-4800;Bashir\|Maaman\|M\|", "chemical_list": "D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D018271:Signal Recognition Particle; D009173:Mycophenolic Acid; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-237647", "fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-237647\n10.1136/bcr-2020-237647\nCase Report\n1506\n508\n520\n532\n541\nSRP-positive necrotising myopathy: takes more than just the muscles\nhttp://orcid.org/0000-0001-8707-4800Below Samantha 1 Bashir Maaman 2 1 Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA\n2 Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA\nCorrespondence to Dr Samantha Below; [email protected]\n2021 \n19 2 2021 \n19 2 2021 \n14 2 e23764710 2 2021 © BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2021http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.\n\nrespiratory medicinelung functionrheumatologymusculoskeletal syndromesspecial-featureunlocked\n==== Body\nBackground\nNecrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.\n\nCase presentation\nA previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.\n\nPatient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.\n\nPatient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.\n\nShe continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.\n\nLaboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.\n\nTreatment\nPatient was treated with prednisone, IVIG and mycophenolate mofetil.\n\nOutcome and follow-up\nPatient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.\n\nDiscussion\nImmune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8\n\nOther autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.\n\nIn fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2\n\nPatient’s perspective\nAs this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.\n\nLearning points\nNecrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.\n\nPatients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.\n\nTreatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.\n\nIt is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology\n\nContributors: MB: served as scientific advisor. SB: wrote and researched case.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Ernste \nFC , Reed \nAM \nIdiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations\n. Mayo Clin Proc \n2013 ;88 :83 –105\n. 10.1016/j.mayocp.2012.10.017 23274022 \n2 Satoh \nM , Tanaka \nS , Ceribelli \nA , et al \nA comprehensive overview on myositis-specific antibodies: new and old biomarkers in idiopathic inflammatory myopathy\n. Clin Rev Allergy Immunol \n2017 ;52 :1 –19\n. 10.1007/s12016-015-8510-y 26424665 \n3 Khan \nMH , Patel \nA , Pendharkar \nS \nAnti-Signal recognition particle necrotizing autoimmune myopathy: an atypical presentation\n. Cureus \n2018 ;10 :e3766. 10.7759/cureus.3766 30820385 \n4 Watanabe \nY , Uruha \nA , Suzuki \nS , et al \nClinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy\n. J Neurol Neurosurg Psychiatry \n2016 ;87 :1038 –44\n. 10.1136/jnnp-2016-313166 27147697 \n5 Basnayake \nSK , Blumbergs \nP , Tan \nJA , et al \nInflammatory myopathy with anti-SRP antibodies: case series of a South Australian cohort\n. Clin Rheumatol \n2015 ;34 :603 –8\n. 10.1007/s10067-014-2512-7 24497174 \n6 Kassardjian \nCD , Lennon \nVA , Alfugham \nNB , et al \nClinical features and treatment outcomes of necrotizing autoimmune myopathy\n. JAMA Neurol \n2015 ;72 :996 –1003\n. 10.1001/jamaneurol.2015.1207 26192196 \n7 Milone \nM \nDiagnosis and management of immune-mediated myopathies\n. Mayo Clin Proc \n2017 ;92 :826 –37\n. 10.1016/j.mayocp.2016.12.025 28473041 \n8 Day \nJA , Limaye \nV \nImmune-Mediated necrotising myopathy: a critical review of current concepts\n. Semin Arthritis Rheum \n2019 ;49 :420 –9\n. 10.1016/j.semarthrit.2019.04.002 31109639 \n9 Cauchi \nJ , Perez-Rosendahl \nM , Mozaffar \nT \nAcute necrotizing myositis in systemic lupus erythematous (4816)\n. Neurology \n2020 .\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1757-790X", "issue": "14(2)", "journal": "BMJ case reports", "keywords": "lung function; musculoskeletal syndromes; respiratory medicine; rheumatology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D001327:Autoimmune Diseases; D004576:Electromyography; D004791:Enzyme Inhibitors; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008875:Middle Aged; D009135:Muscular Diseases; D009173:Mycophenolic Acid; D009336:Necrosis; D011241:Prednisone; D018271:Signal Recognition Particle", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33608334", "pubdate": "2021-02-19", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26192196;23274022;30820385;28473041;31109639;26424665;24497174;27147697", "title": "SRP-positive necrotising myopathy: takes more than just the muscles.", 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{ "abstract": "Coronavirus disease 2019 (COVID-19) has spread to more than 70 countries around the world since its discovery in 2019. More than 2.5 million cases and more than 130,000 deaths have been reported in the United States alone. The common radiological presentation in this disease is noted to be the presence of ground glass opacities and/or consolidations. We report a case of 40-year-old male admitted for COVID-19 and rapidly deteriorated into severe acute respiratory distress syndrome requiring intubation and mechanical ventilation with no prior history of smoking or lung disease. The patient had normal imaging 3 days prior to admission to the hospital and rapidly developed a large pneumatocele with pneumothorax requiring chest tube placement that later on resolved. This is a unique radiologic finding in COVID-19 and likely related to severe inflammation secondary to SARS-CoV-2 infection.", "affiliations": "Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States.;Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, United States.;Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States.;Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States.", "authors": "Sanivarapu\|Raghavendra R\|RR\|;Farraj\|Kristen\|K\|;Sayedy\|Najia\|N\|;Anjum\|Fatima\|F\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2020.101303", "fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(20)30517-7\n10.1016/j.rmcr.2020.101303\n101303\nCase Report\nRapidly developing large pneumatocele and spontaneous pneumothorax in SARS-CoV-2 infection\nSanivarapu Raghavendra R. MD [email protected]\na∗\nFarraj Kristen MD b\nSayedy Najia MD a\nAnjum Fatima MD a\na Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States\nb Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, United States\n∗ Corresponding author. [email protected]\n02 12 2020\n2020\n02 12 2020\n31 10130317 9 2020\n18 11 2020\n19 11 2020\n© 2020 The Author(s)\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCoronavirus disease 2019 (COVID-19) has spread to more than 70 countries around the world since its discovery in 2019. More than 2.5 million cases and more than 130,000 deaths have been reported in the United States alone. The common radiological presentation in this disease is noted to be the presence of ground glass opacities and/or consolidations. We report a case of 40-year-old male admitted for COVID-19 and rapidly deteriorated into severe acute respiratory distress syndrome requiring intubation and mechanical ventilation with no prior history of smoking or lung disease. The patient had normal imaging 3 days prior to admission to the hospital and rapidly developed a large pneumatocele with pneumothorax requiring chest tube placement that later on resolved. This is a unique radiologic finding in COVID-19 and likely related to severe inflammation secondary to SARS-CoV-2 infection.\n\nKeywords\n\nSARS-CoV-2\nCOVID-19\nPneumatocele\nPneumothorax\nARDS\n==== Body\n1 Background\n\nThe clinical syndrome caused by novel corona virus is termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) and the disease is called as coronavirus disease-19 (COVID-19) [1]. The radiographic findings of COVID-19 patients studied in 69 patients showed about 31% presenting with normal chest x-ray and rest presenting with consolidations or ground glass opacities (GGO) [2]. A systematic review by Bao et al. showed the CT-findings in COVID-19 can present as GGO (83%), GGO with consolidation (58%), pleural thickening (52%), interlobular septal thickening (48%), and air bronchograms (46%) [3]. A retrospective analysis of CT-findings in COVID-19 patients from China by Wu et al. reported presence of pneumatocele in only two cases; however no images are available [4]. Here we present the first case of SARS-CoV-2 infection causing pneumatocele formation and spontaneous pneumothorax in the USA.\n\n1.1 Case presentation\n\nA 40-year-old male with no medical history presented to the emergency room in April of 2020, during the peak of COVID-19 infection in NY with shortness of breath, dry cough, and body aches for 2 weeks duration. On admission, he was hemodynamically stable and afebrile. His chest X-ray showed diffuse reticular markings and bilateral mid-lung field airspace opacities concerning for atypical multifocal pneumonia (Fig. 1). He tested positive for SARS-CoV-2 RNA. He was discharged a day later on hydroxychloroquine. Three days post discharge he got readmitted with acute onset shortness of breath and right-sided chest pain which worsened with inspiration. His vitals were blood pressure: 125/74 mmHg, heart rate: 160 bpm, and was tachypneic at 35 breaths per minute. On physical examination, the patient was in respiratory distress with shallow respirations with decreased breath sounds in bilateral lower lung fields.Fig. 1 Chest X-ray on first admission showing diffuse reticular markings with bilateral airspace opacities.\n\nFig. 1\n\nA repeat chest x-ray showed moderate to large sized right-sided pneumothorax with right middle lobe pneumatocele and worsening bilateral airspace opacities (Fig. 2). A right-sided pig tail catheter was placed. His condition worsened requiring intubation and mechanical ventilation. A CT-thorax was performed showing multifocal bilateral ground-glass opacities with bilateral lower lobe consolidations and a 7.3 × 6.6 cm pneumatocele is noted in mid right posterior hemi thorax (Fig. 3). His hospital course was complicated with acute respiratory distress syndrome requiring proning. The patient received azithromycin, hydroxychloroquine, tocilizumab, steroids, and convalescent plasma as part of COVID-19 treatment.Fig. 2 Chest X-ray on second admission showing moderate to large sized right sided pneumothorax with right middle lobe pneumatocele and worsening bilateral airspace opacities (on left) and expanded lung post pig tail catheter placement (on right).\n\nFig. 2\n\nFig. 3 CT thorax showing multi focal bilateral ground-glass opacities and a 7.3 × 6.6 cm pneumatocele in mid right posterior hemi thorax in axial view (on left) and coronal view (on right).\n\nFig. 3\n\n1.2 Outcome & follow-up\n\nThe patient eventually was transitioned to tracheostomy after prolonged intubation. His repeat chest x-ray 2 months later showed near complete resolution of pneumatocele (Fig. 4). He was finally decannulated and discharged home.Fig. 4 Chest X-ray 3 month from admission showing near complete resolution of pneumatocele.\n\nFig. 4\n\n2 Discussion\n\nSARS-CoV-2 infection is known to cause a cytokine storm causing intense inflammatory reaction [5]. The most common radiological findings in COVID-19 are the presence of ground glass opacities. Pneumatoceles are air-filled, thin-walled cystic lesions in lung that commonly develop after a severe infection like empyema [6]. The common noninfectious etiologies include trauma, positive pressure ventilation and hydrocarbon ingestion. The inflammatory reaction causes obstruction and dilation of bronchi which ruptures causing air-filled cysts [7]. The pneumatocele in some instance can dissect through the pleural membrane and cause pneumothorax [8]. Imaging findings of thin-walled cyst on chest X-ray usually appear 5–6 days after infectious process. CT scan is usually performed and helps to differentiate an abscess. The imaging findings in COVID-19 pneumonia rarely showed the presence of pneumatocele. The treatment is usually focused at controlling the infection, in rare cases of tension pneumatocele a percutaneous drainage is performed [9]. In our case the pneumatocele resorbed once the inflammation subsided and did not require any surgical intervention.\n\nDeclaration of competing interest\n\nAre there any relevant conflicts of interest? NO.\n\nRelevant financial activities outside submitted work: None.\n\nNo other relationships/conditions/circumstances that present a potential conflict of interest.\n\nAll authors read the manuscript and approved for submission.\n==== Refs\nReferences\n\n1 World Health Organization Director-General's remarks at the media briefing on 2019-nCoV on 11 February https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 2020\n2 Wong H.Y.F. Lam H.Y.S. Fong A.H. Frequency and distribution of chest radiographic findings in COVID-19 positive patients [published online ahead of print, 2019 Mar 27] Radiology 2019 201160 10.1148/radiol.2020201160\n3 Bao C. Liu X. Zhang H. Li Y. Liu J. Coronavirus disease 2019 (COVID-19) CT findings: a systematic review and meta-analysis J. Am. Coll. Radiol. 17 6 2020 701 709 10.1016/j.jacr.2020.03.006 32283052\n4 Wu J. Feng L.C. Xian X.Y. [Novel coronavirus pneumonia (COVID-19) CT distribution and sign features]. Zhonghua jie he he hu xi za zhi = Zhonghua Jiehe he Huxi Zazhi Chinese Journal of Tuberculosis and Respiratory Diseases 43 4 2020 Apr 321 326 10.3760/cma.j.cn112147-20200217-00106 32125131\n5 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [published correction appears in Lancet. 2020 Jan 30;:] Lancet 395 10223 2020 497 506 10.1016/S0140-6736(20)30183-5 31986264\n6 Kunyoshi V. Cataneo D.C. Cataneo A.J. Complicated pneumonias with empyema and/or pneumatocele in children Pediatr. Surg. Int. 22 2 2006 186 190 10.1007/s00383-005-1620-5 16362309\n7 Boisset G.F. Subpleural emphysema complicating staphylococcal and other pneumonias J. Pediatr. 81 2 1972 Aug 259 266 4537790\n8 Amitai I. Mogle P. Godfrey S. Aviad I. Pneumatocele in infants and children. Report of 12 cases Clin. Pediatr. 22 6 1983 420 422 10.1177/000992288302200605\n9 Zuhdi M.K. Spear R.M. Worthen H.M. Peterson B.M. Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children Crit. Care Med. 24 2 1996 Feb 330 333 8605809\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "31()", "journal": "Respiratory medicine case reports", "keywords": "ARDS; COVID-19; Pneumatocele; Pneumothorax; SARS-CoV-2", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "101303", "pmc": null, "pmid": "33294361", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "4537790;8605809;16362309;31986264;6839622;32125131;32283052", "title": "Rapidly developing large pneumatocele and spontaneous pneumothorax in SARS-CoV-2 infection.", "title_normalized": "rapidly developing large pneumatocele and spontaneous pneumothorax in sars cov 2 infection" }	[ { "companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-293681", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201691", "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": "HYDROXYCHLOROQUINE" } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumothorax spontaneous", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary pneumatocele", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lung opacity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SANIVARAPU RR, FARRAJ K, SAYEDY N, ANJUM F. RAPIDLY DEVELOPING LARGE PNEUMATOCELE AND SPONTANEOUS PNEUMOTHORAX IN SARS?COV?2 INFECTION. RESPIRAT MED CASE REPORT. 2020?31:101303", "literaturereference_normalized": "rapidly developing large pneumatocele and spontaneous pneumothorax in sars cov 2 infection", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210430", "receivedate": "20210430", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19200310, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "Human immunodeficiency virus-infected patients are at increased risk of drug reactions because of immune dysregulation and multiple drug intake. Lichenoid drug reactions to isoniazid have been reported previously in the literature. However, for lichenoid drug reaction to isoniazid to be so extensive to present as exfoliative dermatitis is rare. We report here a rare case of lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome.", "affiliations": "Department of Dermatology and STD, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India [email protected].;Department of Dermatology and STD, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India.;Department of Pathology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India.", "authors": "Thakur\|B K\|BK\|;Verma\|S\|S\|;Mishra\|J\|J\|", "chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid", "country": "England", "delete": false, "doi": "10.1177/0956462414543123", "fulltext": null, "fulltext_license": null, "issn_linking": "0956-4624", "issue": "26(7)", "journal": "International journal of STD & AIDS", "keywords": "AIDS; HIV; adverse drug reaction; antibiotics; antiretroviral therapy; drug rash; exfoliative dermatitis; isoniazid; lichenoid", "medline_ta": "Int J STD AIDS", "mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000995:Antitubercular Agents; D003873:Dermatitis, Exfoliative; D003875:Drug Eruptions; D015658:HIV Infections; D006801:Humans; D007538:Isoniazid; D017512:Lichenoid Eruptions; D008297:Male; D010328:Patch Tests; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary", "nlm_unique_id": "9007917", "other_id": null, "pages": "512-5", "pmc": null, "pmid": "25013221", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome.", "title_normalized": "lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome" }	[ { "companynumb": "IN-WATSON-2015-24043", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE AND TRIMETHOPRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EFAVIRENZ" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080521", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lichenoid keratosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "THAKUR BK, VERMA S, MISHRA J. LICHENOID DRUG REACTION TO ISONIAZID PRESENTING AS EXFOLIATIVE DERMATITIS IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME. INT J STD AIDS. 2015?26(7):512-5.", "literaturereference_normalized": "lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151112", "receivedate": "20151112", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11726929, "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": "PHHY2015IN081662", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULPHAMETHOXAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EFAVIRENZ" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008662", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Papule", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lichenoid keratosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dermatitis exfoliative", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Exfoliative rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin exfoliation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "THAKUR BK, VERMA S, MISHRA J. LICHENOID DRUG REACTION TO ISONIAZID PRESENTING AS EXFOLIATIVE DERMATITIS IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME. INT-J-STD-AIDS. 2015;26(7):512-15", "literaturereference_normalized": "lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20150714", "receivedate": "20150714", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11271273, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "Propranolol emerged as the first-line therapy for infantile hemangioma (IH). Determinants of interindividual variation in drug response and predictors of rebound growth after drug discontinuation are yet to be firmly established. We aimed to evaluate the outcomes of a relatively large cohort of patients with IH treated by propranolol and to determine predictors of (a) an excellent response to treatment (≥90 improvement) and (b) of rebound growth after drug cessation. A retrospective cohort study was conducted to follow all patients with IH receiving systemic propranolol in a referral center-based specialized clinic. Multivariate logistic regression analysis was performed to identify predictors of excellent response and rebound growth. The study included 206 patients who completed oral propranolol treatment. The mean (SD) age in which the drug was initiated was 4.8 (3.1) months. The average improvement rate was estimated at 85.5 (13.8)%. Initiation of propranolol at the age of 0 to 3 (adjusted odds ratio [OR], 3.43; 95% confidence interval [CI], 1.25-9.40; P = .016) and 3 to 6 (adjusted OR, 3.71; 95% CI, 1.50-9.19; P = .005) months was associated with an increased likelihood of excellent response. Twenty-four (11.7%) patients developed rebound growth following cessation of propranolol. No significant predictors of rebound were identified in the multivariate analysis. Eleven (5.3%) patients experienced mild adverse events, which necessitated drug discontinuation in only two (1.0%) patients. Propranolol is highly effective and safe based on the real-life experience of a referral center for IH. The current study supports early initiation of propranolol.", "affiliations": "Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.;Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.;Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.", "authors": "Pam\|Nadav\|N\|;Kridin\|Khalaf\|K\|0000-0001-9971-9151;Khamaysi\|Ziad\|Z\|", "chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol", "country": "United States", "delete": false, "doi": "10.1111/dth.14936", "fulltext": null, "fulltext_license": null, "issn_linking": "1396-0296", "issue": "34(3)", "journal": "Dermatologic therapy", "keywords": "infantile hemangioma; late infancy; post proliferative; propranolol", "medline_ta": "Dermatol Ther", "mesh_terms": "D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists; D015331:Cohort Studies; D006391:Hemangioma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011433:Propranolol; D012017:Referral and Consultation; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "9700070", "other_id": null, "pages": "e14936", "pmc": null, "pmid": "33704861", "pubdate": "2021-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Propranolol for infantile hemangioma: Evaluating efficacy and predictors of response and rebound growth.", "title_normalized": "propranolol for infantile hemangioma evaluating efficacy and predictors of response and rebound growth" }	[ { "companynumb": "IL-INNOGENIX, LLC-2120277", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROPRANOLOL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "070322", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Infantile haemangioma", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPRANOLOL HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hypoglycaemic seizure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Khamaysi Z, Pam N, Kridin K. Propranolol for infantile hemangioma: Evaluating efficacy and predictors of response and rebound growth. Dermatologic Therapy 34: No. 3, Jun 2021. URL: http://onlinelibrary.wiley.com/journal/10.1111/", "literaturereference_normalized": "propranolol for infantile hemangioma evaluating efficacy and predictors of response and rebound growth", "qualification": "3", "reportercountry": "IL" }, "primarysourcecountry": "IL", "receiptdate": "20211007", "receivedate": "20211007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19926588, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220303" } ]
{ "abstract": "BACKGROUND\nTamoxifen is often used as antihormonal therapy in patients with breast cancer. However, it has various side effects, of which pneumonia is a rare occurrence.\n\n\nMETHODS\nA 46-year-old female patient with breast cancer underwent surgical treatment. Tamoxifen was administered as adjuvant therapy on post-operative day 14; 2 days after administration of tamoxifen, the patient developed high fever of more than 39 °C and cough with dyspnea. Based on chest computed tomography findings of ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs, eosinophilic pneumonia was suspected. Tamoxifen was discontinued and methylprednisolone injection was administered; the patient showed improvement of symptoms and radiographic findings.\n\n\nCONCLUSIONS\nTamoxifen was suspected as the cause of eosinophilic pneumonia since the patient developed high-grade fever at the time of tamoxifen administration, which subsided after discontinuation of the treatment. Other factors considered as the cause of pneumonia were examined, but all showed negative results. In order to confirm tamoxifen as the cause of pneumonia, tamoxifen treatment was restarted at follow-up (post-operative day 47); however, after 1 month, regular administration was not possible due to the development of itching symptom and difficulty in obtaining the patient's cooperation.\n\n\nCONCLUSIONS\nThe study highlights that if the patient on tamoxifen develops high fever and cough with dyspnea at 2-3days after the first administration, tamoxifen-induced pneumonia should be suspected.", "affiliations": "Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea. Electronic address: [email protected].", "authors": "Kwon\|Eiyoung\|E\|;Kim\|Mijin\|M\|;Choi\|Eunhye\|E\|;Park\|Youngsam\|Y\|;Kim\|Cheolseung\|C\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijscr.2019.02.026", "fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30086-010.1016/j.ijscr.2019.02.026ArticleTamoxifen-induced acute eosinophilic pneumonia in a breast cancer patient Kwon Eiyoung Kim Mijin Choi Eunhye Park Youngsam Kim Cheolseung [email protected]⁎Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea⁎ Corresponding author at: Department of Surgery, Presbyterian Medical Center, 365 Seowon-ro, Wansan-gu, Jeon-ju 54987, Republic of Korea. [email protected] 2 2019 2019 27 2 2019 60 186 190 13 12 2018 8 2 2019 13 2 2019 © 2019 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• If a patient who is taking tamoxifen coughs, be aware of the possibility of pneumonia caused by Tamoxifen.\n\n• Tamoxifen is one of the cause of drug-induced lung injury.\n\n\n\nIntroduction\nTamoxifen is often used as antihormonal therapy in patients with breast cancer. However, it has various side effects, of which pneumonia is a rare occurrence.\n\nPresentation of case\nA 46-year-old female patient with breast cancer underwent surgical treatment. Tamoxifen was administered as adjuvant therapy on post-operative day 14; 2 days after administration of tamoxifen, the patient developed high fever of more than 39 °C and cough with dyspnea. Based on chest computed tomography findings of ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs, eosinophilic pneumonia was suspected. Tamoxifen was discontinued and methylprednisolone injection was administered; the patient showed improvement of symptoms and radiographic findings.\n\nDiscussion\nTamoxifen was suspected as the cause of eosinophilic pneumonia since the patient developed high-grade fever at the time of tamoxifen administration, which subsided after discontinuation of the treatment. Other factors considered as the cause of pneumonia were examined, but all showed negative results. In order to confirm tamoxifen as the cause of pneumonia, tamoxifen treatment was restarted at follow-up (post-operative day 47); however, after 1 month, regular administration was not possible due to the development of itching symptom and difficulty in obtaining the patient’s cooperation.\n\nConclusion\nThe study highlights that if the patient on tamoxifen develops high fever and cough with dyspnea at 2–3days after the first administration, tamoxifen-induced pneumonia should be suspected.\n\nKeywords\nBreast cancerTamoxifenEosinophilic pneumonia\n==== Body\n1 Introduction\nThe incidence of breast cancer in Korea is increasing, and the incidence of estrogen receptor (ER) positive breast cancer increased from 58.2% in 2002 to 73.7% in 2015 [1]. Tamoxifen is a selective estrogen receptor modulator that can be used to increase the treatment effect in hormone receptor (HR) positive breast cancer diagnosed prior to menopause and metastatic or recurrent HR positive breast cancer [1]. Various side effects of tamoxifen such as weight gain, sexual dysfunction, hot flashes, neurocognitive deficits, thrombogenic events, and ocular events have been reported [2]. However, tamoxifen-induced pneumonia is a very rare side effect [3].\n\nHerein, we present a case of acute eosinophilic pneumonia after tamoxifen administration in a patient with ER positive breast cancer patient who underwent mastectomy. This work is reported in line with the SCARE criteria [13].\n\n2 Presentation of case\nA 46-year-old female patient presented to our outpatient clinic for further evaluation of a mass in the left breast that was detected incidentally at a routine health screen in February 2018. She was transferred from the intensive care unit at another center where she was admitted for the treatment of exacerbated epilepsy. Anamnesis revealed a history of mental retardation and medication for epilepsy, but no history of allergy, smoking, and surgery; family history indicated that her sister had received treatment for breast cancer. Ultrasound-guided core needle biopsy performed at our center confirmed a diagnosis of invasive ductal carcinoma. Positron emission tomography–computed tomography and breast ultrasound showed the absence of axillary lymph node involvement, and breast magnetic resonance imaging could not be performed due to the patient’s lack of cooperation. Skin-sparing mastectomy and reconstruction with silicone was performed on April 11, 2018. Histology indicated invasive ductal carcinoma with a mass of 26 × 15 × 15 mm and metastasis in 9 of 10 axillary lymph nodes. The cancer stage was IIIA with T2N2aM0, with ER 8(5 + 3), PR 8(5 + 3), c-erbB2(1+/3), and KI-67(10%).\n\nTreatment with tamoxifen (20 mg/daily) was started on post-operative day 14. On post-operative day 16 (day 3 of tamoxifen treatment), she showed no symptoms other than fever of 39.1 °C. The results of investigation to determine the cause of fever were normal (WBC 6.6 × 103/uL, eosinophil 0.6%) except for mild elevation in the C-reactive protein (CRP) level of 1.13 mg/dL. Culture test for wound infection, using 7 mL of fluid obtained under ultrasound guidance was negative.\n\nSince wound infection could not be completely ruled out as a cause of fever, rifampin (150 mg twice daily) was administered. However, there was persistence of fever of above 39 °C on post-operative day 19 (day 6 of tamoxifen treatment), and absence of redness or pain at the wound site. To rule out antibiotic-related fever, the antibiotic regimen was switched to combined piperacillin and tazobactam, and vancomycin.\n\nOn post-operative day 20 (day 7 of tamoxifen treatment), the patient had cough with profuse sputum production and fever of 40.5 °C. Chest radiograph showed soft haziness at the right middle lung field and blunting of the costophrenic angle with subsegmental atelectasis at the left lower lung field [Fig. 1]. Complete blood count showed a marked increase in the level of eosinophils from 0.2% on day 5 to 3.7% on day 7 of tamoxifen treatment, but WBC was not elevated at 4.8 × 103/uL and the CRP level was increased to 7.94 mg/dL.Fig. 1 Chest x-ray on post-operative Day 20. Soft haziness in the right middle lung field and costophrenic angle blunting with subsegmental atelectasis in left lower lung field are observed.\n\nFig. 1\n\nOn postoperative day 21(day 8 of tamoxifen treatment), chest computed tomography(CT) was performed, which showed ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs. Based on these findings, the patient was diagnosed with suspicious eosinophilic pneumonia [Fig. 2]. She complained of severe dyspnea and showed unstable oxygen saturation of 88% and was transferred to the intensive care unit for close monitoring. The laboratory investigations at the time showed WBC 5.2 × 103/uL, eosinophil 3.6%, and a further increase in CRP level to 8.63 mg/dL. Concomitant blood culture was negative.Fig. 2 Chest CT on post-operative Day 21. Ground-glass opacification and interlobular septal thickening, and mild pleural effusion in both lungs.\n\nFig. 2\n\nTamoxifen, administered from post-operative day 14, was considered as the probable cause of eosinophilic pneumonia, and discontinued on post-operative day 21 after chest CT was performed. Methylprednisolone (30 mg twice daily) was administered intravenously and tapered by 10 mg every 3 days. Oral methylprednisolone (24 mg daily) was started from post-operative day 29, and reduced dose of the drug (12 mg daily) was administered from post-operative day 33. After the discontinuation of tamoxifen, there was less fever and recovery to normal temperature at day 3 post-discontinuation of tamoxifen. Oxygen saturation was recovered to normal level, and dyspnea was improved. Chest radiographs acquired daily after discontinuation of tamoxifen showed a decrease in haziness, and sputum and cough were reduced.\n\nMycoplasma pneumonia immunoglobulin M (IgM), Chlamydia pneumonia IgM, pneumonia urinary antigen, Gram stain, and polymerase chain reaction for Mycoplasma tuberculosis performed in the intensive care unit on post-operative day 22 demonstrated negative results. On postoperative day 33 (day 12 post-discontinuation of tamoxifen), the patient showed improvement of symptoms and was discharged.\n\n3 Discussion\nEosinophilic lung disease refers to a condition with an increase in eosinophil count in the peripheral blood or lung tissue [[4], [5], [6]]. Allen and Davis classified eosinophilic pneumonia as an increase in eosinophils in the peripheral blood accompanied by lung infiltration on chest radiography, or eosinophil infiltration through lung histology without an increase in eosinophils in the peripheral blood, or alveolar lavage fluid [4,5]. Eosinophilic lung diseases include simple pulmonary eosinophilia, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, idiopathic hypereosinophilic syndrome, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, parasites, and drugs [4,5]. Acute eosinophilic pneumonia can be defined as fever and respiratory distress with myalgia, chest pain, and hypoxia of 1–5 days’ duration that completely resolve without recurrence spontaneously or after the administration of an adrenal cortex hormone in patient without underlying respiratory disease [4,5].\n\nAcute eosinophilic pneumonia shows the following test results: minute interstitial lung infiltration on the chest radiograph that progresses rapidly within 2 days to mixed alveolar and interstitial infiltration, bilateral ground glass opacity and diffuse, reticular densities on CT [6,7]. Acute eosinophilic pneumonia can be caused by drugs. Drugs known to cause acute eosinophilic pneumonia are listed in Table 1 [5,6].Table 1 Drugs causing eosinophilic lung disease.\n\nTable 1Ampicillin\tMethylphenidate\t\nBeclomethasone dipropionate\tMinocycline\t\nBleomycin\tNaproxen\t\nCarbamazepine\tNickel\t\nChlorpromazine\tNitrofurantoin\t\nClofibrate\tPara-aminosalicylic acid\t\nCocaine(inhaled)\tPenicillin\t\nCromolyn(inhaled)\tPentamidine(inhaled)\t\nDesipramine\tPhenytoin\t\nDiclofenac\tPyrimethamine\t\nFebarbamate\tRapeseed oil\t\nGlafenine\tSulfadimethoxime\t\nGM-CSF\tSulfasalazine\t\nIbuprofen\tSulindac\t\nInterleukin 2&3\tTamoxifen\t\nIodinated contrast media\tTetracycline\t\nl-Tryptophan\tTolazamide\t\nMephenesin carbamate\tTolfenamic acid\t\nMethotrexate\tVaginal sulfonamide cream\t\nAdapted from Allen and Davis [5].\n\nTamoxifen, often used as antihormonal therapy in the treatment of breast cancer, can cause various side effects such as weight gain, sexual dysfunction/loss of libido, hot flashes, neurocognitive deficits, thromboembolic events, ocular events, mood alterations, depression, GI disturbance, bone pain, leg cramps, and insomnia [2]. Pneumonia is a rare side effect of tamoxifen and there are only a few reports of pneumonia in patients who were started on tamoxifen after surgery for breast cancer [[7], [8], [9], [10], [11]].\n\nIn our case, tamoxifen was considered as the cause of eosinophilic pneumonia due to the association between fever onset and time of first tamoxifen administration. The patient developed high-grade fever of over 39 °C from day 3 of tamoxifen administration, which subsided after the discontinuation of tamoxifen [Fig. 3].Fig. 3 Patient’s body temperature and eosinophil count by tamoxifen administration.\n\nFig. 3\n\nTo confirm tamoxifen as the cause of a patient’s pneumonia, tamoxifen should be restarted under patient monitoring for pneumonia recurrence as described in Etori et al. [3]. Previous case reports of tamoxifen-induced pneumonia according to the symptoms, symptom onset-time from medication, and restarting or not are summarized in Table 2.Table 2 Side effects of tamoxifen-induced pneumonia in previous case report.\n\nTable 2\tSymptom onset at post-medication time point\tSymptoms\tRestarting\tSymptoms after restarting\t\nAhmed et al. [10]\t1week\tCough\tNo\tNot reported\t\n\t\tdyspnea\t\t\t\n\t\tintermittent fever\t\t\t\n\t\tmechanical ventilation\t\t\t\nShiiki et al. [12]\t2day\tCough\tYes\tCough\t\n\t\tdyspnea\t\tdyspnea\t\nEtori et al. [3]\t3month\tMild cough\tYes\tCough\t\n\t\t\t\tdyspnea on exertion\t\nKwon et al.a\t3day\tCough\tYes\tItching sense\t\n\t\tdyspnea\t\t\t\n\t\tFever (40.5 °C)\t\t\t\nAll cases had initial and restarting dose of tamoxifen of 20 mg daily.\n\na Current study.\n\n\n\nIn this case, the patient was restarted on tamoxifen 20 mg once daily from May 28, 2018 to confirm tamoxifen as the cause of pneumonia and as choice treatment based on the patient’s age, histology, and pre-menopausal status. Since the patient experienced tamoxifen-related adverse events, alternative therapy with an aromatase inhibitor was considered. Unlike tamoxifen, aromatase inhibitors are only administered after menopause, hence bilateral salpingooophorectomy(BSO) was required in our patient to induce menopause. The option of BSO and aromatase inhibitor was discussed with the patient’s caregiver, and declined based on the concern that the patient’s mental status would prevent her from accepting the consequences of surgery and increase her feelings of loss. Concurrent silicone implantation performed at the time of mastectomy was also due to the caregiver’s concern for the patient’s feeling of loss, though the patient was foreseen to require radiotherapy due to suspicion of axillary lymph node metastasis. However, since the time to natural menopause was too long in our patient, she was administered tamoxifen with methylprednisolone (4 mg twice daily) from May 18, 2018. However, after 1 months’ treatment, regular administration was not possible due to the patients’ symptom of itching and lack of cooperation.\n\n4 Conclusion\nThe current study highlights that in patients undergoing treatment with tamoxifen, if there is development of high-grade fever at 2–3 days after first administration and chest CT shows ground-glass opacification, interlobular septal thickening, and mild pleural effusion, eosinophilic pneumonia due to tamoxifen should be suspected, and tamoxifen should be discontinued. Discontinuation of tamoxifen alone may improve the patient’s symptoms. However, for patients with advanced symptoms, steroid therapy may help to alleviate the symptoms.\n\nConflicts of interest\nThe authors declare that they have no competing interests.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nIn our institute, ethical approval is exempted, depend on acquired patient consent.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAuthor’s contribution\nKwon EY: writing paper, data collection, table making\n\nKim MJ : data analysis, figure making\n\nChoi EH : data collection, manuscript review\n\nPark YS : manuscript review\n\nKim CS : study design, manuscript review\n\nRegistration of research studies\nWe don’t need to register this work.\n\nGuarantor\nCheolseung Kim.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n==== Refs\nReferences\n1 Korean Breast Cancer Society [Internet], Seoul: Korean Breast Cancer Facts and Figures; c2017 [Cited 10 October 2018]. Available from : http://kbcs.or.kr/journal/file/2017_Breast_Cancer_Facts_and_Figures.pdf.\n2 Pemmaraju N. Munsell M.F. Hortobagyi G.N. Giordano S.H. Retrospective review of male breast cancer patients: analysis of tamoxifen-related side-effects Ann. Oncol. 23 June (6) 2012 1471 1474 22085764 \n3 Etori S. Nakano R. Kamada H. Hosokawa K. Takeda S. Fukuhara M. Tamoxifen induced lung injury Intern. Med. 56 November (21) 2017 2903 2906 28943550 \n4 Choi D.C. Eosinophilic lung disease : diagnosis & treatment Korean J. Intern. Med. 76 3 2009 274 281 \n5 Allen J.N. Davis W.B. Eosinophilic lung disease Am. J. Respir. Crit. Care Med. 150 November (5) 1994 1423 1438 7952571 \n6 Kim Y.K. Lee K.S. Choi D.C. Primack S.L. Im J.G. The spectrum of eosinophilic lung disease J. Comput. Assist. Tomogr. 21 November (6) 1997 920 930 9386285 \n7 Cheon J.E. Lee K.S. Jung G.S. Chung M.H. Cho Y.D. Acute eosinophilic pneumonia: radiographic and CT findings in six patients AJR Am. J. Roentgenol. 167 November (5) 1996 1195 1199 8911179 \n8 Camus P. Fanton A. Bonniaud P. Camus C. Foucher P. Interstitial lung disease induced by drugs and radiation Respiration 71 July (4) 2004 301 326 15316202 \n9 Bentzen S.M. Skoczylas J.Z. Overgaard M. Overgaard J. Radiotherapy-related lung fibrosis enhanced by tamoxifen J. Natl. Cancer Inst. 88 July (13) 1996 918 922 8656444 \n10 Ahmed S. Shahid R.K. Acute interstitial pneumonitis following adjuvant tamoxifen therapy J. Clin. Oncol. 27 15 2009 e11637 \n11 Katayama N. Sato S. Katsui K. Takemoto M. Yoshoida A. Morito T. Analysis of factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia syndrome after breastconserving therapy Int. J. Radiat. Oncol. Biol. Phys. 73 March (4) 2009 1049 1054 18755559 \n12 Shiiki S. A case of drug-induced pneumonia due to tamoxifen Nihon Rinsho Geka Gakkai Zasshi (J. Jpn. Surg. Assoc.) 64 April (12) 2003 3040 3043 \n13 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus surgical case report (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279\n\n", "fulltext_license": "CC BY", "issn_linking": "2210-2612", "issue": "60()", "journal": "International journal of surgery case reports", "keywords": "Breast cancer; Eosinophilic pneumonia; Tamoxifen", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "186-190", "pmc": null, "pmid": "31229774", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "8656444;30342279;28943550;18755559;9386285;7952571;8911179;15316202;22085764", "title": "Tamoxifen-induced acute eosinophilic pneumonia in a breast cancer patient.", "title_normalized": "tamoxifen induced acute eosinophilic pneumonia in a breast cancer patient" }	[ { "companynumb": "KR-TEVA-2019-KR-1081469", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TAMOXIFEN" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "070929", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MILLIGRAM DAILY; STARTED ON POST-OPERATIVE DAY 14; DISCONTINUED ON POST-OPERATIVE DAY 21", "drugenddate": null, "drugenddateformat": null, "drugindication": "INVASIVE DUCTAL BREAST CARCINOMA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "1", "drugrecurrence": [ { "drugrecuraction": "Eosinophilic pneumonia" }, { "drugrecuraction": "Pruritus" } ], "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TAMOXIFEN" } ], "patientagegroup": null, "patientonsetage": "46", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pruritus", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Eosinophilic pneumonia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "KWON E, KIM M, CHOI E, PARK Y, KIM C. 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{ "abstract": "OBJECTIVE\nCiprofloxacin is considered to be a safe and effective treatment for acute infectious colitis. However, this drug may cause drug-induced pancreatitis, albeit rarely.\n\n\nMETHODS\nFrom March 2007 to February 2012, we studied 227 patients who were hospitalized for infectious colitis at St. Mary's Hospital. All of the patients received ciprofloxacin therapy for the treatment of infectious colitis. We observed a few cases of rare adverse events, including ciprofloxacin-induced acute pancreatitis diagnosed based on the Naranjo algorithm.\n\n\nRESULTS\nDuring ciprofloxacin therapy, seven of 227 patients (3.1%) developed rare pancreatitis as defined by the Naranjo algorithm; pancreatic enzyme activity was sporadically elevated with ciprofloxacin use. After ciprofloxacin administration, the average interval until the development of pancreatitis was 5.5 days (range, 4 to 7 days). On abdominal computed tomography, pancreatic swelling and homogenous enhancement was noted in three of seven patients. Complicating acute pancreatitis was gradually but completely resolved after cessation of ciprofloxacin administration. The mean recovery time was 11.3 days (range, 8 to 15 days).\n\n\nCONCLUSIONS\nWe observed that ciprofloxacin-induced pancreatitis may occur with an incidence of approximately 3%. Ciprofloxacin-induced pancreatitis presents a short latency, suggesting an idiosyncratic hypersensitivity reaction. Practitioners should be aware that drug-induced pancreatitis can occur during ciprofloxacin therapy.", "affiliations": "Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.", "authors": "Sung\|Hye Young\|HY\|;Kim\|Jin Il\|JI\|;Lee\|Hyun Jeong\|HJ\|;Cho\|Hyung Jun\|HJ\|;Cheung\|Dae Young\|DY\|;Kim\|Sung Soo\|SS\|;Cho\|Se Hyun\|SH\|;Kim\|Jae Kwang\|JK\|", "chemical_list": "D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004952:Esters; D006146:Guanidines; C034532:camostat; D016670:Gabexate; D002939:Ciprofloxacin", "country": "Korea (South)", "delete": false, "doi": "10.5009/gnl.2014.8.3.265", "fulltext": "\n==== Front\nGut LiverGut LiverGNLGut and Liver1976-22832005-1212The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Pancreatobiliary Association; Korean Society of Gastrointestinal Cancer 2482762210.5009/gnl.2014.8.3.265Original ArticleAlimentary TractAcute Pancreatitis Secondary to Ciprofloxacin Therapy in Patients with Infectious Colitis Sung Hye Young aKim Jin Il Lee Hyun Jeong Cho Hyung Jun Cheung Dae Young Kim Sung Soo Cho Se Hyun Kim Jae Kwang Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.\nCorrespondence to: Jin Il Kim. Division of Gastroenterology, Department of Internal Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, 10 63-ro, Yeongdeungpo-gu, Seoul 150-713, Korea. Tel: +82-2-3779-1519, Fax: +82-2-3779-1331, [email protected] affiliation: Department of Internal Medicine, Wonkwang University Sanbon Hospital, Gunpo, Korea.\n\n5 2014 24 12 2013 8 3 265 270 25 3 2013 03 6 2013 03 6 2013 Copyright © 2014 by the Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association for the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nCiprofloxacin is considered to be a safe and effective treatment for acute infectious colitis. However, this drug may cause drug-induced pancreatitis, albeit rarely.\n\nMethods\nFrom March 2007 to February 2012, we studied 227 patients who were hospitalized for infectious colitis at St. Mary's Hospital. All of the patients received ciprofloxacin therapy for the treatment of infectious colitis. We observed a few cases of rare adverse events, including ciprofloxacin-induced acute pancreatitis diagnosed based on the Naranjo algorithm.\n\nResults\nDuring ciprofloxacin therapy, seven of 227 patients (3.1%) developed rare pancreatitis as defined by the Naranjo algorithm; pancreatic enzyme activity was sporadically elevated with ciprofloxacin use. After ciprofloxacin administration, the average interval until the development of pancreatitis was 5.5 days (range, 4 to 7 days). On abdominal computed tomography, pancreatic swelling and homogenous enhancement was noted in three of seven patients. Complicating acute pancreatitis was gradually but completely resolved after cessation of ciprofloxacin administration. The mean recovery time was 11.3 days (range, 8 to 15 days).\n\nConclusions\nWe observed that ciprofloxacin-induced pancreatitis may occur with an incidence of approximately 3%. Ciprofloxacin-induced pancreatitis presents a short latency, suggesting an idiosyncratic hypersensitivity reaction. Practitioners should be aware that drug-induced pancreatitis can occur during ciprofloxacin therapy.\n\nAnti-bacterial agentsPancreatitisDrug toxicityInfectious colitis\n==== Body\nINTRODUCTION\nCiprofloxacin, a synthetic 4-quinolone derivative, is a widely used, broad-spectrum antibiotic.1 Generally, it is considered to be a safe and effective treatment of acute infectious colitis.2,3 Additionally, it is a widely used empirical therapy for travelers' diarrhea.4 However, ciprofloxacin can, in rare cases, cause drug-induced pancreatitis. Until now, there has only been one case report associated with ciprofloxacin in the literature.5 In March 2007, we observed ciprofloxacin-induced pancreatitis in a patient with infectious colitis during therapeutic use. Since 2007, we have been aware that drug-induced pancreatitis can occur during ciprofloxacin therapy. And we have continued monitoring chemical profiles during ciprofloxacin use in patients with infectious colitis. As a result, here we describe seven patients who developed acute pancreatitis after receiving ciprofloxacin to treat infectious colitis. The patients with infectious colitis were kept nil per os (NPO; keeping off ingestion) other than ciprofloxacin during treatment of infection colitis, so other drug effects can be excluded completely. As a result, we think that hospitalized patients with infectious colitis are a good cohort to discriminate side effects of ciprofloxacin. The study's aim was to identify the clinical features and natural course of drug-induced pancreatitis by ciprofloxacin during therapeutic use.\n\nMATERIALS AND METHODS\n1. Patients\nBetween March 2007 and February 2012, 227 patients were hospitalized for moderate to severe infectious colitis at St. Mary's Hospital, Seoul, Korea. Infectious colitis was diagnosed according to clinical history with colonoscopy finding. After admission, they were enrolled in the infectious colitis registry. At initial admission, all patients received ciprofloxacin therapy while keeping NPO for bowel rest. During ciprofloxacin therapy, rare adverse events suggesting drug-induced pancreatitis were recorded in a few patients. In these cases, we stopped ciprofloxacin and recorded their clinical features while administering conservative treatment. We excluded the patients who had acute pancreatitis at initial admission or who had gallstones or common bile stones from this registry.\n\n2. Clinical assessment and management in patients with infectious colitis\nThe patients visited our emergency department because of severe abdominal pain, diarrhea, and/or vomiting for several days. At initial admission, all patients were assessed via colonoscopy and blood chemical profiles such as hemoglobin, white blood cell, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase (γ-GTP), amylase, and lipase. Initially, abdominal computed tomography was performed to exclude vascular insufficiency or other diseases. After admission, patients were started on intravenous ciprofloxacin therapy (400 mg of intravenous ciprofloxacin two times daily for 3 days to 4 days). They were kept NPO for a bowel rest with parenteral nutritional support. If their abdominal pain and diarrhea were improved, they receive a soft diet and oral ciprofloxacin therapy (500 mg of oral ciprofloxacin two times daily for 3 days to 5 days). Chemical profiles were monitored regularly, once every 3 days. If an adverse event was recorded on chemical profiles during ciprofloxacin therapy, the therapy was ceased, and clinical feature were observed while conservative treatment was administered. All patients were monitored using the Naranjo algorithm for assessing probability of an adverse drug reaction.6\n\n3. Statistical analysis\nWe assessed whether initial demographic variables were associated with drug-induced pancreatitis by ciprofloxacin. All statistical analyses were performed using the SPSS version 12.0 (SPSS Inc., Chicago, IL, USA). Pearson chi-square test was used for comparison of the categorical variables. Statistical comparisons of the symptom score between the normal and abnormal test group was performed using an independent-samples t-test. For all tests, the significance level was established at a value of p<0.05.\n\n4. Ethical considerations\nThis study was approved by the Institutional Review Board (IRB) at the St. Mary's Hospital of The Catholic University of Korea College of Medicine (IRB number, SC11RISI0065). The study was carried out in accordance with the recommendations of the Declaration of Helsinki.\n\nRESULTS\n1. Demographic characteristics\nBetween March 2007 and February 2012, 227 patients were hospitalized and enrolled in an infectious colitis registry at St. Mary's Hospital (113 males and 114 females with a mean age of 50.5±21.8 years; range, 14 to 92 years). Mean hospital stay was 5.1±5.3 days. After admission, all patients received intravenous ciprofloxacin and nutritional support. Ciprofloxacin was a safe and effective drug for the treatment of infectious colitis in 220 of 227 (96.9%) patients. These patients successfully recovered from infectious colitis. However, seven of 227 patients (3.1%) experienced an adverse event (four males and three females with a mean age of 46.9±17.4 years; range, 24 to 71 years). Clinical characteristics are summarized at Table 1. The development of drug-induced pancreatitis had no relation with age or sex (p=0.33, p=0.36, respectively). The total duration of hospital stay was much longer in patients with drug-induced pancreatitis (5.1±5.3 vs 19.0±6.8, p=0.002).\n\n2. Diagnosis of drug-induced pancreatitis\nSeven patients showed abnormal pancreatic enzymes; amylase and lipase levels were elevated. Pancreatitis was diagnosed by the concurrence of at least two of the following findings:7 1) newly onset epigastric abdominal pain during admission; 2) elevated serum amylase and lipase levels at three times the upper level of the normal range; and 3) imaging evidence of pancreatic inflammation on radiologic study. In all seven cases described, other causes of pancreatitis were completely ruled out. None of the patients had significant alcohol use, nor were there family histories of pancreatitis. Cholelithiasis was not present, and triglyceride levels were normal. Furthermore, all the seven patients were not receiving any medications except for ciprofloxacin. They were kept NPO after admission with infectious colitis for bowel rest. Having probable pancreatitis was considered secondary to ciprofloxacin by the Naranjo algorithm.6 After ciprofloxacin administration, the average time interval until development of pancreatitis was 5.5 days (range, 4 to 7 days) (Table 1, Fig. 1). This short time frame of latency suggests a hypersensitivity reaction. Abdominal imaging was performed to exclude other possible causes of pancreatitis and to assess the severity of pancreatitis. Abdominal imaging did not show gallstones or gallbladder wall thickening in any of these patients. Pancreas swelling and homogenous enhancement were noted in three of seven patients (42.9%) (Figs 2 and 3).\n\n3. Treatment option for drug-induced pancreatitis and therapeutic efficiency after conservative care\nIn cases of adverse reactions, we immediately stopped ciprofloxacin administration. These patients were kept NPO with parenteral nutritional support. The treatment was targeted to pancreatic enzyme intravenous Gabexate Mesilate (Foy inj®, 200 mg/day; Dong-A ST Co., Seoul, Korea) was given for several days for acute pancreatitis. If the pancreatic enzyme was declined, treatment was changed to per oral Camostat Mesilate (Foipan®, 300 mg/day; Ilsung Co., Seoul, Korea) until the chemical profile returned to normal. Complicating acute pancreatitis was completely resolved gradually after the removal of ciprofloxacin. Mean recovery time for drug-induced pancreatitis was 11.3 days (range, 8 to 15 days) (Table 1, Fig. 1). The patients had no further abdominal pain episodes and remained stable for the remainder of the hospital day. All the patients have been doing well and denied any gastrointestinal symptoms. After discharge, an outpatient follow-up of blood chemistries demonstrated that the pancreatic enzyme stayed in the normal range.\n\nDISCUSSION\nCiprofloxacin is now widely used for a number of conditions and, in particular, is thought to be appropriate for early self-treatment of moderate to severe travelers' diarrhea in adults.4 Additionally, it is considered to be a safe and effective treatment for acute infectious colitis.2,3 Its lack of serious adverse effects has been an important factor in its use for what is usually a benign, self-limiting condition. Of 63,059 patients given oral ciprofloxacin, adverse effects occurred in 5.8% of patients, with 3.4% being of a gastrointestinal nature.7 The U.K. Medicine Control Agency received 635 reports of serious reactions per 1 million prescriptions of ciprofloxacin since the drug launch in 1987 through 1995.7 Common gastrointestinal side effects include diarrhea, Clostridium difficile enterocolitis, and abnormalities of liver biochemistry. The drug is generally associated with mild, reversible elevation of liver enzymes and bilirubin in approximately 2% to 3% of patients.2 In the pancreatic field, ciprofloxacin can be a useful tool as an empirical therapy in necrotizing pancreatitis to prevent secondary bacterial infection,8,9,10,11 because ciprofloxacin penetrates the human pancreas very well.12,13 However, ironically, it is claimed that the ciprofloxacin can, in rare cases, cause drug-induced pancreatitis. Until now, there has only been one case report associated with ciprofloxacin in the literature.5 Since March 2007, we observed seven cases of ciprofloxacin-induced pancreatitis in patients with infectious colitis during therapeutic use. In the prior report, the first episode of pain was undiagnosed, the clinical features were compatible with acute pancreatitis and on rechallenge with the same drug 18 months later, a similar episode of pain was confirmed as acute pancreatitis.5 Drug-induced pancreatitis is a rare cause of acute pancreatitis, accounting for approximately 2% to 5% of all cases of pancreatitis.2,3,4,14 In our hospital, total number of acute pancreatitis patients during the study was 251. Out of 251 acute pancreatitis patients reported during the study, 11 cases were found to be drug-induced, accounting for 4.4% (11/251). Possible drugs that may have caused the acute pancreatitis include ciprofloxacin which is suspected to be responsible for seven cases, augmentin for one, anticancer drug tacrolimus for one, anti-inflammatory caridase for one, diuretics for one. However, these speculations were not rechallenged by retrospective studies, and thus not confirmed.\n\nDrug-induced pancreatitis is not a negligible disease, but it is hard to diagnose. The most frequently implicated medications are metronidazole, tetracycline, azathioprine, furosemide, thiazide diuretics, angiotensin converting enzyme inhibitors, didanosine, aspirin, valproic acid, and codeine.1,15,16 The pathogenetic mechanism of drug-induced pancreatic injury remains unclear. The pathophysiology is likely an idiosyncratic hypersensitivity reaction that differs among the aforementioned medications depending on their chemical structures. A positive rechallenge is considered when the drug is stopped after a patient is found to have acute pancreatitis and after resolution of the pancreatitis, when the drug is restarted, acute pancreatitis develops again. However, due to the character of the disease and ethical considerations, rechallenge is usually unintended. Despite the lack of a rechallenge, a drug may also be strongly suspected if there is a consistent latency among the case reports between initiating the drug and the onset of acute pancreatitis. A consistent latency may be a sign that the drug has a common mechanism of action.17 In our cases, ciprofloxacin had a latency from drug administration to the development of acute pancreatitis of 4 to 7 days. This short time frame suggests a hypersensitivity reaction.17 In our observations, drug-induced pancreatitis caused by ciprofloxacin occurs at a low incidence of less than 3%. In most cases, the patient was not aware of typical symptoms of acute pancreatitis. The prognosis of drug-induced pancreatitis by ciprofloxacin is good. We had the patients fast and quit the drug suspected of inducing acute pancreatitis meanwhile continuously intravenous administrating gabexate mesilate. Elevated enzyme levels of amylase and lipase improved dramatically within a week after stopping drug administration. Ciprofloxacin is a broad spectrum antibiotic and is widely used to treat a number of conditions. However, the question of why ciprofloxacin-inducing pancreatitis is rarely observed remains. The answer to this is quite simple: routine screening of the chemical profile has been overlooked, despite the risk of an adverse event. It is important that practitioners be aware that this potential adverse effect may be occurring. We advise more caution in recommending this antibiotic for therapeutic use or empirical use. Close monitoring for an adverse event may be necessary. During ciprofloxacin use, regular screening of chemical profiles including amylase, lipase, liver enzyme, and creatinine is warranted. We consider it necessary that larger, prospective studies aimed at drug-induced pancreatitis caused by ciprofloxacin be conducted.\n\nWe described seven cases of ciprofloxacin-induced acute pancreatitis; the patients' pancreatic enzymes were at a normal range at initial admission. Pancreatic enzyme was sporadically elevated with ciprofloxacin use. We observed that ciprofloxacin-induced pancreatitis may occur with an incidence of approximately 3%. Drug-induced pancreatitis by ciprofloxacin displays a short latency, suggesting an idiosyncratic hypersensitivity reaction. If pancreatitis was detected early, the prognosis was very good, and all of our patients fully recovered within 3 weeks. Although the exact mechanism for this reaction remains a mystery, ciprofloxacin use may be considered a rare risk factor for the development of acute pancreatitis.\n\nACKNOWLEDGEMENTS\nWe appreciate Ka Young Kim from Cornell University who provided great support in data analysis and English proofreading as well as secretory assistance.\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Laboratory findings of drug-induced pancreatitis by ciprofloxacin. Among 227 patients who received ciprofloxacin, seven (3.1%) demonstrated an adverse reaction; the pancreatic enzyme levels spiked after ciprofloxacin injection. Ciprofloxacin has a latency of 4 to 7 days from the beginning of drug infusion to the development of acute pancreatitis. This short time frame suggests a hypersensitivity reaction.\n\nFig. 2 A 58-year-old Korean male presented to the emergency department of our institution with a 4-day history of lower abdominal pain with diarrhea and fever. He was diagnosed with infectious colitis. The results of an initial chemical profile were within the normal ranges. He received 400 mg of intravenous ciprofloxacin twice daily for 2 days while remaining nil per os for bowel rest. On the third day of treatment, he complained of severe abdominal pain. At this time, his serum amylase and lipase activities were elevated to 677 U/L (reference range, 45 to 160 IU/L) and 1,405 U/L (reference range, 42 to 168 mg/dL), respectively. (A, B) Abdominal computed tomography demonstrated swelling of the pancreatic head and peripancreatic inflammation. (A) Mild swelling of the duodenal second and third loops was noted. The patient was diagnosed with probable drug-induced pancreatitis secondary to ciprofloxacin using the Naranjo algorithm for assessing the probability of an adverse drug reaction.11\n\nFig. 3 A 71-year-old male presented to the emergency department of our institution with nausea, vomiting, and watery diarrhea over the previous 3 days. Amylase and lipase levels were normal at 130 U/L (reference range, 45 to 160 IU/L) and 51 U/L (reference range, 13 to 60 U/L), respectively. The patient was given 400 mg of intravenous ciprofloxacin twice daily for 2 days. Subsequently, he was given 500 mg of oral ciprofloxacin twice daily for 3 days. On the sixth day of treatment, follow-up laboratory parameters worsened; the serum amylase and lipase activities were elevated to 246 and 566 U/L, respectively. (A, B) Seven days after admission, abdominal computed tomography demonstrated swelling and homogeneous enhancement of the pancreas head and body. The patient was managed conservatively and had an uneventful recovery, and has remained well since discharge. He was diagnosed with probable drug-induced pancreatitis secondary to ciprofloxacin based on the Naranjo algorithm.11\n\nTable 1 Demography and Clinical Characteristics of Drug-Induced Pancreatitis Secondary to Ciprofloxacin Use\n\nM, male; F, female; IV, intravenous; PO, per oral.\n\n*Normal range of amylase, 45 to 160 IU/L; †Normal range of lipase, 13 to 60 U/L.\n==== Refs\n1 Vinklerová I Procházka M Procházka V Urbánek K Incidence, severity, and etiology of drug-induced acute pancreatitis Dig Dis Sci 2010 55 2977 2981 20499176 \n2 Wolfson JS Hooper DC Overview of fluoroquinolone safety Am J Med 1991 91 153S 161S 1767803 \n3 Ericsson CD Johnson PC Dupont HL Morgan DR Bitsura JA de la Cabada FJ Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea: a placebo-controlled, randomized trial Ann Intern Med 1987 106 216 220 3541724 \n4 Nathwani D Wood MJ The management of travellers' diarrhoea J Antimicrob Chemother 1993 31 623 626 8335493 \n5 Mann S Thillainayagam A Is ciprofloxacin a new cause of acute pancreatitis? J Clin Gastroenterol 2000 31 336 11129278 \n6 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 7249508 \n7 Ball P Tillotson G Tolerability of fluoroquinolone antibiotics: past, present and future Drug Saf 1995 13 343 358 8652079 \n8 Cinar E Ateskan U Baysan A Is late antibiotic prophylaxis effective in the prevention of secondary pancreatic infection? Pancreatology 2003 3 383 388 14526147 \n9 Mithöfer K Fernández-del Castillo C Ferraro MJ Lewandrowski K Rattner DW Warshaw AL Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis Gastroenterology 1996 110 232 240 8536862 \n10 Isenmann R Rünzi M Kron M Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial Gastroenterology 2004 126 997 1004 15057739 \n11 García-Barrasa A Borobia FG Pallares R A double-blind, placebo-controlled trial of ciprofloxacin prophylaxis in patients with acute necrotizing pancreatitis J Gastrointest Surg 2009 13 768 774 19082671 \n12 Isenmann R Friess H Schlegel P Fleischer K Büchler MW Penetration of ciprofloxacin into the human pancreas Infection 1994 22 343 346 7843813 \n13 Adam U Herms S Werner U The penetration of ciprofloxacin into human pancreatic and peripancreatic necroses in acute necrotizing pancreatitis Infection 2001 29 326 331 11787833 \n14 Norrby SR Lietman PS Safety and tolerability of fluoroquinolones Drugs 1993 45 Suppl 3 59 64 7689453 \n15 Trivedi CD Pitchumoni CS Drug-induced pancreatitis: an update J Clin Gastroenterol 2005 39 709 716 16082282 \n16 Lankisch PG Dröge M Gottesleben F Drug induced acute pancreatitis: incidence and severity Gut 1995 37 565 567 7489946 \n17 Tenner S Drug-induced acute pancreatitis: underdiagnosis and overdiagnosis Dig Dis Sci 2010 55 2706 2708 20686844\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1976-2283", "issue": "8(3)", "journal": "Gut and liver", "keywords": "Anti-bacterial agents; Drug toxicity; Infectious colitis; Pancreatitis", "medline_ta": "Gut Liver", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D002939:Ciprofloxacin; D003092:Colitis; D004791:Enzyme Inhibitors; D004952:Esters; D005260:Female; D016670:Gabexate; D006146:Guanidines; D006801:Humans; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D055815:Young Adult", "nlm_unique_id": "101316452", "other_id": null, "pages": "265-70", "pmc": null, "pmid": "24827622", "pubdate": "2014-05", "publication_types": "D016428:Journal Article", "references": "7249508;20499176;8652079;15057739;3541724;11787833;19082671;7689453;1767803;16082282;8335493;14526147;7843813;11129278;8536862;20686844;7489946", "title": "Acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis.", "title_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis" }	[ { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01801", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. GUT AND LIVER. 2014 MAY;8(3):265-270.", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20141218", "receivedate": "20141218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10661114, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01797", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "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": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. GUT AND LIVER. 2014 MAY;8(3):265-270.", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20141218", "receivedate": "20141218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10661104, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00003", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, UNK", "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": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "58", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080814, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01800", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. GUT AND LIVER. 2014 MAY;8(3):265-270.", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20141218", "receivedate": "20141218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10661117, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00007", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080817, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00002", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG, UNK", "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": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080818, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00006", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080816, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01803", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "59", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. GUT AND LIVER. 2014 MAY;8(3):265-270.", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20141218", "receivedate": "20141218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10661116, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150529" }, { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01802", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080815, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01799", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "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": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080873, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00005", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]
{ "abstract": "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a serious autoimmune disorder characterized by psychiatric symptoms, seizures and movement disorder. Predisposing factors have been reported since the time it was described, and its pathophysiology has been tried to be clarified over the years. Although overlap with other demyelinating diseases had been reported, such an association between Multiple Sclerosis (MS) anti ANTİ-NMDAR encephalitis is limited to only a few case reports. In this article, a patient diagnosed with relapsing remitting multiple sclerosis (RRMS) for ten years who then developed NMDA-R encephalitis while on disease modifying treatment will be presented and possible common pathophysiology with previously reported literature will be discussed.", "affiliations": "Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul. Electronic address: [email protected].;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Anesthesiology and Reanimation, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Anesthesiology and Reanimation, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Nuclear Medicine, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Istanbul School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.", "authors": "Gulec\|Bade\|B\|;Kurucu\|Hatice\|H\|;Bozbay\|Suha\|S\|;Dikmen\|Yalım\|Y\|;Sayman\|Haluk\|H\|;Tuzun\|Erdem\|E\|;Tutuncu\|Melih\|M\|;Uygunoglu\|Ugur\|U\|;Yalcinkaya\|Cengiz\|C\|;Saip\|Sabahattin\|S\|;Siva\|Aksel\|A\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2020.102075", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "42()", "journal": "Multiple sclerosis and related disorders", "keywords": "Multiple sclerosis; NMDAR encephalitis; Overlapping demyelinating syndromes", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D015897:Comorbidity; D005260:Female; D006801:Humans; D020529:Multiple Sclerosis, Relapsing-Remitting", "nlm_unique_id": "101580247", "other_id": null, "pages": "102075", "pmc": null, "pmid": "32388459", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Co-existence of multiple sclerosis and anti-NMDA receptor encephalitis: A case report and review of literature.", "title_normalized": "co existence of multiple sclerosis and anti nmda receptor encephalitis a case report and review of literature" }	[ { "companynumb": "TR-TEVA-2019-TR-1118457", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201306", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NATALIZUMAB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FINGOLIMOD" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201207", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FINGOLIMOD." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INTERFERON BETA-1A" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": "201207", "drugenddateformat": "610", "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "200902", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON?BETA?1A" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TERIFLUNOMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "209549", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "HAD BEEN ON TERIFLUNOMIDE FOR 15 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2017", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TERIFLUNOMIDE." } ], "patientagegroup": null, "patientonsetage": "26", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Encephalitis autoimmune", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201805" } }, "primarysource": { "literaturereference": "GULEC B. CO?EXISTENCE OF MULTIPLE SCLEROSIS AND ANTI?NMDA RECEPTOR ENCEPHALITIS: A CASE REPORT AND REVIEW OF LITERATURE. MULTIPLE SCLEROSIS AND RELATED DISORDERS 42. 2020 JUL?42:.", "literaturereference_normalized": "co existence of multiple sclerosis and anti nmda receptor encephalitis a case report and review of literature", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200707", "receivedate": "20200626", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17949588, "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": "TR-SA-2020SA156594", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FINGOLIMOD" }, 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"drugseparatedosagenumb": null, "drugstartdate": "200902", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INTERFERON BETA-1A" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NATALIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201701", "drugenddateformat": "610", "drugindication": "MULTIPLE SCLEROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201306", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NATALIZUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sleep disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalitis autoimmune", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Memory impairment", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Autonomic nervous system imbalance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuritis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus node dysfunction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201704" } }, "primarysource": { "literaturereference": "GULECA B, KURUCU H, BOZBAY S, DIKMENB Y, SAYMANC H, TUZUND E, ET AL.. CO-EXISTENCE OF MULTIPLE SCLEROSIS AND ANTI-NMDA RECEPTOR ENCEPHALITIS: A CASE REPORT AND REVIEW OF LITERATURE. MULTIPLE SCLEROSIS AND RELATED DISORDERS. 2020?42:102075", "literaturereference_normalized": "co existence of multiple sclerosis and anti nmda receptor encephalitis a case report and review of literature", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200625", "receivedate": "20200625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17939909, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]
{ "abstract": "Long-term survival of liver transplant recipients is endangered by tumorigenesis at different sites. Little is known about primary de novo tumors developing in the graft.\nWe analyzed the follow-up data of 2731 liver recipients that were transplanted between 1988 and 2019 at our institution (Charité - Universitätsmedizin Berlin, Department of Surgery). All cases with new intrahepatic tumors during follow-up were identified.\nA total of nine patients were diagnosed at a median of 16 years (range, 2-24 years) after surgery. Eight patients presented with hepatocellular carcinoma (HCC), and one patient presented with epithelioid hemangioendothelioma (EHE). All eight HCC patients had a recurrence of the initial disease that had caused liver failure before transplantation. This was associated with viral reinfection with either HCV or HBV in seven cases. Of the nine patients, three underwent surgical resection and only one patient was alive at data abstraction.\nIntrahepatic de novo neoplasms in the liver graft need to be considered in the long-term follow-up of liver recipients and were strongly associated with recurrent viral hepatitis in our study. Although prognosis of this rare complication is generally poor, patients may benefit from surgical resection of localized disease.", "affiliations": "Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Radiology (including Pediatric Radiology), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte \| Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.", "authors": "Pflüger\|Michael J\|MJ\|;Maurer\|Max M\|MM\|;Hillebrandt\|Karl H\|KH\|;Andreou\|Andreas\|A\|;Geisel\|Dominik\|D\|;Schmelzle\|Moritz\|M\|;Pratschke\|Johann\|J\|;Eurich\|Dennis\|D\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1016/j.jceh.2020.11.003", "fulltext": null, "fulltext_license": null, "issn_linking": "0973-6883", "issue": "11(4)", "journal": "Journal of clinical and experimental hepatology", "keywords": "AFP, alpha-fetoprotein; ALF, acute liver failure; CA 19-9, carbohydrate antigen 19-9; CCA, cholangiocarcinoma; CEA, carcinoembryonic antigen; DCV, daclatasvir; EHE, epithelioid hemangioendothelioma; ESLD, end-stage liver disease; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; IS, immunosuppressive therapy; LT, liver transplantation; NUCs, nucleos(t)ide analogues; PSC, primary sclerosing cholangitis; PTLD, post-transplantation lymphoproliferative disorder; PegIFN, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained viral response; epithelioid hemangioendothelioma; hepatocellular carcinoma; liver transplant; long-term survival; surgical resection", "medline_ta": "J Clin Exp Hepatol", "mesh_terms": null, "nlm_unique_id": "101574137", "other_id": null, "pages": "435-442", "pmc": null, "pmid": "34276150", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "28039946;26597456;15048797;17404871;19766646;28590598;28364823;17008365;9873096;12037793;29359020;16967310;8188183;19659806;15964379;17060864;21989430;26405713;14702536;23915066;26807385;17019735;19460546;26269665;8594428;18813102;20602682;19737373;19857941;12752322;24106037", "title": "Intrahepatic De Novo Tumors in Liver Recipients are Highly Associated With Recurrent Viral Hepatitis.", "title_normalized": "intrahepatic de novo tumors in liver recipients are highly associated with recurrent viral hepatitis" }	[ { "companynumb": "DE-GILEAD-2021-0541453", 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null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Viraemia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "Pfluger, MJ, et al. Intrahepatic De Novo Tumors in Liver Recipients are Highly Associated With Recurrent Viral Hepatitis. 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INTRAHEPATIC DE NOVO TUMORS IN LIVER RECIPIENTS ARE HIGHLY ASSOCIATED WITH RECURRENT VIRAL HEPATITIS. JOURNAL OF CLINICAL + EXPERIMENTAL HEPATOLOGY. 2021?11:435?442. 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN HEPATITIS B VIRUS IMMUNE GLOBULIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "HEPATITIS B IMMUNE GLOBULIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Viraemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "PFLUGER, MJ, ET AL. INTRAHEPATIC DE NOVO TUMORS IN LIVER RECIPIENTS ARE HIGHLY ASSOCIATED WITH RECURRENT VIRAL HEPATITIS.. JOURNAL OF CLINICAL + EXPERIMENTAL HEPATOLOGY. 2021?11:435?442", "literaturereference_normalized": "intrahepatic de novo tumors in liver recipients are highly associated with recurrent viral hepatitis", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210811", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19682649, "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": "Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC).\n\n\n\nGEM (1000 mg/m2) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS).\n\n\n\nIn total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients.\n\n\n\nThe combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit.", "affiliations": "Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Biostatistic Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].", "authors": "Zucali\|Paolo Andrea\|PA\|;Perrino\|Matteo\|M\|;De Vincenzo\|Fabio\|F\|;Giordano\|Laura\|L\|;Cordua\|Nadia\|N\|;D'Antonio\|Federica\|F\|;Santoro\|Armando\|A\|", "chemical_list": "D000068437:Pemetrexed; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; C056507:gemcitabine", "country": "Ireland", "delete": false, "doi": "10.1016/j.lungcan.2020.02.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0169-5002", "issue": "142()", "journal": "Lung cancer (Amsterdam, Netherlands)", "keywords": "Combination therapy; Gemcitabine; Imatinib; Mesothelioma", "medline_ta": "Lung Cancer", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D000086002:Mesothelioma, Malignant; D000068437:Pemetrexed; D010997:Pleural Neoplasms; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate", "nlm_unique_id": "8800805", "other_id": null, "pages": "132-137", "pmc": null, "pmid": "32102735", "pubdate": "2020-04", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma.", "title_normalized": "a phase ii study of the combination of gemcitabine and imatinib mesylate in pemetrexed pretreated patients with malignant pleural mesothelioma" }	[ { "companynumb": "NVSC2020IT066291", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMCITABINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "090993", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLEURAL MESOTHELIOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMCITABINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "IMATINIB MESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021588", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "PLEURAL MESOTHELIOMA MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IMATINIB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pleural mesothelioma malignant", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZUCALI PA, PERRINO M, VINCENZO FD, GIORDANO L, CORDUA N, ANTONIO FD ET AL.. A PHASE II STUDY OF THE COMBINATION OF GEMCITABINE AND IMATINIB MESYLATE IN PEMETREXED-PRETREATED PATIENTS WITH MALIGNANT PLEURAL MESOTHELIOMA. LUNG CANCER. 2020?1-6", "literaturereference_normalized": "a phase ii study of the combination of gemcitabine and imatinib mesylate in pemetrexed pretreated patients with malignant pleural mesothelioma", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17521903, "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": "Kaposi sarcoma is a mesenchymal tumor associated to a human herpes virus-8. It often occurs in human immunodeficiency virus-positive subjects. Colorectal localization is rare. We report the case of a colorectal Kaposi sarcoma complicating a refractory ulcerative colitis treated with surgery after the failure of immunomodulator therapy in a human immunodeficiency virus-negative heterosexual man.", "affiliations": "Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Histopathology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;General surgery department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Histopathology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;General surgery department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.", "authors": "Hamzaoui\|Lamine\|L\|;Kilani\|Houda\|H\|;Bouassida\|Mahdi\|M\|;Mahmoudi\|Moufida\|M\|;Chalbi\|Emna\|E\|;Siai\|Karima\|K\|;Ezzine\|Heykel\|H\|;Touinsi\|Hassen\|H\|;Azzouz\|Mohamed M'saddak\|MM\|;Sassi\|Sadok\|S\|", "chemical_list": "D000911:Antibodies, Monoclonal; D013256:Steroids; D000069285:Infliximab; D001379:Azathioprine", "country": "Uganda", "delete": false, "doi": "10.11604/pamj.2013.15.154.2988", "fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-15-15410.11604/pamj.2013.15.154.2988Case ReportIatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient Hamzaoui Lamine 1Kilani Houda 2Bouassida Mahdi 3&Mahmoudi Moufida 1Chalbi Emna 2Siai Karima 1Ezzine Heykel 1Touinsi Hassen 3Azzouz Mohamed M'Saddak 1Sassi Sadok 11 Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia2 Histopathology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia3 General surgery department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia& Corresponding author: Mahdi Bouassida, MD, Department of Surgery, Mohamed Tahar Maamouri Hospital, 8000 Mrazga, Nabeul, Tunisia29 8 2013 2013 15 15418 6 2013 23 8 2013 © Mahdi Bouassida et al.2013The Pan African Medical Journal - ISSN 1937-8688. 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.Kaposi sarcoma is a mesenchymal tumor associated to a human herpes virus-8. It often occurs in human immunodeficiency virus-positive subjects. Colorectal localization is rare. We report the case of a colorectal Kaposi sarcoma complicating a refractory ulcerative colitis treated with surgery after the failure of immunomodulator therapy in a human immunodeficiency virus-negative heterosexual man.\n\nKaposi's Sarcomaulcerative colitisHuman Herpes Virus-8Infliximabimmunosuppression\n==== Body\nIntroduction\nKaposi's sarcoma (KS) is a mesenchymal tumor, arising predominantly in the skin but which can affect any organ system. It's associated to human herpes virus-8 (HHV8) [1, 2]. Patients with inflammatory bowel disease, in particular ulcerative colitis (UC), are often treated with immunosuppressive therapy and can develop colorectal KS [3]. We report the case of a human immunodeficiency negative-virus (HIV) man, with a severe refractory UC, who was treated with steroids, azathioprine and infliximab (IFX). Failure of medical treatment indicated surgery. Histological examination of the colon revealed KS.\n\nPatient and observation\nA 30-year-old heterosexual man, without familial and personal history, was diagnosed with rectosigmoid ulcerative colitis since 2010 revealed by chronic bloody diarrhea with abdominal pain and weight loss. He had a 3 pack-year history of smoking (stopped 3 years ago). He was initially treated with oral and local mesalamine with a good response. In 2011, he was treated 3 times with steroids (1mg/kg/day of prednisone) for a moderately active disease without a complete relief of diarrhea. In December 2011, at physical exam, his body mass index was 17kg/m2. Abdominal exam was normal. There was no skin lesion. Iron deficiency anemia (11g/dL) and signs of inflammation: erythrocyte sedimentation rate (ESR) of 37mm and C - reactive protein (CRP) of 74mg/L were noted. Albumin level was 25g/L. Ileocolonoscopy showed large superficial ulcerations, spontaneous bleeding and pseudo-polyps. Lesions were mainly located in the rectosigmoid colon and the colitis was extended to the hepatic flexure. Histology found clear signs of active UC with no signs of malignancy. Oral corticosteroids were prescribed with a good initial response. At week 4 of corticosteroid therapy, we noted a relapse of bloody diarrhea, inflammation and aggravation of anemia (7,3g/dL). A left-sided colonoscopy didn't show severe endoscopic signs. Copro-parasitological examinations were negative. Cytomegalovirus testing was negative too. Detection of Clostridium difficile toxins was not done. Intravenous corticosteroids and parenteral nutrition were prescribed during 1week. At week 5 of corticosteroid therapy, another relapse occurred (7 to 8 stools daily, anemia 6g/dL, ESR 40mm, albumin 17g/L) and we had considered that it was a refractory severe UC. As the patient was reticent to surgery, medical treatment with immunomodulators was indicated. Assessment before immunosuppressive therapy was normal. He received blood transfusion, albumin infusion, parenteral nutrition and intravenous corticosteroids (with progressive decreasing doses). After improvement in health status, anemia (9g/dL) and albumin concentration (37g/L), azathioprine (2,5mg/kg/day, total of 3 months of treatment) and IFX (induction regimen with 5mg/kg, weeks 0, 2 and 6) were prescribed with unchanged disease activity. Drug failure led to a surgical treatment. A subtotal colectomy with double stomy of the ileum and of the sigmoid colon was performed. Colon macroscopic examination revealed multiple polypoid red lesions associated with large ulcerations. Histologic examination of polypoid lesions showed fusocellular spindle cells proliferation with a slit like vascular channels and extravased red blood cells consistent with the diagnosis of KS, associated with typical features of UC (Figure 1). Immunolabelling for HHV8 stained the nuclei of the spindle cells (Figure 2, Figure 3). Involvement in 1 of the 25 perivisceral lymph nodes isolated was demonstrated. The patient underwent mucosal proctectomy and ileoanal anastomosis.\n\nFigure 1 Histology (H and E stain x 40): Spindle cell proliferation with vascular channels infiltrating a colonic mucosa\n\nFigure 2 HHV8 immunohistochemical stain: strong nuclear positivity in spindle tumor cells x200\n\nFigure 3 Fig CD31 immunohistochemical stain: positivity in vascular channels x40\n\nDiscussion\nThere are four clinical variants of KS with distinct clinical and epidemiological characteristics: classic, endemic, acquired immunodeficiency syndrome and iatrogenic [4]. Iatrogenic KS has been described in kidney and liver transplant recipients and also auto-immune diseases [5, 6]. KS of gastrointestinal tract is rarely seen in the developed countries. Involvement by KS has been noted in 80% of patients with visceral disease in endemic areas [7]. Case studies have reported colorectal KS associated with inflammatory bowel disease in HIV-negative patients (since until now 11 observations). Most of cases were refractory UC on immunosuppressive therapy [8]. Our patient has received a triple immunosuppression (steroids, azathioprine and infliximab). It's the second case occurring into IFX. The diagnosis is difficult to establish in the absence of skin lesions, as in our patient. Nodular and polypoid lesions are observed in endoscopy and biopsies may fail to sample diagnostic tissue before tumor infiltration of the mucosa [8]. Intraluminal polyps are red or blue, due to high vascular and conjunctive tissue proliferation. Distinction from pseudo-polyps is difficult [9]. Seven months before diagnosis, the colonoscopy showed polypoid lesions, considered as inflammatory pseudo-polyps by the histologist. Immunohistochemistry of HHV-8 is helpful in the histological assessment of the lesions and may demonstrate infiltration of the mucosa by KS [8]. HHV-8 was positive in our case. Proctocolectomy associated to immunosuppressor withdrawal is usually effective to treat both UC and KS. After subtotal colectomy and confirmation of KS associated to UC, the patient will undergo proctectomy.\n\nConclusion\nAlthough it is rare, it is important to consider a concomitant KS in patients with refractory severe ulcerative colitis, on immunosuppressor therapy, independently of HIV status.\n\nCompeting interests\nThere authors declare no competing interest.\n\nAuthors’ contributions\nAll authors contributed in this work in ways that conform to ICMJE authorship criteria. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1 Chang Y Cesarman E Pessin MS Identification of herpesvirus-like DNA sequences in AIDSassociated Kasposi's sarcoma Science. 1994 266 5192 1865 9 7997879 \n2 Antman K Chang Y Kaposi's sarcoma N Engl J Med. 2000 342 14 1027 38 10749966 \n3 Meltzer SJ Rotterdam HZ Korelitz BI Kaposi's sarcoma in association with ulcerative colitis Am J Gastroenterol. 1987 82 4 378 81 3565348 \n4 Martin RW III Hood AF Farmer ER Kaposi sarcoma Medicine. 1993 72 4 245 61 8341141 \n5 García-Astudillo LA Leyva-Cobián F Human herpesvirus-8 infection and Kaposi′s sarcoma after liver and kidney transplantation in different geographical areas of Spain Transpl Immunol. 2006 17 1 86 9 \n6 Klein MB Pereira FA Kantor I Kaposi sarcoma complicating systemic lupus erythematosus treated with immunosuppression Arch Dermatol. 1974 110 4 602 4 4414026 \n7 Taylor FJ Templeton AC Vogel CL Kaposi's sarcoma in Uganda: a clinicopathological study Int J Cancer. 1971 8 1 122 35 5118203 \n8 Girelli CM Serio G Rocca E Rocca F Refractory ulcerative colitis and iatrogenic colorectal Kaposi's sarcoma Dig Liver Dis. 2009 41 2 170 4 18054849 \n9 Tavassolie H Mir-Madjlessi SH Sadr-Ameli MA The endoscopic demonstration of Kaposi's sarcoma of the colon Gastrointest Endosc. 1983 29 4 331 332 6642174\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "15()", "journal": "The Pan African medical journal", "keywords": "Human Herpes Virus-8; Infliximab; Kaposi's Sarcoma; immunosuppression; ulcerative colitis", "medline_ta": "Pan Afr Med J", "mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D001379:Azathioprine; D003093:Colitis, Ulcerative; D015179:Colorectal Neoplasms; D018023:HIV Seronegativity; D006801:Humans; D007049:Iatrogenic Disease; D000069285:Infliximab; D008297:Male; D012514:Sarcoma, Kaposi; D013256:Steroids; D017211:Treatment Failure", "nlm_unique_id": "101517926", "other_id": null, "pages": "154", "pmc": null, "pmid": "24396560", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10749966;3565348;5118203;17157220;18054849;8341141;7997879;4414026;6642174", "title": "Iatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient.", "title_normalized": "iatrogenic colorectal kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative virus patient" }	[ { "companynumb": "TN-WATSON-2014-16636", "fulfillexpeditecriteria": "1", "occurcountry": "TN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "1 MG/KG, DAILY, THREE TIMES", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "2.5 MG/KG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION REGIMEN OF 5 MG/KG WEEKS 0, 2 AND 6", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAMZAOUI L, KILANI H, BOUASSIDA M, MAHMOUDI M, CHALBI E, SIAI K. ET AL. IATROGENIC COLORECTAL KAPOSI SARCOMA COMPLICATING A REFRACTORY ULCERATIVE COLITIS IN A HUMAN IMMUNODEFICIENCY NEGATIVE-VIRUS PATIENT. PAN AFR MED J. 2013;15:154", "literaturereference_normalized": "iatrogenic colorectal kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative virus patient", "qualification": "3", "reportercountry": "TN" }, "primarysourcecountry": "TN", "receiptdate": "20140806", "receivedate": "20140806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10366245, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]
{ "abstract": "Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation.\n\n\n\nBetween 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation.\n\n\n\nIn the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3.\n\n\n\nPatients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.", "affiliations": "Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Pneumology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Pneumology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.", "authors": "Grambozov\|Brane\|B\|0000-0003-2454-7425;Wass\|Romana\|R\|;Stana\|Markus\|M\|;Gerum\|Sabine\|S\|;Karner\|Josef\|J\|;Fastner\|Gerd\|G\|;Studnicka\|Michael\|M\|;Sedlmayer\|Felix\|F\|;Zehentmayr\|Franz\|F\|0000-0001-5931-3907", "chemical_list": null, "country": "Singapore", "delete": false, "doi": "10.1111/1759-7714.13884", "fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n33586228\n10.1111/1759-7714.13884\nTCA13884\nOriginal Article\nOriginal Articles\nImpact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single‐center retrospective analysis\nGrambozov et al.\nGrambozov Brane https://orcid.org/0000-0003-2454-7425\n1 [email protected]\n\nWass Romana 2 3\nStana Markus 1\nGerum Sabine 1\nKarner Josef 1\nFastner Gerd 1\nStudnicka Michael 2\nSedlmayer Felix 1 4\nZehentmayr Franz https://orcid.org/0000-0001-5931-3907\n1 4\n1 Department of Radiation Oncology Paracelsus Medical University, SALK Salzburg Austria\n2 Department of Pneumology Paracelsus Medical University, SALK Salzburg Austria\n3 Department of Pulmonology Kepler University Hospital Linz Austria\n4 radART – Institute for Research and Development on Advanced Radiation Technologies Paracelsus Medical University Salzburg Austria\n* Correspondence\nBrane Grambozov, Radiation Oncology, Salzburg University Clinic, Müllner Hauptstraße 48, A‐5020 Salzburg, Austria.\nEmail: [email protected]\n\n14 2 2021\n4 2021\n12 8 10.1111/tca.v12.8 11621170\n26 1 2021\n21 12 2020\n26 1 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nGiven the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high‐dose reirradiation.\n\nMaterials and methods\n\nBetween 2013 and 2019, 47 consecutive patients with in‐field tumor recurrence underwent high‐dose thoracic reirradiation at our institute. Twenty patients (43%) received high‐dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work‐up included a mandatory fluorodeoxyglucose‐positron emission tomography‐computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation.\n\nResults\n\nIn the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5–21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8–25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log‐rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3.\n\nConclusion\n\nPatients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.\n\nThe aim of our retrospective study was to investigate whether reccurrent lung patients would benefit in terms of overall survival by adding immunotherapy to high‐dose reirradiation. Between 2013 and 2019, 47 consecutive patients with in‐field tumor recurrence underwent high‐dose thoracic reirradiation at our institute. Twenty patients (43%) received high dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.\n\nimmunotherapy\nlocal recurrence\nlung cancer\noverall survival and toxicity\nreirradiation\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:14.04.2021\nGrambozov B , Wass R , Stana M , et al. Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single‐center retrospective analysis. Thorac Cancer. 2021;12 :1162–1170. 10.1111/1759-7714.13884\n==== Body\nAbbreviations\n\nCCI Charlson co‐morbidity index\n\nCTCAE common toxicity criteria for adverse events\n\nDART dose‐differentiated accelerated radiotherapy\n\nECOG Eastern cooperative oncology group\n\nEQD2 biologically equivalent dose in 2 Gy fractions\n\nFDG‐PET‐CT fluorodeoxyglucose‐positron emission tomography\n\nIMRT intensity modulated radiotherapy\n\nmOS median overall survival\n\nNSCLC nonsmall cell lung cancer\n\nOS overall survival\n\nRT radiotherapy\n\nSABR stereotactic ablative body therapy\n\nSCLC small‐cell lung cancer\n\nTNM tumor, node, metastasis\n\nVMAT volumetric intensity modulated arc therapy\n\nINTRODUCTION\n\nImmunotherapy has led to revolutionary advancements in cancer treatment 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 and has given new hope to the large number of patients who die from lung cancer each year. 9 Immunotherapy is now a standard first‐ and second‐line therapy for patients with advanced lung cancer. 1 , 2 , 3 , 4 , 6 , 8\n\nWith the aim of improving the options available for the treatment of lung cancer patients and based on the potential synergistic effect of radiation therapy and immunotherapy in terms of both local and systemic antitumor response as already described in preclinical models, 10 , 11 , 12 the interest of the oncological community in combining these therapeutic modalities in a clinical setting has increased. 1 , 2 , 13 , 14 As a result, clinical studies have shown remarkable benefits in terms of both progression‐free and overall survival (OS) in lung cancer patients with acceptable toxicity, 1 , 2 , 13 which may be attributed to the synergistic antitumor effect mentioned above. In contrast, numerous publications have suggested that the very complex interaction between the irradiated cells, tissue, and the immune system could enhance the effect of immunotherapy. 1 , 2 , 5 , 7 , 12 , 15 , 16 , 17\n\nIn light of this, the potential for antitumor immune activation by irradiation could play an important role for radiotherapy in systemic disease, especially since the presence of immunosuppressive mediators in the tumor microenvironment could limit the number of patients who experience the therapeutic benefits of immunotherapy. 12 , 18 Despite progress in all related clinical disciplines, there is a need to improve clinical outcomes in patients at all tumor, node, metastasis (TNM) stages, including those with recurrent lung cancer for whom curative treatment is already limited. 5 , 19 , 20 Hence, combining therapeutic modalities such as radiotherapy, chemotherapy, and immunotherapy in the hope of overcoming their therapeutic limitations and achieving a synergistic effect seems plausible. 1 , 2 With respect to the combination of reirradiation for loco‐regional relapse and immunotherapy, there is currently one review extant. 5 Additionally, the results of an ongoing study are pending (ClinicalTrials.gov identifier NCT03087760), which—as opposed to our study—uses proton reirradiation rather than photons.\n\nThe aim of our retrospective analysis was to investigate whether patients with recurrent lung cancer would benefit from adding immunotherapy to ablative reirradiation in terms of OS, taking into account toxicity. Local control after reirradiation and dose to organs at risk are the subject of another paper that is currently under review.\n\nMETHODS\n\nPatients\n\nBetween 2013 and 2019, 47 consecutive patients who underwent high‐dose thoracic reirradiation were included in a prospective observational database. While 20 patients were reirradiated only, 27 received systemic therapy in addition to high‐dose reirradiation. In this subgroup, immunotherapy was administered alone or with chemotherapy in 21/27 patients (78%). Six out of 27 patients (22%) received chemotherapy alone. The inclusion criteria were as follows: (1) all patients had to be classified as inoperable and in all patients both the primary and the secondary tumor had to be located in the lungs; (2) if possible, patients should have received two courses of curatively intended radiation therapy with a time interval of 9 months or more between them (an exception was made in only one patient who was reirradiated 5 months after the first radiation therapy treatment); (3) the tumor was histologically verified and categorized according to the 8th edition of the TNM classification; (4) fluorodeoxyglucose‐positron emission tomography‐computed tomography (18F‐FDG‐PET‐CT) was required in the diagnostic work‐up; (5) the performance status had to be ≤2 according to the Eastern Cooperative Oncology Group (ECOG). Patients who received palliative radiation treatment, postoperative radiotherapy (RT), or those with chest wall tumors and/or out‐of‐field tumor recurrences were excluded. All patients were discussed in a multidisciplinary tumor board with pneumologists, medical oncologists, radiologists, thoracic surgeons, pathologists, and radiation oncologists. This study was reviewed and approved by the ethics committee of the Federal Province of Salzburg (No. 1070/2020).\n\nRadiation and systemic therapy\n\nPatients were reirradiated using intensity modulated radiotherapy (IMRT/VMAT) or stereotactic body radiotherapy (SABR). A planning computed tomography (CT) scan with an acquisition time of 3 s was performed prior to IMRT/VMAT. Additionally, four‐dimensional computed tomography (4D‐CT) was performed in SABR patients. Patients were immobilized using a vacuum cradle and WingSTEP. Subsequently, the planning CT was registered with 18F‐FDG‐PET‐CT. For SABR patients, the internal target volume (ITV) was created by contouring the gross tumor volume (GTV) on three breathing phases (expiration, inspiration, and average) and their subsequent union (ITV = CTV‐clinical target volume). The planning target volume (PTV) was created by adding a symmetric margin of 5 mm to the ITV and an additional 4 mm margin in the cranio‐caudal direction. In IMRT/VMAT patients, the GTV was contoured on a so called “slow CT” with an acquisition time of 4 s. This GTV actually constitutes an ITV/CTV as it includes the respiration‐dependent movement of the tumor. The PTV was defined by adding a symmetric margin of 7 mm to GTV. IMRT/VMAT was delivered in three fractionation regimens: dose‐differentiated accelerated RT in twice daily fractions of 1,8 Gy (dose‐differentiated accelerated radiotherapy [DART]‐bid) as described in two previous publications, 21 , 22 conventionally with 2 Gy per fraction, and hypofractionated RT (one fraction of 3 Gy per day). SABR included two different schemes: eight fractions of 8 Gy (65% isodose) delivered daily for central tumors (i.e. within 2 cm of the proximal bronchial tree) and three fractions of 15.4 Gy in (65% isodose) every other day for peripheral tumors. Since various fractionation regimens were used, total radiation doses were compared by biologically equivalent dose in 2 Gy fractions (EQD2). Organs at risk (OAR), such as esophagus, central vessels and airways, spinal cord, lungs, and heart were routinely contoured and dose volume histograms of both initial and reirradiation plans were used to determine the cumulative radiation dose of each critical organ.\n\nPrior to reirradiation, patients with nonsmall cell lung cancer (NSCLC) received two cycles of either cisplatin (75 mg/m2/d) combined with pemetrexed (500 mg/m2/d) or gemcitabine (1000 mg/m2/d), while small‐cell lung cancer (SCLC) patients received four cycles of cisplatin (75 mg/m2/d) together with etoposide (120 mg/m2 days 1 to 3). In the case of renal dysfunction carboplatin at an area under the curve (AUC) of 5 on day 1 (absolute maximum dose 1100 mg) was applied instead of cisplatin. Depending on the tumor histology, patients received one of the following immunotherapeutic agents after the second ablative radiation therapy: atezolizumab, durvalumab, nivolumab, or pembrolizumab.\n\nToxicity\n\nThe Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 were used to report toxicity. Grade 1 toxicities were not considered as clinically relevant and have therefore not been assessed in this study. A cutoff of 90 days after completion of reirradiation was used to distinguish between acute and late toxicities, with the exception of pneumonitis, which was still considered acute if it occurred within 180 days of the end of RT.\n\nFollow up\n\nPatients were seen 6 weeks after completion of radiotherapy, then every 3 months for the first 2 years and twice a year thereafter. Clinical examinations, contrast‐enhanced CTs, and pulmonary function tests were performed at every follow‐up. If local recurrences or new lung lesions were suspected on the chest CT, 18F‐FDG‐PET‐CT was performed. Local relapse was defined as tumor growth within the reirradiated volume covered by the 95% or 65% isodose after IMRT/VMAT or SABR, respectively.\n\nStatistics\n\nThe primary endpoint was OS, which was calculated using the Kaplan–Meier method. We defined OS as the time between the end of reirradiation and death or latest follow‐up. Although the subgroup of 27 patients was of interest for our analysis, a total of 47 patients—20 of whom were only reirradiated—were also analyzed. With the aim of retaining as much potential information regarding the effects of the three therapy modalities on OS as possible, the threshold for first‐order errors (α) was set at 0.2, which is a more permissible limit usually used in exploratory studies. 23 , 24 For intergroup comparisons the log‐rank test was used.\n\nRESULTS\n\nPatients\n\nOf the 47 patients in the whole cohort, 29 (62%) were men and 18 (38%) were women. The median age at the start of the reirradiation was 66 years (range 52–83 years) in both the entire cohort and the subgroup. Based on histological findings at initial diagnosis, 35/47 (75%) patients had NSCLC and 10/47 (21%) patients had SCLC across the cohort. No pathological confirmation could be obtained in two patients (4%). For details, see Table 1.\n\nTABLE 1 Patient‐ and treatment‐related parameters in the cohort (N = 47)\n\nPatients N = 47\t\nPatient parameters\tAge (years)\tMedian\t66,3\t\nRange\t52–83\t\nSex\tMale\t29\t\nFemale\t18\t\nWeight loss (%)\t>5%\t22\t\n<5%\t25\t\nECOG\t0–1\t40\t\n2\t7\t\nHistology\tSCLC\t10\t\nNSCLC\t35\t\nUnknown\t2\t\nT stage\tx\t3\t\n1\t9\t\n2\t21\t\n3\t9\t\n4\t5\t\nN stage\t0\t11\t\n1\t7\t\n2\t22\t\n3\t7\t\nM stage\t0\t40\t\n1\t7\t\nUICC stage\tI\t7\t\nII\t8\t\nIII\t25\t\nIV\t7\t\nFEV1 (%)\tMedian\t71\t\nRange\t35–100\t\nCOPD grade\t0\t17\t\n1\t3\t\n2\t9\t\n3\t10\t\n4\t6\t\nUnknown\t2\t\nCharison Comorbidity Index\tMedian\t5\t\nRange\t2‐10\t\nTreatment‐related parameters\tReirradiation volume (ml)\tMedian\t47\t\nRange\t4–541\t\nTumor location (n)\tPeripheral\t22\t\nCentral\t25\t\nCumulative EQD2 (Gy)\tMedian\t131\t\nRange\t77‐339\t\nSystemic therapy (n)\tYes\t27\t\nNo\t20\t\nInterval between radiation courses (months)\tMedian\t20\t\nRange\t5–145\t\nRadiation technique\tAccelerated\t23\t\nSTX\t13\t\nConventional (= 2 Gy/d)\t6\t\nHypofractionated\t5\t\nNote: Tx‐means that the tumor was not able to be evaluated\n\nAbbreviations: COPD, chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control.\n\nThe subgroup included 27 patients, of whom 17 (63%) were men and 10 (37%) were women. All tumors were histologically verified at initial diagnosis, according to which 21/27 patients (78%) had NSCLC and 6/27 patients (22%) had SCLC. The vast majority of patients (25/27, 92.5%) had an ECOG performance score ≤1 with a mean Charlson co‐morbidity index (CCI) of 6 (range 3–10). More than half of the patients (16/27, 60%) had stage III disease. Four patients (15%) were classified as oligometastic at reirradiation. Further details are shown in Table 2.\n\nTABLE 2 Patient‐ and treatment‐related parameters in the systemic therapy subgroup (N = 27)\n\nPatients N = 27\t\nPatient parameters\tAge (years)\tMedian\t66,3\t\nRange\t52–83\t\nSex\tMale\t17\t\nFemale\t10\t\nWeightless (%)\t>5%\t13\t\n<5%\t14\t\nECOG\t0–1\t25\t\n2\t2\t\nHistology\tSCLC\t6\t\nNSCLC\t21\t\nT stage\tx\t2\t\n1\t6\t\n2\t11\t\n3\t4\t\n4\t4\t\nN stage\t0\t5\t\n1\t4\t\n2\t13\t\n3\t5\t\nM stage\t0\t23\t\n1\t4\t\nUICC stage\tI\t2\t\nII\t5\t\nIII\t16\t\nIV\t4\t\nFEV1 (%)\tMedian\t71,1\t\nRange\t36–100\t\nCOPD grade\t0\t13\t\n1\t1\t\n2\t4\t\n3\t6\t\n4\t2\t\nUnknown\t1\t\nCharison comorbidity index\tMedian\t6\t\nRange\t3–10\t\nTreatment‐related parameters N = 27\tReirradiation volume (ml)\tMedian\t48.8\t\nRange\t4.5–217\t\nTumor location (n)\tPeripheral\t14\t\nCentral\t13\t\nCumulative EQD2 (Gy)\tMedian\t132,8\t\nRange\t79–211\t\nSystemic therapy\tChemotherapy\t6\t\nImmunotherapy with/without Chemotherapy\t21\t\nInterval between radiation courses (months)\tMedian\t14\t\nRange\t5–80\t\nRadiation technique\tAccelerated\t13\t\nSTX\t6\t\nConventional (= 2 Gy/d)\t5\t\nHypofractionated\t3\t\nAbbreviations: COPD,chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control.\n\nReirradiation and systemic therapy\n\nWhile 20 of the 47 patients were only reirradiated (43%), 27/47 (57%) received systemic therapy in addition to reirradiation. In this subgroup of interest, the tumor was located peripherally in 14/27 (52%) patients and centrally in 13/27 (48%) patients. Almost half of the patients (13/27, 48%, median EQD2 128 Gy, range 89–150.5 Gy) were reirradiated with DART‐bid, while 6/27 (22%, median EQD2 191 Gy, range 148–211 Gy) received SABR; in 5/27 patients (19%, median EQD2 122 Gy, range 79–134 Gy) conventional radiation therapy was applied and in 3/27 (11%, median EQD2 99 Gy, range 94–135.5 Gy) a hypofractionated schedule was used. The median reirradiation PTV was 48.8 ml (range 4.5–217 ml) and the median cumulative radiation dose EQD2 delivered in both treatments was 132.8 Gy (range 79–211 Gy). The median interval between the first and second treatment courses was 14 months (range 5–80 months). Twenty‐one patients (78%) received immunotherapy with or without chemotherapy (Table 2). The immunotherapeutic agents were administered after reirradiation over a median treatment time of 6 months (range 0.5–24 months). Six patients (22%) received chemotherapy alone prior to reirradiation.\n\nOverall survival\n\nThe median follow‐up across the cohort was 11.7 months (range 0.3–64.4 months). Of the 47 patients, 21 are still alive (45%). The median OS (mOS) after reirradiation was 18.9 months (95% CI 16.5–21.3 months; Figure 1(a)). The difference in OS between the three treatment modalities in the whole cohort, i.e. reirradiation only vs. reirradiation plus chemotherapy vs. reirradiation plus immunotherapy with/without chemotherapy was in favor of the third group (log‐rank p value = 0.132; Figure 1(b)).\n\nFIGURE 1 (a) The median overall survival (mOS) in the whole cohort of 47 patients was 18.9 months (95% confidence interval [CI] 16.5–21.3 months). (b) The 47 patients in the whole cohort were stratified according to the type of systemic therapy received together with reirradiation: immunotherapy or immunochemotherapy (orange), reirradiation alone without systemic treatment (blue), chemotherapy (green). Of these, the first group had the longest survival (mOS 23.7 months, 95% CI 20.3–27.1 months, overall log‐rank p value = 0.132)\n\nIn the immunotherapy subgroup, the mOS after the second radiation course was 21.8 months (95% CI 17.8–25.8 months; Figure 2(a)). Patients were followed up for a median of 18.4 months (range 1.4–60.9 months), and of these 12 (44%) are still alive, while 14 (52%) patients died from cancer‐related conditions. One patient (4%) died from peritonitis caused by bacterial infection. The median local progression‐free survival was 7.9 months (95% CI 6.7–9 months). The difference in OS was in favor of the immunotherapy subgroup (log‐rank p value = 0.063; Figure 2(b)).\n\nFIGURE 2 (a) The median OS (mOS) in the systemic therapy subgroup was 21.8 months (95% confidence interval [CI] 17.8–25.8 months). (b) Patients who received immunotherapy or chemo‐immunotherapy together with reirradiation lived longer than patients who underwent reirradiation with chemotherapy alone (mOS 23.7 months, 95% CI 20.3–27.1 months, log‐rank p value = 0.063)\n\nToxicity\n\nOf the 47 patients, eight (17%) experienced acute side effects greater than or equal to grade 2 and 1/47 (2%) patients had late ≥grade 2 toxicity. A grade 5 acute heart failure 1 week after the end of reirradiation was reported in 1/47 (2%) patients with no history of cardiac disease. In this patient, the cumulative maximum EQD2 delivered in both radiation courses was 110 Gy, which was below the 115 Gy classified as tolerable in the literature. 25 The 43% total V20 lung (volume receiving ≥20 Gy) met the above limitation while the 45% V25 (volume receiving ≥25 Gy) heart did not because the tumor was in the central upper lobe including the left hilum and upper segments of the lower lobe. Since a therapeutic cause of death, although unlikely, could not be entirely excluded this patient was scored as having grade 5 toxicity (Table 3).\n\nTABLE 3 Treatment‐related toxicity in the whole cohort\n\nToxicity (N = 47)\t\nType of toxicity\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tGrade 5\t\nAcute\tEsophagitis\tna\t4\t2\t0\t0\t\nPneumonitis\tna\t1\t0\t0\t0\t\nHeart\tna\t0\t0\t0\t1\t\nLate\tEsophagitis\tna\t0\t0\t0\t0\t\nPneumonitis\tna\t0\t0\t0\t0\t\nHemorrhage\tna\t0\t1\t0\t0\t\nChest wall pain\tna\t0\t0\t0\t0\t\nAbbreviation: na, not assessed.\n\nIn contrast, there were no grade 4 or 5 toxicities in the immunotherapy subgroup. Acute toxicities occurred as grade 2 in three patients (11%). Two of these patients had acute esophagitis and one reported acute pneumonitis. A late grade 3 hemorrhage occurred in one patient (4%, Table 4).\n\nTABLE 4 Treatment‐related toxicity in the subgroup\n\nToxicity (N = 27)\t\nType of toxicity\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tGrade 5\t\nAcute\tEsophagitis\tna\t2\t0\t0\t0\t\nPneumonitis\tna\t1\t0\t0\t0\t\nHeart\tna\t0\t0\t0\t0\t\nLate\tEsophagitis\tna\t0\t0\t0\t0\t\nPneumonitis\tna\t0\t0\t0\t0\t\nHemorrhage\tna\t0\t1\t0\t0\t\nChest wall pain\tna\t0\t0\t0\t0\t\nAbbreviation: na, not assessed.\n\nDISCUSSION\n\nIn this analysis we could show that in patients with locoregional relapse of lung cancer a second course of irradiation together with immunotherapy leads to better OS than a combination with chemotherapy (log‐rank p value = 0.063; Figure 2(b)).\n\nOur finding is consistent with a concept published in a review by Evans 5 intended for recurrent lung cancer patients who already have limited chances of successful curative treatment. 5 , 19 , 26 , 27 According to Evans, 5 the combination of the two therapy modalities would have a synergistic effect in terms of both local and systemic disease control, given the high potential for local and systemic failure, possibly due to radiation resistance and the aggressiveness of the disease in recurrent lung cancer patients. 5 Immunotherapy could potentially play an important role in enhancing the effectiveness of reirradiation and vice versa, which could hypothetically explain the prolonged survival of the subgroup who received reirradiation followed by immunotherapy in our study.\n\nIn the absence of published studies on reirradiation with immunotherapy, this consideration relies on data from patients receiving first‐time irradiation, assuming that outcome and toxicity would be similar in the reirradiation setting. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 15 , 16 , 20 , 28 , 29 , 30 In this context, there is data already available on the combination of RT and immunotherapy with primarily curative intent, indicating the potential clinical benefit in lung cancer patients. 1 , 2 This could be attributed to the potential synergistic effect of radioimmunotherapy, resulting in a local and systemic anti‐tumor response, which is currently attracting great academic interest and generating many hypotheses about the exact trigger and interaction mechanism behind it. 5 , 7 , 12 , 17 , 18 , 29 In this regard, a recently published review 17 highlighted the possible synergistic benefits of combining chemotherapy, radiation therapy, and immunotherapy such as the increase of cytotoxicity, the enhancement of immunogenic cell death and tumor necrosis as well as increased tumor‐derived and neoantigen generation, all of which could lead to a potentially enhanced antitumor effect.\n\nThe details of the complex mechanism of immunotherapy and radiation, as well as the interaction between the two, are described elsewhere. 5 , 7 , 16 , 17 , 29 , 30 Briefly summarized, tumor cells evade the immune response by up‐regulating specific proteins such as programmed cell death 1 ligand 1 (PDL‐1) on their surface. These immune checkpoint ligands interact with the programmed cell death protein 1 (PD‐1) surface receptors of activated cytotoxic T cells, thereby inhibiting them. By inhibiting the PD‐1/PDL‐1 signaling pathway with inhibitors such as nivolumab, pembrolizumab, durvalumab, and atezolizumab, which were administered in our immunotherapy subgroup, the T cells can recognize the tumor cells as pathogens and eliminate them. 1 , 2 , 5 , 7 , 20 Relatedly, radiation‐induced antitumor activity is immune‐mediated by the T cells. 11 Radiation stimulates tumor antigen presentation on the surface of dendritic cells to T cells, which is to prime the T cells in the lymph nodes to respond effectively against tumor cells. 15 , 18 , 31\n\nThe sequence in which RT and immunotherapy would be applied is still under investigation, 13 , 32 however available data showed clinical benefit with acceptable toxicity when immunotherapy was administered after radiation treatment, 12 , 14 which corresponds to the toxicity results obtained in our study. Accordingly, in our study, considering the side effects of immunotherapy, particularly with regard to pneumonitis 33 and the severe systemic 7 and local side effects that could be caused by the reirradiation treatment, immunotherapy was given after reirradiation. This treatment sequence was well tolerated. Eleven percent of the patients experienced grade 2 toxicity, with esophagitis and pneumonitis being the only radiogenic side effects, and 4% reported grade 3 toxicity. No grade 4 or 5 toxicity events were reported.\n\nAn obvious weakness of our analysis is the rather permissive threshold for first‐order errors (α). However, this is not unusual in exploratory studies with the aim of extracting as much potentially important information as possible. 23 , 34 Despite the small cohort and the retrospective nature, our data may gain additional significance given the fact that prospective studies on the combination of reirradiation combined with immunotherapy are lacking.\n\nCONCLUSION\n\nThe combination of reirradiation with immunotherapy could potentially prolong survival with acceptable toxicity. Although prospective studies are warranted, we believe that this combined treatment approach can transform the way patients with recurrent lung cancer are treated.\n\nCONFLICT OF INTEREST\n\nAll authors declare that they have no conflict of interest.\n==== Refs\nREFERENCES\n\n1 Antonia SJ , Villegas A , Daniel D , Vicente D , Murakami S , Hui R , et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. 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Nat Commun. 2018;9 :5228.30531873\n\n", "fulltext_license": "CC BY", "issn_linking": "1759-7706", "issue": "12(8)", "journal": "Thoracic cancer", "keywords": "immunotherapy; local recurrence; lung cancer; overall survival and toxicity; reirradiation", "medline_ta": "Thorac Cancer", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011879:Radiotherapy Dosage; D000069475:Re-Irradiation; D012189:Retrospective Studies; D016019:Survival Analysis", "nlm_unique_id": "101531441", "other_id": null, "pages": "1162-1170", "pmc": null, "pmid": "33586228", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": 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{ "abstract": "Malignant pleural mesothelioma (MPM) is an asbestos-related tumor arising in the pleural cavity. Symptoms reflect extension of disease and include shortness of breath and chest pain. Unexplained pleural effusion and pleural pain in patients exposed to asbestos should raise the suspicion of MPM. The most common radiologic presentation is ipsilateral pleural effusion with or without pleural thickening or a mass. Thoracoscopic biopsy remains the most appropriate procedure for definitive diagnosis of mesothelioma. Despite advancement in diagnostic procedures and biomolecular research, this tumor nevertheless has poor prognosis. Mesothelioma remains a diagnostic and therapeutic challenge and is likely to remain one in the years to come. Here we present the first reported case of steroid treatment responsive pleural effusion in a 72 year-old-male that initially was misdiagnosed as rheumatoid related effusion. However, Pleuroscopy with biopsy revealed mesothelioma.", "affiliations": "Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.;Department of Pulmonary and Critical Care Medicine, Veterans Administration Medical Center, Huntington, WV 25701, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.", "authors": "Shehata\|Mena\|M\|;Zaid\|Fouad\|F\|;Ottaviano\|Peter\|P\|;Shweihat\|Yousef\|Y\|;Munn\|Nancy\|N\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2018.12.006", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30324-110.1016/j.rmcr.2018.12.006Case ReportCase report: Steroid responsive mesothelioma-related pleural effusion Shehata Mena [email protected]∗Zaid Fouad bcOttaviano Peter cShweihat Yousef bMunn Nancy bca Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USAb Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USAc Department of Pulmonary and Critical Care Medicine, Veterans Administration Medical Center, Huntington, WV 25701, USA∗ Corresponding author. [email protected] 12 2018 2019 19 12 2018 26 131 135 19 10 2018 11 12 2018 11 12 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Malignant pleural mesothelioma (MPM) is an asbestos-related tumor arising in the pleural cavity. Symptoms reflect extension of disease and include shortness of breath and chest pain. Unexplained pleural effusion and pleural pain in patients exposed to asbestos should raise the suspicion of MPM. The most common radiologic presentation is ipsilateral pleural effusion with or without pleural thickening or a mass. Thoracoscopic biopsy remains the most appropriate procedure for definitive diagnosis of mesothelioma. Despite advancement in diagnostic procedures and biomolecular research, this tumor nevertheless has poor prognosis. Mesothelioma remains a diagnostic and therapeutic challenge and is likely to remain one in the years to come.\n\nHere we present the first reported case of steroid treatment responsive pleural effusion in a 72 year-old-male that initially was misdiagnosed as rheumatoid related effusion. However, Pleuroscopy with biopsy revealed mesothelioma.\n==== Body\n1 Introduction\nMalignant mesothelioma is a tumor arising from the mesothelial cells or sub-mesothelial cells of the pleura, peritoneum or pericardium, with more than 80% originate in the pleura [1]. The most common cause of diffuse malignant mesothelioma in the United States is inhalation of asbestos [2]. The latency from the time of exposure to the development of malignant mesothelioma is several decades [3]. Low-level exposures, as well as bystander are risk factors for the mesothelioma. No threshold of asbestos exposure has been established for the development of malignant mesothelioma [4]. Despite the fact that industrial use of asbestos was forbidden many years ago, new cases of mesothelioma continue to appear because of the long latency of the disease [5].\n\nHere, we report a case of 72-years-old male with multiple admissions for pleuritic chest pain associated with recurrent exudative pleural effusions with dramatic response to steroids, initially misdiagnosed as connective tissue disease related pleural effusion. Yet it was found to be mesothelioma.\n\n2 Case presentation\nHerein a 72-year-old male patient with no significant past medical history apart from hyperlipidemia. He is a retired plumber and former Veteran. He quit smoking 38 years ago. He presented to the Emergency department (ED) with complain of worsening chest pain for few days that increased with deep inspiration. Pain was piercing in nature affecting his right side, sometimes associated with cough but no concomitant shortness of breath. His vital signs at that time were within normal and his cardiopulmonary exam was unremarkable. Acute coronary syndrome was ruled out through negative troponin series and a normal EKG. Patient was diagnosed with pleurisy and was released home from ED with a NSAID along with short steroid taper.\n\nTwo weeks later the patient presented again with the same complain. Physical exam was unremarkable and initial laboratory results were significant for mild leukocytosis. Chest x-ray showed new right sided effusion with infiltrate versus consolidation (Fig. 1). Computed tomography of the chest with intravenous contrast ruled out pulmonary embolism yet it has showed a small right-sided pleural effusion as well as right lower lobe infiltration versus consolidation. Patient also had right hilar small lymphadenopathy on imaging and minimal pericardial effusion (Fig. 2, Fig. 3, Fig. 4).Fig. 1 Admission Plain radiograph with small pleural effusion.\n\nFig. 1Fig. 2 CT mediastinal view of the chest with lymphadenopathy.\n\nFig. 2Fig. 3 Pleural effusion on the right.\n\nFig. 3Fig. 4 Right lower lobe infiltrate.\n\nFig. 4\n\nPatient then was admitted to the hospital and was treated as community acquired pneumonia with intravenous ceftriaxone and Azithromycin. Patient was also started on intravenous methylprednisolone every six hours and ibuprofen as needed for pain control. The white-cell count on subsequent days has increased from 14.5 × 103 to 30.5 × 103/μL on day 3. Antibiotics were escalated to intravenous vancomycin, Piperacillin and tazobactam. Pulmonary service was consulted for worsening leukocytosis in setting of pneumonia and parapneumonic pleural effusion. At that time patient symptoms had improved and there was no indication for aspiration because of minimal effusion and subjective improvement. The pulmonologist has recommended repeat chest scan in 8–12 weeks to reassess adenopathy and confirm resolution. His white count was attributed to steroid administration. He was discharged on oral antibiotics along with a prednisone taper upon improvement of his symptoms and labs.\n\nTwo weeks later the patient represented to ED with recurrence of his symptoms few days after he had finished his steroid course. Physical exam was significant for tachycardia 111 bpm and tachypnea, laboratory testing was Significant for leukocytosis of 19.6 × 103/μL. EKG showed sinus tachycardia. Plain chest radiograph showed recurrence of pleural effusion in the right side (Fig. 5a). Repeat Chest CT showed worsening right pleural effusion along with progressive consolidative changes in the right lower lobe (Fig. 5, Fig. 6, Fig. 7). Patient was admitted and was started on intravenous vancomycin, Piperacillin, tazobactam as well as methylprednisolone for presumed worsening pneumonia. Echocardiogram demonstrated normal biventricular function.Fig. 5 Worsening pleural effusion (a and b).\n\nFig. 5Fig. 6 Right middle lobe infiltrate.\n\nFig. 6Fig. 7 Worsening right lower lobe infiltrate.\n\nFig. 7\n\nPulmonary service was re-consulted who did bedside ultrasound on the next day showed very small right sided pleural effusion that is unsafe to tap. The dramatic improvement of pleural fluid after steroid treatment increased the suspicion of possible connective tissue disease as a cause. Connective tissue diseases work-up was done, revealed positive rheumatoid factor along with strongly positive Anti-cyclic citrullinated peptide (level > 70). Erythrocyte sedimentation rate C-reactive protein were both elevated 61 mm/hr and 260.4, respectively. ANA, ANCA profile and anti SCL-70 were negative. Before being discharged the pleural effusion as resolved (Fig. 8). He was discharged on prednisone 40 mg daily for two weeks until seen by pulmonary clinic for follow up.Fig. 8 Dramatic improvement of right-side pleural effusion at hospital (a) and then at the clinic (b).\n\nFig. 8\n\nPatient stopped the treatment as a repeat x-ray done in his primary care physician office after following up hospital visit showed complete resolution of his effusion (Fig. 8b).\n\nFew days later, patient was due for his pulmonary clinic follow up and he complained of return of his pleurisy symptoms when he tapered steroid. At that time, he was restarted on a prolonged steroid taper starting at 60 mg of prednisone per day. Repeat chest scan for follow up on the hilar lymphadenopathy showed near normalization of the size of the lymph nodes and trace residual right pleural effusion (Fig. 8a and b). Also, right lower lobe infiltrate showed resolution compared to prior imaging. At that time the patient was still on steroid taper and was asymptomatic (see Fig. 9).Fig. 9 CT scan showed regression of lymphadenopathy and near complete resolution of pleural effusion.\n\nFig. 9\n\nOne month later the patient was seen in the pulmonary clinic for follow-up. Chest plain radiograph was normal and prednisone dose was further reduced to 10 mg. Yet few days later the patient developed pleuritic type chest pain and chest x ray showed re-accumulation of his pleural effusion at the emergency department (Fig. 10).Fig. 10 Plain radiograph with recurrent moderate pleural effusion.\n\nFig. 10\n\nPatient refused admission and Video-Consult to pulmonary was done and patient was advised to restart on prednisone 40 mg until future appointment in the pulmonary clinic for thoracentesis. Due to the prolonged steroid course the patient was also started on Trimethoprim/Sulfamethoxazole for prophylaxis against pneumocystis. And patient returned to the pulmonary clinic one week later, and a repeat CXR showed decreased pleural effusion responding to steroid (Fig. 11). At that time, he was thought of as rheumatoid induced pleural effusion steroid responsive, yet no tapping has been done.Fig. 11 Plain radiograph with decreasing right pleural effusion.\n\nFig. 11\n\nAbout one month later (4 months since initial presentation) while the patient was still taking 30 mg prednisone, his pleural effusion recurred, and first-time thoracentesis was done at the pulmonary clinic with inconclusive fluid studies. Gram stain was negative and culture later on had no growth. Patient was discharged on same treatment.\n\nPatient developed atrial fibrillation with rapid ventricular rhythm and was admitted through another facility and chest x ray still had pleural effusion. Repeat thoracentesis results were exudative, Serum protein 6.7 g/dl, Serum LDH 149 (87-241 IU/L), Fluid LDH 851 IU/L, Negative microbiology, Fluid glucose 137 mg/dl, Fluid protein 3.2 g/dl, WBC 206 × 103/μL (16 neutrophils, 12 monocytes, 60 lymphocytes), Cytology results came back with atypical cells present on both thoracentesis. Patient again was readmitted for therapeutic and diagnostic purposes from effusion recurrence. Third time thoracentesis done week later was same on analysis. Patient was referred for pleuroscopy with biopsy.\n\nPleuroscopy showed lots of loculations as well as adhesions. The parietal pleural was infiltrated with what seemed to be inflammatory tissue and had some areas of nodularity. Multiple biopsies were obtained from the parietal pleura. The entire surface of the parietal pleura including some of the diaphragmatic pleura was involved. Visceral pleura was noted to be unaffected by gross exam. For his recurrent pleural effusion, a Pleurx catheter was left for drainage and symptomatic relief.\n\nPathological exam report was positive for a tumor consistent with mesothelioma (epithelioid type). Immunohistochemical stains performed. Results were of cells positive for Calretinin, CK5/6, CK7, and WT-1 but negative for Napsin-A, CK20, and TTF-1.\n\nPET scan results revealed diffuse abnormal right pleural uptake consistent with history of mesothelioma with no evidence of disease elsewhere (Fig. 12).Fig. 12 Pet scan results with disease limited to pleura on the right side.\n\nFig. 12\n\nPatient disease was classified as stage 1 as per the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) [6].Patient was referred to a specialized cancer center for management.\n\n3 Discussion\nDespite the presence of some clinical and laboratory findings on review of the case, these can be as misleading if not carefully assessed. The differential diagnosis of this unexplained pleuropulmonary process includes collagen vascular disease, thromboembolic disease, and malignant tumors. The recurrent effusion that occurred in the absence of evidence of infection, as well as recurrent worsening chest pain that was reported by the patient on admissions in lieu of dramatic response to steroid on multiple occasions plus inability to do thoracentesis early made the diagnosis of the case challenging.\n\nPneumonia can be a cause of exudative pleural effusions especially if partially treated. Parapneumonic pleural effusion refers to pleural effusion associated with bacterial pneumonia, a pulmonary abscess or infected bronchiectasis [7]. This is less likely to be the case here since the patient symptoms didn't fit with this diagnosis. Also, his very rapid response to steroid treatment with marked regression of the effusion is less likely to happen with a parapneumonic effusion.\n\nPatients with collagen vascular disease can initially present with recurrent pleural effusions [8]. Rheumatoid effusions are well described in the literature with pleural involvement is the most common thoracic manifestation of rheumatoid disease [9], yet the absolute incidence of rheumatoid pleural effusion is low. Especially with the presence of anti-rheumatoid factor and anti-Citrullinated peptide antibodies, rheumatoid disease is a high suspicion. Despite these suspicions the patient had no history of a rheumatoid disease. Additionally, in rheumatoid induced pleural effusion, one would see numerous polymorphonuclear leukocytes at the time of presentation and as the effusion matures a lymphocytic predominance can be appreciated [10]. Rheumatoid effusion is also characterized by low pleural fluid glucose level, usually less than 30 mg/dl [11]. His pleural effusion analysis was atypical of rheumatoid induced pleural effusion.\n\nMalignant pleural effusion can result from primary malignancies of the pleura or with intrathoracic and extra-thoracic malignancies that reach the pleural space by hematogenous, lymphatic, or contiguous spread [9]. Lung carcinoma is the most common cause of chest pain and pleural effusions in this age group [8] These effusions are known as paraneoplastic or paramalignant pleural effusions [9]. Malignant mesothelioma is a tumor arising from the mesothelial cells or sub-mesothelial cells of the pleura, peritoneum or pericardium, with more than 80% originate in the pleura [1]. The most common radiographical presentation is unilateral pleural effusion with or without ipsilateral pleural thickening or mass [12]. Only a small number of patients are asymptomatic at diagnosis, having an incidental detection of abnormality on imaging undertaken for a different reason [13]. Dyspnea is the first symptom of pleural mesothelioma cases [14,15]. Pleural mesothelioma can cause pain by irritating intercostal nerves or by infiltrating into the chest wall. Rarer manifestations include phrenic nerve palsy, irritative cough, para-neoplastic phenomena, and spontaneous pneumothorax [16]. Malignant pleural effusion is often one of the primary manifestation of mesothelioma and can be found in about 90% of patients at diagnosis [17]. Effusion sampling obtained by thoracentesis and cytological examination is the most informative laboratory test for diagnosis. In patients who do not appear to have a history of asbestos exposure, mesothelioma should not be ruled out if other symptoms and signs of the disease are present. Unfortunately establishing the diagnosis of mesothelioma can be difficult. In malignant mesothelioma of the pleura, cytology displays a low sensitivity and is not an accurate assay in differentiating malignant cells from reactive mesothelial cells or lung cancer cells [18,19]. When nodular pleural thickening is present, a fine-needle biopsy can be performed to establish the diagnosis, but there is only a 25% chance that the biopsy will yield a diagnosis in the presence of a no diagnostic effusion. Video-assisted thoracoscopic surgery (VATS) is the diagnostic procedure of choice; it yields a diagnosis in more than 90% of cases.\n\nUpon careful review of literature and to the best of our knowledge, we were unable to find any case report describing steroid responsive pleural effusion secondary to mesothelioma.\n\nDeclaration of conflicting interests\nThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 Kim J. Bhagwandin S. Labow D.M. Malignant peritoneal mesothelioma : a review 5 11 2017 1 11 \n2 L. S. Welch, “Asbestos Exposure Causes Mesothelioma, But Not This Asbestos Exposure:,” no. 133178, pp. 318–327.\n3 Iwatsubo Y. Pairon J. De Beaune C.A. Bignon J. Brochard P. Pleural Mesothelioma : a Descriptive Analysis Based on a Case-Control Study and Mortality Data in Ile de 88 1994 77 88 \n4 Craighead J.E. Epidemiology of Mesothelioma and Historical Background 2011 \n5 Delgermaa V. Takahashi K. Park E. Le V. Sorahan T. Global Mesothelioma Deaths Reported to the World Health Organization between 1994 and 2008,” No. January 2011 716 724 \n6 Amin MB S. Edge S.B. Greene F.L. AJCC (American Joint Committee on Cancer) Cancer Staging Manual eighth ed. 2017 \n7 Yu H. Management of pleural effusion, empyema, and lung abscess 1 212 2011 75 86 \n8 Kradin R.L. Fidias P. Case 17-2014 : a 64-year-old Man with Chest Pain and a Pleural Effusion 2014 \n9 Press D. Pleural effusion: diagnosis, treatment, and management 2012 31 52 \n10 Avnon L.S. Abu-Shakra M. Flusser D. Heimer D. Sion-Vardy N. Pleural effusion associated with rheumatoid arthritis: what cell predominance to anticipate? Rheumatol. Int. 27 10 2007 Aug 1 919 925 17294192 \n11 Article R. Differential diagnosis of pleural effusions 49 9 2006 315 319 \n12 Fayed H.E. Woodcock V.K. Grayez J. Simultaneous bilateral spontaneous hydropneumothorax : a rare presentation of bilateral malignant pleural mesothelioma 2013 1 3 \n13 Bianco A. Valente T. De Rimini M.L. Sica G. Fiorelli A. Clinical diagnosis of malignant pleural mesothelioma 10 7 2018 253 261 \n14 Scherpereel A. Guidelines of the european respiratory society and the european society of thoracic surgeons for the management of malignant pleural mesothelioma 35 3 2010 479 495 \n15 Health O. Neumann V. Löseke S. Nowak D. Herth F.J.F. Tannapfel A. Malignant pleural mesothelioma 110 2013 18 \n16 Article O. Malignant Mesothelioma ± German Mesothelioma Register 1987±1999 2001 383 395 \n17 Franceschini M.C. Mesothelin in Serum and pleural effusion in the diagnosis of malignant pleural mesothelioma with non-positive cytology 7430 2014 7425 7429 May 2013 \n18 A. A. Renshaw, B. R. Dean, and K. H. Antman, “The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma *,” Chest, vol. 111, no. 1, pp. 106–109.\n19 Rakha E.A. The sensitivity of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma 38 2010 12\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "26()", "journal": "Respiratory medicine case reports", "keywords": null, "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "131-135", "pmc": null, "pmid": "30603603", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "11563601;17294192;17915546;19717482;20049969;21479893;22084509;22379278;23682089;23720698;24869724;25503183;29507793;8074126;8996002", "title": "Case report: Steroid responsive mesothelioma-related pleural effusion.", "title_normalized": "case report steroid responsive mesothelioma related pleural effusion" }	[ { "companynumb": "US-TEVA-2019-US-1010356", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN MANAGEMENT", "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": "042", "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": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "042", "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 ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "042", "drugauthorizationnumb": "085600", "drugbatchnumb": null, "drugcharacterization": "1", "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": "METHYLPREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHEHATA M, ZAID F, OTTAVIANO P, SHWEIHAT Y, MUNN N. 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"drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": "3", "drugadministrationroute": "065", "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": "PIPERACILLIN AND TAZOBACTAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZITHROMYCIN ANHYDROUS" }, "drugadditional": "3", "drugadministrationroute": "065", "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 ANHYDROUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHEHATAA M, ZAID F, OTTAVIANOC P, SHWEIHATB Y, MUNN N. CASE REPORT: STEROID RESPONSIVE MESOTHELIOMA-RELATED PLEURAL EFFUSION. RESPIRATORY MEDICINE CASE REPORTS. 2019?26:131-5", "literaturereference_normalized": "case report steroid responsive mesothelioma related pleural effusion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190204", "receivedate": "20190204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15906192, "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": "A seven years old girl presented with history of sudden onset of generalized body weakness to an extent that she was not able to move any body part. On thorough history it was revealed that she was given intramuscular injection lincomycin at private clinic which lead to neuromuscular paralysis of whole body. This antibiotic is currently not being used in humans and being only used as veterinary medication.", "affiliations": null, "authors": "Shah\|Syed Sajid Hussain\|SS\|;Saleem\|Munaza\|M\|;Mehood\|Tahir\|T\|", "chemical_list": "D000900:Anti-Bacterial Agents; D008034:Lincomycin", "country": "Pakistan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1025-9589", "issue": "26(3)", "journal": "Journal of Ayub Medical College, Abbottabad : JAMC", "keywords": null, "medline_ta": "J Ayub Med Coll Abbottabad", "mesh_terms": "D000900:Anti-Bacterial Agents; D002648:Child; D005260:Female; D006801:Humans; D008034:Lincomycin; D010243:Paralysis", "nlm_unique_id": "8910750", "other_id": null, "pages": "406-7", "pmc": null, "pmid": "25671960", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Neuromuscular paralysis by a single injection of lincomycin.", "title_normalized": "neuromuscular paralysis by a single injection of lincomycin" }	[ { "companynumb": "PK-PFIZER INC-2015109394", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LINCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "050317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RASH GENERALISED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINCOMYCIN HCL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LINCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRURITUS GENERALISED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINCOMYCIN HCL" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paralysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH SS. NEUROMUSCULAR PARALYSIS BY A SINGLE INJECTION OF LINCOMYCIN. JOURNAL OF AYUB MEDICAL COLLEGE, ABBOTTABAD: JAMC. 2014;26(3):406-407", "literaturereference_normalized": "neuromuscular paralysis by a single injection of lincomycin", "qualification": "3", "reportercountry": "PK" }, "primarysourcecountry": "PK", "receiptdate": "20150402", "receivedate": "20150402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10979347, "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" }, { "companynumb": "PK-WATSON-2015-08347", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LINCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "063180", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "URTICARIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINCOMYCIN (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paralysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH SS, SALEEM M, MEHOOD T. NEUROMUSCULAR PARALYSIS BY A SINGLE INJECTION OF LINCOMYCIN. J AYUB MED COLL ABBOTTABAD. 2014;26(3):406-7", "literaturereference_normalized": "neuromuscular paralysis by a single injection of lincomycin", "qualification": "3", "reportercountry": "PK" }, "primarysourcecountry": "PK", "receiptdate": "20150428", "receivedate": "20150428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11072248, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20150821" } ]
{ "abstract": "OBJECTIVE\nTo describe the long-term outcomes of intravitreal bevacizumab (IVB) for the treatment of pediatric retinal and choroidal diseases.\n\n\nMETHODS\nThis was a multicenter, retrospective, consecutive case series of patients <18 years of age treated with IVB from 2005 to 2013. Primary outcome measures included visual acuity and central macular thickness at 12 months' follow-up.\n\n\nRESULTS\nA total of 95 eyes of 90 patients (average age, 8.7 years [range, 0.33-17 years]) were included, in which 352 injections (average, 3.7/eye) were administered for choroidal neovascular membrane (CNVM, n = 35), Coats disease (n = 35), familial exudative vitreoretinopathy (FEVR, n = 13), cystoid macular edema (CME, n = 6), and other (n = 6). Mean follow-up was 679 ± 581 days. IVB was used as monotherapy in 27 eyes and as part of combination therapy in 68. Mean Snellen equivalent visual acuity improved from 20/224 at baseline to 20/120 at 6 months (P = 0.034) and 20/108 at 12 months (P = 0.005). Mean central macular thickness improved from 426 μm to 349 μm at 6 months (P = 0.025) and 340 μm at 12 months (P = 0.002). Statistically significant visual acuity gains at 12 months were achieved in patients with CNVM (P = 0.009) but not in eyes with CME (P = 0.06), Coats disease (P = 0.15), or FEVR (P = 0.93). Adverse effects included ocular hypertension in 8 eyes and worsening tractional retinal detachment in 3 eyes.\n\n\nCONCLUSIONS\nPatients receiving IVB as part of the treatment for pediatric retinal and choroidal diseases experienced significant visual acuity gains and reductions in central macular thickness. IVB was generally well tolerated, although safety concerns persist.", "affiliations": "Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: [email protected].;Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.;Murray Ocular Oncology and Retina, Miami, Florida.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.", "authors": "Henry\|Christopher R\|CR\|;Sisk\|Robert A\|RA\|;Tzu\|Jonathan H\|JH\|;Albini\|Thomas A\|TA\|;Davis\|Janet L\|JL\|;Murray\|Timothy G\|TG\|;Berrocal\|Audina M\|AM\|", "chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1091-8531", "issue": "19(6)", "journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus", "keywords": null, "medline_ta": "J AAPOS", "mesh_terms": "D000293:Adolescent; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D002648:Child; D002675:Child, Preschool; D015862:Choroid Diseases; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D008297:Male; D012164:Retinal Diseases; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity", "nlm_unique_id": "9710011", "other_id": null, "pages": "541-8", "pmc": null, "pmid": "26691034", "pubdate": "2015-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Long-term follow-up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases.", "title_normalized": "long term follow up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases" }	[ { "companynumb": "US-ROCHE-1399195", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOROIDITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 MG/0.05 ML VIA THE PARS PLANA USING A 30- OR 32-GAUGE HALF-INCH NEEDLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Retinal detachment", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ocular hypertension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", SISK R, TZU J, ALBINI T, DAVIS J, MURRAY T AND BERROCAL A. LONG-TERM FOLLOW-UP OF INTRAVITREAL BEVACIZUMAB FOR THE TREATMENT OF PEDIATRIC RETINAL AND CHOROIDAL DISEASES. JOURNAL OF AAPOS 2015;19 (6):541-548.", "literaturereference_normalized": "long term follow up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170606", "receivedate": "20140516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10175509, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170829" }, { "companynumb": "US-ROCHE-1400958", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOPATHY CONGENITAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 MG/0.05 ML OF BEVACIZUMAB", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Idiopathic intracranial hypertension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", SISK R, TZU J, ALBINI T, DAVIS J, MURRAY T AND BERROCAL A. LONG-TERM FOLLOW-UP OF INTRAVITREAL BEVACIZUMAB FOR THE TREATMENT OF PEDIATRIC RETINAL AND CHOROIDAL DISEASES. JOURNAL OF AAPOS 2015;19 (6):541-548.", "literaturereference_normalized": "long term follow up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170606", "receivedate": "20140516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10175505, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170829" } ]
{ "abstract": "Data from clinical trials do not always provide adequate information to judge the impact of new treatments when used in a real-world setting. The aim of our study was to analyze adverse events (AEs) associated with enzalutamide (ENZ) and abiraterone (ABI) using real-life data from the EudraVigilance (EV) database.\n\n\n\nThe EV database is the system for managing and analyzing information on suspected adverse reactions to medicines, which have been authorized or are being studied in clinical trials in the European Economic Area. We recorded the number of AEs for ABI and ENZ per category and severity from January 2013 to January 2019. In addition, we recorded AEs per age group. A meta-analysis of AEs reported in registrational phase III studies (AFFIRM, PREVAIL, COU-AA) was performed.\n\n\n\nThe number of individual cases identified in EV database was 13,562 for ABI and 40,599 for ENZ. Over 90% of the reported AEs were defined as serious for both drugs. Older patients (>85 years and 65-85 years) treated with ABI or ENZ are at increased risk of cardiac, infectious, metabolic, and respiratory disorders when compared with younger patients (<65). According to registrational phase III studies, the most frequent AEs in patients treated with ABI are hepatobiliary disorders, while the most frequent AEs in patients treated with ENZ are psychiatric and vascular disorders. Several AEs present in the EV database are not reported in the registrational phase III studies. It is important to note that we have no information on the number of patients under treatment in the EV database.\n\n\n\nThe EV database highlights several AEs that are not reported in registrational phase III studies as well as different AEs profiles according to age. Clinicians should consider these data when treating patients with castration-resistant prostate cancer with ABI or ENZ.", "affiliations": "Department of Urology, Ospedale Sant'Andrea, Rome, Italy. [email protected].;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Oncologia Medica, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Rome, Italy.;Department of Urology, Azienda Ospedaliera di Terni, Terni, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.", "authors": "De Nunzio\|Cosimo\|C\|;Lombardo\|Riccardo\|R\|;Tema\|Giorgia\|G\|;Voglino\|Olivia\|O\|;Sica\|Angela\|A\|;Baldassarri\|Valeria\|V\|;Nacchia\|Antonio\|A\|;Iacovelli\|Roberto\|R\|;Bracarda\|Sergio\|S\|;Tubaro\|Andrea\|A\|", "chemical_list": "D000736:Androstenes; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone", "country": "England", "delete": false, "doi": "10.1038/s41391-019-0182-x", "fulltext": null, "fulltext_license": null, "issn_linking": "1365-7852", "issue": "23(2)", "journal": "Prostate cancer and prostatic diseases", "keywords": null, "medline_ta": "Prostate Cancer Prostatic Dis", "mesh_terms": "D000736:Androstenes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D017326:Clinical Trials, Phase III as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin; D011379:Prognosis; D011471:Prostatic Neoplasms; D012189:Retrospective Studies", "nlm_unique_id": "9815755", "other_id": null, "pages": "199-206", "pmc": null, "pmid": "31685981", "pubdate": "2020-06", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review", "references": null, "title": "Adverse events related to abiraterone and enzalutamide treatment: analysis of the EudraVigilance database and meta-analysis of registrational phase III studies.", "title_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies" }	[ { "companynumb": "IT-JNJFOC-20190512256", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "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": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Mediastinal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Connective tissue disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product quality issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Lymphatic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatobiliary disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Breast disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Eye disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angiopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infestation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neoplasm", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Inner ear disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metabolic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Laboratory test abnormal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Reproductive tract disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Disability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Endocrine disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Surgery", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Immune system disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Skin disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Musculoskeletal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Social problem", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pregnancy of partner", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "TUBARO A, LOMBARDO R, TEMA G, VOGLINO O, SICA A, BALDASSARRI V, NACCHIA A, IACOVELLI R, BRACARDA S, NUNZIO C. ADVERSE EVENTS RELATED TO ABIRATERONE AND ENZALUTAMIDE TREATMENT: ANALYSIS OF THE EUDRAVIGILANCE DATABASE AND META?ANALYSIS OF REGISTRATIONAL PHASE III STUDIES. PROSTATE CANCER AND PROSTATIC DISEASES. 2019 NOV 04?.", "literaturereference_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200820", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17970418, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IT-JNJFOC-20200641345", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neonatal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Paternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COSIMO D, RICCARDO L, GIORGIA T, OLIVIA V, ANGELA S, VALERIA B, ANTONIO N, ROBERTO I, SERGIO B, ANDREA T. ADVERSE EVENTS RELATED TO ABIRATERONE AND ENZALUTAMIDE TREATMENT: ANALYSIS OF THE EUDRAVIGILANCE DATABASE AND META?ANALYSIS OF REGISTRATIONAL PHASE III STUDIES. PROSTATE CANCER AND PROSTATIC DISEASES. 2019 NOV 04?.", "literaturereference_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200701", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17967796, "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": "IT-JNJFOC-20200641205", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Congenital anomaly", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "COSIMO D. ADVERSE EVENTS RELATED TO ABIRATERONE AND ENZALUTAMIDE TREATMENT: ANALYSIS OF THE EUDRAVIGILANCE DATABASE AND META?ANALYSIS OF REGISTRATIONAL PHASE III STUDIES. PROSTATE CANCER AND PROSTATIC DISEASES. 2019 NOV 04?.", "literaturereference_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200701", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17967811, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Anticoagulants are commonly prescribed in medical practices and could be of significant harm in the case of medication errors. We conducted a retrospective observational study to determine the frequency and consequences of the therapeutic duplication of anticoagulants (TDA). As a secondary objective, we aimed to determine the characteristics of the population in which TDA occurs.\nWe conducted a retrospective observational study among admitted patients who concomitantly received at least two anticoagulants from August 2017 to August 2018.\nA total of 107 patients with TDA are included in the research. The patients with TDA have a mean age of 73. The TDA population has a high rate of associated comorbidities with 69% of patients having arterial hypertonia, 40% with chronic kidney disease, 26% with a history of malignancy, and 20.5% with a history of stroke. More than 65% of patients were under anticoagulation before admission, mostly due to atrial fibrillation. The TDA occurred in more than 95% of cases in the first week or the last week of hospitalization. Patients had a high risk of bleeding prior to the TDA-event with about 62.5% of TDA patients having a HAS-BLED score at least 3. A total of 8 patients showed a significant Hemoglobin (Hb)-drop of at least 10 g/L within 24 h after TDA-event. Two patients had a new or worsened hematuria following TDA-event.\nTDA occurred in 0.8% of patients who were under anticoagulation and in 6.7% of patients who received direct oral anticoagulants (DOACs). TDA led in about 7.4% of cases to hemoglobin-relevant bleeding. The old patients with significant comorbidities and a high HAS-BLED score were mainly affected. The female gender and presence of anemia independently predicted the occurrence of bleeding following TDA.", "affiliations": "Faculty of Medicine, University of Basel, Basel, Switzerland.;Hospital Pharmacy, Kantonsspital Aarau, Aarau, Switzerland.;Hospital Pharmacy, Kantonsspital Aarau, Aarau, Switzerland.;Faculty of Medicine, University of Basel, Basel, Switzerland.;Department of Internal Medicine, Kantonsspital Aarau, 5000 Aarau, Switzerland.", "authors": "Rahmanzade\|Ramin\|R\|;Cabrera Diaz\|Francisco\|F\|;Zaugg\|Claudia\|C\|;Schuetz\|Philipp\|P\|;Salili\|Ali Reza\|AR\|0000-0003-2488-646X", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12959-020-00227-w", "fulltext": "\n==== Front\nThromb J\nThromb J\nThrombosis Journal\n1477-9560 BioMed Central London \n\n227\n10.1186/s12959-020-00227-w\nResearch\nTherapeutic duplication of anticoagulants: a retrospective study of frequency and consequences in a tertiary referral hospital\nRahmanzade Ramin 12 Cabrera Diaz Francisco 3 Zaugg Claudia 3 Schuetz Philipp 14 http://orcid.org/0000-0003-2488-646XSalili Ali Reza [email protected] 45 1 grid.6612.30000 0004 1937 0642Faculty of Medicine, University of Basel, Basel, Switzerland \n2 grid.410567.1Biomedical Research and Training, University Hospital Basel, Basel, Switzerland \n3 grid.413357.70000 0000 8704 3732Hospital Pharmacy, Kantonsspital Aarau, Aarau, Switzerland \n4 grid.413357.70000 0000 8704 3732Department of Internal Medicine, Kantonsspital Aarau, 5000 Aarau, Switzerland \n5 Department of Internal Medicine, Clinical Pharmacology, Kantonsspital Aarau, Tellstrasse 51, CH-5001 Aarau, Switzerland \n3 8 2020 \n3 8 2020 \n2020 \n18 1430 3 2020 18 6 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\nAnticoagulants are commonly prescribed in medical practices and could be of significant harm in the case of medication errors. We conducted a retrospective observational study to determine the frequency and consequences of the therapeutic duplication of anticoagulants (TDA). As a secondary objective, we aimed to determine the characteristics of the population in which TDA occurs.\n\nMethods\nWe conducted a retrospective observational study among admitted patients who concomitantly received at least two anticoagulants from August 2017 to August 2018.\n\nResults\nA total of 107 patients with TDA are included in the research. The patients with TDA have a mean age of 73. The TDA population has a high rate of associated comorbidities with 69% of patients having arterial hypertonia, 40% with chronic kidney disease, 26% with a history of malignancy, and 20.5% with a history of stroke. More than 65% of patients were under anticoagulation before admission, mostly due to atrial fibrillation. The TDA occurred in more than 95% of cases in the first week or the last week of hospitalization. Patients had a high risk of bleeding prior to the TDA-event with about 62.5% of TDA patients having a HAS-BLED score at least 3. A total of 8 patients showed a significant Hemoglobin (Hb)-drop of at least 10 g/L within 24 h after TDA-event. Two patients had a new or worsened hematuria following TDA-event.\n\nConclusion\nTDA occurred in 0.8% of patients who were under anticoagulation and in 6.7% of patients who received direct oral anticoagulants (DOACs). TDA led in about 7.4% of cases to hemoglobin-relevant bleeding. The old patients with significant comorbidities and a high HAS-BLED score were mainly affected. The female gender and presence of anemia independently predicted the occurrence of bleeding following TDA.\n\nKeywords\nAnticoagulantsTherapeutic duplicationMedication errorDirect Oral anticoagulantsHAS-BLED scoreissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAccording to the Institute for Safe Medication Practice (ISMP), anticoagulants (AC) are among the high-alert-medications leading to serious complications in the case of medication errors [1]. Anticoagulants are involved in about 8.3% of all medication errors in admitted patients [2]. In a 5-year retrospective study, the investigators showed that medication errors are the cause by about 48.8% of all AC-associated adverse drug events [3]. The AC-related medication errors have been mainly classified according to the phase of medication process in which the error occurred into the following types: prescribing, transcribing, dispensing, administering, and monitoring errors. A cross-sectional study on the nation-wide drug safety system of the Netherland showed that the anticoagulant-related medication errors occurred mainly in the prescribing phase and in about 56% of errors low-molecular-weight heparins (LMWH) were involved [2, 4]. Consistently, a similar descriptive study on the Danish patient safety database reported that the adverse medication incidents occurred mainly in the prescribing phase, and in about 80% of incidents the errors occurred at the time of sector changes (at the admission, at the discharge or ward changes) [5]. Among different error subtypes occurring in the prescribing phase, the wrong dosage and drug omission have been repeatedly found as the most common subtype [3, 6, 7]. The affected patients are usually polymorbid patients in advanced ages having already high risk of bleeding [8]. Accordingly, the AC-related errors occur in about 78% of cases in adults older than 60 and in about one third in patients older than 80 years old [9]. The studies reporting the frequency and complications of AK-related medication errors have been mostly done based on data reported to in-house or nation-wide drug safety systems [2, 3, 5–10]. As many of these errors could not be detected or have not been reported by medical staff, the studies based on them could not reliably show the incidence of errors, the affected population and the rate of consequences. For different categories of ACs, the rates of adverse complications, especially the minor and major bleeding rates, have been well studied and reported [11–15].\n\nTherapeutic duplication is defined a concomitant prescription of two medications of the same class. Except for a few indications, the therapeutic duplication of anticoagulants is contraindicated. The therapeutic duplication of anticoagulants (TDA) as a medication error occurring in the prescribing phase was rarely studied [15–17]. As the primary objective, we aimed to comprehensively investigate the incidence, affected population, and complications of TDA in patients admitted to our tertiary referral hospital from 21.08.2017 to 20.08.2018.\n\nMaterial & Methods\nPatient population\nThis study is a retrospective observational study conducted at Kantonsspital Aarau (KSA), a 450-bed tertiary care facility providing medical and surgical care in all general and specialized medical disciplines. The hospital utilizes an electronic health care system (KISIM) gathering all medical and personal data of patients who received medical care, either in the in-patient or out-patient settings. For the present study, we retrospectively collected data of admitted patients who received AC, using a computerized export from KISIM. From this population, all patients admitted to our in-patient wards, from 21.08.2017–20.08.2018, who concomitantly received at least two ACs were included in the study. Subsequently, the following patients have been excluded: [1] patients who received the anticoagulants separately, no overlapping prescription [2] patients treated with the combination of heparin/ heparin analogs and vitamin-K antagonists (VKA) [3] patients receiving heparin/ heparin analogs based on a weekly schedule such as patients with hemodialysis [4] patients receiving low-dose alteplase (= < 4 mg) as a catheter locking solution [5] patients treated with the combination of VKA and direct oral anticoagulants (DOACs) during bridging from DOACs to VKA [6] patients who explicitly refused participation in research.\n\nData collection and data analysis\nAn export (in CSV format) from the data storage system of our hospital (KISIM) has been done. The mentioned export includes all patients who received at least one anticoagulant during their admission from 21.08.2017–20.08.2018 and contains the following patient data: Patient number, admission number, sex, date of birth, dates of admission and discharge, the name of prescribed anticoagulants and the dates of prescriptions.\n\nAccording to the inclusion and exclusion criteria, the patients with a contraindicated combination of at least two AK have finally been separated. Then, the corresponding demographic, biochemical and clinical parameters, listed ahead were extracted from KISIM: The para-clinical data including pre-error and post-error Hb (Hemoglobin of patient before and after TDA), pre-error and post-error urine analysis, the indication of anticoagulant therapy, the presence of underlying diseases predisposing, the patients to develop complications under TDA: arterial hypertension, renal insufficiency and its stage according to glomerular filtration rate (GFR), hepatic failure, active gastrointestinal ulcers, concomitant therapy with NSAIDs or thrombocyte-aggregation inhibitors, documented bleeding diathesis (abnormal post-operative bleeding, hematoma or bleeding under anticoagulant therapy in therapeutic dosage, known hemorrhagic disorders, etc.), prior anticoagulant therapy, history of recent trauma or upcoming surgery and finally the HAS-BLED score prior to the error. Subsequently, all demographic, biochemical and, clinical data of patients included in the study have been analyzed statistically. The variables have consequently been analyzed descriptively. A Hemoglobin-drop of more than 10 g/L within 24 h has been considered as significant Hb-drop. The patients have been divided into two groups with and without significant Hb-drop. Then, unpaired T-test and chi-square have been done for continuous and binary variables, respectively, to study whether there is a significant difference in variables between two patients groups. Finally, to determine the effect of different risk factors on the bleeding following TDA, we performed univariate and multivariate logistic regression.\n\nResults\nAmong 14,812 patients who received at least one anticoagulant, a total of 1663 patients met the inclusion criteria and have been treated with at least two anticoagulants during the one-year period. Among them, a total of 1542 patients met the first five exclusion criteria. Then, a total of 121 patients with a contraindicated combinative therapy of at least two anticoagulants (TDA) have been found. Out of them, 14 patients refused to participate and the rest 107 patients were included in the study (Fig. 1).\nFig. 1 Diagram of patient recruitment\n\n\n\nCharacteristics of the patient population\nAge and sex\nFrom 107 patients included in the study, 72 patients (67.3%) were male and 35 patients (32.7%) were female. The minimum and maximum of age were 35 and 97 years, respectively. The mean age of patients was 73.67 (95% CI, 71.2–76.1) and 78.5% of the population was older than 65 years.\n\nDuration of hospitalization\nThe minimum and maximum of the hospitalization duration were 2 and 72, respectively. The mean duration of hospitalization was 11.52 (CI 95%: 9.69–13.3).\n\nHAS-BLED score related comorbidities\nTable 1 shows the HAS-BLED score related parameters and comorbidities. Out of 107 patients, 74 patients (69.1%) had long-term arterial hypertension. Among them, 38 patients had uncontrolled arterial hypertension with systolic blood pressure higher than 160 mmHg. A high proportion of patients (40.1%) had a known chronic kidney disease prior to admission. Among them, 69.7% had stage 3 or higher. Abnormal liver function has been found in 7 patients; 2 with liver cirrhosis and 5 others with hepathopaties. 20.5% of patients had a history of stroke. A relevant co-medication with other drugs (aspirin, clopidogrel, NSAIDs etc.) or alcohol consumption predisposing patients to bleed has been found in 28 Out of 107 patients (26%). Seventeen patients were known to have a bleeding diathesis or a history of major bleeding (See Table 1).\nTable 1 A summary of the HAS-BLED score, the modified score and the related parameters\n\nCharacteristics\tTDA-patients (whole population)\tPatients with Hb-relevant bleeding\tPatients without Hb-relevant bleeding\t\nNumber\t107\t8\t99\t\nHypertension\t38\t4\t34\t\nAbnormal liver function\t7\t1\t6\t\nAbnormal renal function\t43\t3\t40\t\nStroke\t22\t3\t19\t\nLabile INR\t15\t2\t13\t\nBleeding diathesis\t17\t2\t15\t\nAge > 65 years\t84\t7\t77\t\nDrug/alcohol concomitantly\t28\t2\t26\t\nPrior anticoagulation\t71\t7\t64\t\nHAS-BLED score\t2.37 (CI95% 2.14–2.60)\t3.00 (CI95% 2.26–3.74)\t2.32 (CI95% 2.08–2.55)\t\nModified HAS-BLED score\t3.04 (CI95% 2.8–3.28)\t3.87 (CI95% 3.09–4.66)\t2.97 (CI95% 2.72–3.22)\t\n\n\nHAS-BLED score of the patient population\nThe minimum and maximum values of the HAS-BLED scores were 0 and 7, respectively. The mean HAS-BLED score was 2.37 (CI95% 2.14–2.60) with a median value of 3.\n\nFurther bleeding-related parameters and comorbidities\nTable 2 shows further bleeding-related comorbidities, which have not been considered by the HAS-BLED score. Most of the patients with TDA (66.3%) were on anticoagulation prior to admission. Diabetes mellitus has been found in 24 patients (22.4%). A high proportion of patients had a history of malignancy (26.1%). Out of 107 included patients, 22 (20.5%) and 13 (12.1%) patients had ischemic and congestive heart disease, respectively. A fresh fracture or traumatic brain injury has been found in 12 patients (11.2%) at admission. A total of 13 patients had a documented thrombocytopenia prior to the medication error and 8 patients had a known falling tendency. The higher proportion of patients with falling tendency, ischemic heart disease or with a history of a recent fracture or brain injury in the group of patients with Hb-relevant bleeding may put this population at increased risk of complications following TDA. Although it was suggested that anemia might contribute to the major bleeding under rivaroxaban therapy [18], our study showed a lower proportion of anemia in patients with Hb-relevant bleeding. However, the risk of bleeding may also be affected by other contributing factors. It has been demonstrated that AC therapy in patients with deep vein thrombosis leads more frequently to bleeding complications compared to those with atrial fibrillation [19, 20]. While 50% of patients with Hb-relevant bleeding were under anticoagulation due to AF, this was 68% for patients without Hb-relevant bleeding.\nTable 2 Comparison of bleeding-relevant characteristics of TDA-patients with and without significant Hb-drop\n\nParameters\tTDA-patients (whole population)\tPatients with Hb-relevant bleeding\tPatients without Hb-relevant bleeding\t\nPre-error anemia\t63.5%\t37.5%\t65.6%\t\nPre-error thrombocytopenia\t12.1%\t12.5%\t12.1%\t\nHistory of malignancy\t26.1%\t0%\t26.1%\t\nDiabetes mellitus\t22.4%\t0%\t22.4%\t\nIschemic/ congestive heart disease\tIHD 20.5%\n\nCHF 12.1%\n\n\tIHD 37.5%\n\nCHF 12.5%\n\n\tIHD 19.1%\n\nCHF 12.1%\n\n\t\nRecent fracture or traumatic brain injury\t11.2%\t37.5%\t0.9%\t\nFalling tendency\t7.5%\t12.5%\t0.7%\t\nDeath in 2 years\t18.6%\t25%\t18.1%\t\n\n\nModified HAS-BLED score\nPrior anticoagulation is not considered in the HAS-BLED score as a parameter. Indeed, the HAS-BLED score is employed to assess the risk of bleeding following initiation of an anticoagulative therapy in patients who were not being anticoagulated before. As taking anticoagulants before admission might have predictive value for hemorrhagic complications, we defined and applied a modified score by considering the prior anticoagulation as a criterion as well. Another rationale for employing the modified value is the above-mentioned finding that more than 66% of TDA patients were on anticoagulation therapy before admission. The modified HAS-BLED score was calculated by adding one score for prior anticoagulation to the HAS-BLED score. Using the modified HAS-BLED score, the TDA population had a mean value of 3.04 (CI95% 2.8–3.28) and about 67.2% of TDA patients had a score of at least 3.\n\nRate of anemia prior to medication error of TDA\nFor 8 patients, no hemoglobin value has been found within 72 h prior to TDA. The rest population with available pre-error hemoglobin had a mean hemoglobin value of 120.7 (95%CI: 116–125). 47 out of 72 male patients (65.2%) had a hemoglobin value lower than 140 g/L prior to error. From 35 females with TDA, 21 patients (60%) had a hemoglobin value lower than 120 g/L prior to error. Altogether, 63.5% of TDA patients had anemia prior to medication error.\n\nTDA-related parameters\nDuration of TDA\nTDA lasted, before detection and stop, for a minimum and maximum of 1 and 7 days, respectively. The mean duration of TDA was 1.68 (95%CI: 1.42–1.94).\n\nTime interval of the error to admission or discharge\nTDA events began in a short interval to the admission or discharge with a mean interval of 2.15 (95%CI: 1.67–2.63). In 21.4% of patients the TDA began on the day of admission or discharge. In 86 patients (83.3%) the error began in within 72 h after admission or before discharge (Table 3).\nTable 3 Comparison of characteristics of TDA between the whole population and the patients with Hb-relevant bleeding\n\nParameters\tTDA-patients (whole population)\tPatients with Hb-relevant bleeding\t\nDuration of TDA\t1.68 (SD 1.35)\t1.75 (SD 1.38)\t\nTime interval to admission or discharge\t2.15 (SD 2.55)\t1.125 (SD 0.99)\t\nWard\tMedical 38.3%\n\nSurgical 61.6%\n\n\tMedical 62.5%\n\nSurgical 37.5%\n\n\t\nSetting\t27.1% post-op\n\n8.4% pre-op\n\n\t25% post-op\n\n12.5% pre-op\n\n\t\nInvolved anticoagulants\tLMWH+DOAC (88.7%)\n\nHeparin+DOAC (7.5%)\n\nLMWH+Heparin (0.9%)\n\nDOAC+DOAC (0.9%)\n\nVKA + Heparin+LMWH (0.9%)\n\n\tLMWH+DOAC (87.5%)\n\nLMWH+Heparin (12.5%)\n\n\t\n\n\nInvolved anticoagulants\nMost of TDA patients (88.7%) had a combination of LMWH and DOAC. Among them, 43 patients (40.1%) have been treated with the combination of rivaroxaban and dalteparin and 40 patients (37.3%) with the combination of apixaban and dalteparin as the most common combination of anticoagulants (Table 4).\nTable 4 The anticoagulants involved in the TDA events of 107 patients\n\nInvolved ACs\tNr. of patients\tProportion\t\nRivaroxaban+Dalteparin\t43\t40.1%\t\nApixaban+ Dalteparin\t40\t37.3%\t\nDabigataran+ Dalteparin\t7\t6.5%\t\nEdoxaban+ Dalteparin\t5\t4.6%\t\nLiquemin+ Rivaroxaban\t3\t2.8%\t\nLiquemin+Apixaban\t2\t1.8%\t\nLiquemin+ Dalteparin\t2\t1.8%\t\nEdoxaban+Heparin\t1\t0.9%\t\nLiquemin+Dabigatran\t1\t0.9%\t\nApixaban+rivaroxaban\t1\t0.9%\t\napixaban+Arixtra\t1\t0.9%\t\nMarcoumar+Liquemin+Dalteparin\t1\t0.9%\t\n\n\nIn total, 1737 patients received at least one DOAC during the study period. Among them, 104 patients who were included in the study (See Table 4) and all of the excluded TDA patients i.e. fourteen patients were under DOAC at the time of TDA. Thus, TDA occurred in 6.7% of patients who were on DOAC.\n\nSignificant Hb-drop following TDA\nTo evaluate the bleeding events following TDA, we considered the last hemoglobin value reported within 72 h prior to TDA and the fist hemoglobin value reported within 72 h after TDA. A significant Hb-drop, which could be attributed to the bleeding, has been defined as a drop of more than 10 g/L within 24 h. The patients with Hb-drops, which could be attributed to other etiologies rather than TDA such as infusion therapies, operations, or known bleeding sources prior to TDA have been excluded. A total of 8 patients showed significant Hb-drop, which could not be attributed to the above-mentioned etiologies; please see the diagram of patients recruitment. Among patients with significant Hb-drop, two patients were taking platelet-aggregation inhibitors before admission; one was on acetylsalicylic acid 100 mg daily and the other one was on clopidogrel 75 mg daily (See case 2 in the part case study). Both drugs were stopped upon admission i.e. none of the patients with significant Hb-drop was receiving any platelet-aggregation inhibitors at the time of TDA events.\n\nBleeding risk factors in TDA patients\nUnpaired T-test and Chi-square have been done for all continuous and binary variables, respectively, to study whether there is a significant difference of variables between two patients groups; with and without Hb-drop. A p-value under 0.05 was defined as statistically significant. The relative risks for binary variables are also reported in Table 4. The modified HAS-BLED score was the only variable that reached the statistical significance in the univariate analysis (p = 0.028). HAS-BLED score did not reach the significance (p = 0.064). Although the TDA patients with a history of prior anticoagulation may have been at increased risk of bleeding (RR 3.55, CI95% 0.45–27.75), this risk was not translated into statistically significant TDA events (p = 0.22) (Table 5).\nTable 5 Univariate Analysis results\n\nRisk factor\tOdds ratio\tRelative risk\t\nAnemia\t0.17 (CI 95% 0.03–0.87)\t0.19\t\nAbnormal renal function\t0.78 (CI 95% 0.18–3.45)\t0.8\t\nUncontrolled hypertention\t1.91(CI 95% 0.45–8.12)\t1.82\t\nStroke\t2.53 (CI 95% 0.55–11.51)\t2.32\t\nAge > 65\t2.0 (CI 95% 0.23–17.14)\t1.92\t\nPrior anticoagulation\t3.83 (CI 95% 0.45–32.39)\t3.55\t\nAbnormal liver function\t2.21 (CI 95% 0.23–21.05)\t2.04\t\nDrug/ alcohol concomitantly\t0.94 (CI 95% 0.18–4.93)\t0.94\t\nBleeding diathesis\t1.87 (CI 95% 0.34–10.14)\t1.76\t\n\n\nLegend. The odds ratio and relative risks of bleeding risk factors have been reported. As mentioned above, the prior anticoagulation carries the highest relative risk between 3 and 4.\n\nMultivariate logistic regression\nTo determine the effect of different risk factors on the bleeding following TDA, we performed a multivariate logistic regression. Only two of 15 independent variables did reach the significance. The female sex (odds ratio .075 and a coefficient − 2.58) and anemia (odds ratio .022 and a coefficient − 3.80) showed a p-value lower than 0.05. As the coefficient of these variables is negative, they negatively correlate the risk of bleeding secondary to TDA. The HAS-BLED score (p = 0.97) and the modified HAS-BLED score (p = 0.13) did not reach the statistical significance in the multivariate regression model.\n\nDiscussion\nAnticoagulants are among the most common medications prescribed in clinical practice. Although they are given in order to prevent or treat life-threatening thromboembolic events such as stroke or pulmonary embolism, they could be dangerous if prescribed inappropriately [21]. Owing to the wider therapeutic window and the lower dietary and drug interactions of the newer ACs, which are recently introduced to the pharmaceutical marketing, their use in clinical practice have been surpassed that of vitamin-K-antagonists or heparin. However, lack of specific blood tests with wide availability for monitoring the blood level and therapeutic effects of the newer ACs increases the risk of drug bioaccumulation and, subsequently, the risk of bleeding complications [19]. Owing to being critically harmful in the case of medication errors, the AC- related errors have been largely studied. The adverse drug events commonly occur in clinical practice, with a frequency of 6.5 pro 100 admissions [22]. It has been shown that ACs-related medication errors comprise a significant proportion of medication errors in in-patient setting (7.2–8.3%) and the subsequent adverse events could be prevented in about 70% of cases [3, 22]. Pizza et al. retrospectively analyzed the AC-associated adverse drug events reported to the drug safety system at their tertiary hospital and showed that AC-associated medication errors comprise about half of the adverse drug events owing to AC prescription [3]. In addition, these errors have been significantly correlated with the 30-days mortality rate and higher hospitalization costs [3, 23]. Despite similarities of different reports in showing the high frequency of AC-associated medication errors, there are discrepancies regarding involved AKs, the proportion of error types, and the time of medication process in which errors occur. It seems that the following parameters play a role in the above-mentioned discrepancies: time of study according to the first appearance of the newer AK agents, pharmaceutical market varieties among countries in which the studies have been done, and the difference in study population [2, 24].\n\nAlthough the therapeutic duplication of ACs (TDA) has been written in medication safety alerts of national and international healthcare authorities [25, 26], there is not any study investigating the frequency and the rate of bleeding complications secondary to TDA. From a total of 1663 patients who have received at least two ACs during a 1-year period, 121 TDA-events have occurred. Out of them, 14 patients have been excluded due to the refusal of participation. The TDA-events have been mainly occurred, in about 88.7% of cases, due to the concomitant prescription of DOACs and LMWHs in prophylactic doses. Consistently, Andreica I. et al. reported a few similar cases in which a new LMWH has been prescribed while the previous DOAC prophylaxis was not discontinued [7]. Among 105 patients treated with heparins, either LMWH or unfractionated heparin, 85 patients received the heparin in prophylactic dose (8 patients with low-dose and other with a prophylactic dose higher than 3400 U/d) and 20 patients in therapeutic dose. Leonardi MJ, et al. in a systematic review of 33 randomized control trial evaluating the bleeding complications of patients under pharmacologic deep vein thrombosis (DVT) prophylaxis showed that patients receiving a high prophylactic dose of LMWH carry a risk of 5.8, 1 and 0.3% for hematuria, gastrointestinal (GI) bleeding and retroperitoneal bleeding, respectively. In comparison, the patients receiving a low dose of LMWH develop in < 0.6% of cases the above-mentioned bleeding complications [27].\n\nWe found that the risk for TDA was higher for Rivaroxaban and apixaban compared to other DOACs. Although we do not know the specific reason for this difference, these drugs are routinely prescribed for patients with AF, which may also have a higher likelihood for receiving other anticoagulants. Thus, it is rather the patient population and underlying indication that puts them at risk than the drugs itself.\n\nAlthough different clinical trials have already investigated the bleeding complications due to each AC class and compared them together, there is not any study reporting the bleeding rate following the concomitant prescription of two different classes i.e. the TDA [9, 11–14]. It has been shown that DOACs, although are not superior to the VKA in the prevention of stroke and systemic embolism, are associated with a significantly lower rate of intracranial bleeding [28–30].\n\nAccording to the ROCKET-AF study, clinically relevant bleeding occurs in about 14.9% of atrial fibrillation (AF) patients (per year) under rivaroxaban therapy [31]. The ARISTOTLE study assessed the risk of major bleeding complications in AF patients receiving apixaban as prophylaxis for stroke. The study reported a bleeding rate of 0.33, 0.13, 0.68, and 0.01% for intracranial hemorrhage, hematuria, GI bleeding, and retroperitoneal bleeding, respectively [14]. Notably, about 85% of TDA patients received either apixaban or rivaroxaban, mostly as prophylaxis for AF.\n\nHerein, we showed that TDA leads in about 7.5% of cases to Hb-relevant bleeding, defined as a drop more than 10 g/L in hemoglobin value within 24 h, in the first 3 days following the medication error. Pre-existing anemia has been attributed to an increased risk of bleeding secondary to AC therapy [31, 32]. From a clinical standpoint, a bleeding event in anemic patients, especially those with ischemic heart disease, would be more devastating. In our study, 63.5% of patients had anemia and 20.5% suffered from ischemic heart disease (IHD) before a TDA occurred. Furthermore, anemia and IHD were documented in 3 patients with TDA-associated bleeding. It has been demonstrated that AC therapy in patients with deep vein thrombosis leads more frequently to bleeding complications compared to those with atrial fibrillation [19, 20]. It has been attributed to the concomitant polymorbidity and polypharmacy of patients with venous thromboembolic disorders [33, 34]. Among patients with TDA, more than 70% have been subjected to AC-therapy due to atrial fibrillation. Therefore, in a population with a higher proportion of patients having been anticoagulated due to venous thromboembolism (VTE) rather than AF, TDA may lead more frequently to bleeding events compared with the present study.\n\nTo assess the risk of bleeding prior to AC therapy, different risk stratification tools have been proposed. Among them, HAS-BLED score, HEMORR2HAGES, and ATRIA are most commonly used in daily clinical practice. Despite having a similar accuracy, the HAS-BLED score has the best predictive performance [35, 36]. These scores have been mainly validated for VKA therapy in patients with atrial fibrillation and, therefore, modified HAS-BLED scores have been proposed to assess the risk of bleeding in other circumstances such as anticoagulation with DOACs [18, 37]. Except for one patient who has been found to concomitantly receive VKA, LMWH, and heparin and one other who received the combination of LMWH and heparin, all other TDA patients have been anticoagulated by DOACs. In addition, 66.3% of TDA patients have been received anticoagulants prior to admission. Prior anticoagulation, though, increases the bleeding risk, has not been considered in the above-mentioned risk stratification tools. Therefore, we measured in addition to the currently used HAS-BLED score, a modified score considering the prior anticoagulant therapy similar to the other medications such as NSAIDs and thrombocyte-aggregation inhibitors, as well.\n\nInterestingly, TDA patients have a mean HAS-BLED score of more than 2 and a mean modified score of more than 3, indicating that the affected population carries a high bleeding risk before TDA-event takes place. In addition to the components of the HAS-BLED score, other clinical parameters predisposing the AK-receiving patients to bleed such as the history of congestive heart failure, cerebrovascular disease, and anemia have also been taken into account. Tamaya et al. in a case-control study of 3252 patients with atrial fibrillation under rivaroxaban-therapy showed that the mentioned parameters, which have been ignored by HAS-BLED score, are the strongest predictive factors for bleeding complications [18]. Consistently, more than 20% of patients with TDA had a positive history of stroke or TIA. In addition, about 18.6% of TDA patients were died at the time of this study i.e. within a maximum of 2 years after discharge from hospital. Altogether, the above-mentioned findings indicate that the involved population carries a high risk of bleeding.\n\nCase study\nHerein, we discuss two cases with TDA-related bleeding.\nAn 80 years-old hypertensive patient presented with frequent episodes of syncope to the emergency department. The clinical examination revealed a hematoma in the right flank and also multiple ecchymosis in different locations. The falling episodes have been attributed to the side effects of Ropinirole, a dopamine agonist prescribed due to Parkinson’s disease. Furthermore, atrial fibrillation has been detected at the time of admission and, therefore, anticoagulation with apixaban (5 mg daily) has begun. As admitted, the patient received also dalteparin in prophylactic dose (5000 IU daily). Just after 1 day of combinative anticoagulation with apixaban and dalteparin the hemoglobin value dropped from 140 g/L to the 117 g/L. The occurrence of gastrointestinal bleeding presenting with melena has been documented during admission. One day later the TDA has been detected and stopped.\n\nA 98 years-old hypertensive patient under long-term anticoagulation with rivaroxaban (20 mg daily) due to atrial fibrillation, presented with bilateral subarachnoidal hemorrhage following falling. The patient has been admitted in neurosurgical ward and her medical situation improved without surgical intervention. She received clopidogrel (75 mg daily) following percutaneous transluminal angioplasty, since 1 month ago. Both medications have been stopped at admission. Instead, she received dalteparin in prophylactic dose (2500 IE daily), which has been continued until 1 day before discharge. Clopidogrel and rivaroxaban have been re- started from 4 and 3 days before discharge, respectively. Thus, the patient received for 2 days the combination of Clopidogrel, rivaroxaban and dalteparin, which resulted in Hb-drop from 86 g/L to the 66 g/L (= the Hb-value at first day of TDA) within 48 h. The Hb-value after the second day of TDA is not available. The patient was still disoriented at discharge and has been referred to the nursing house. Finally, she died 3 days after discharge. However, the reason of death is not documented, whether it occurred due to the deterioration of the pre-existing intracranial hemorrhage or/ and new bleeding events or not.\n\n\n\nConclusion\nTDA is a known medication error of anticoagulants with unknown frequency and clinical importance. We retrospectively analyzed the frequency and complications of TDA in all patients admitted to our 450-bed referral hospital in 1 year. TDA occurred in 0.8% of patients who were under anticoagulation and in 6.7% of patients who received DOACs. TDA led in about 7.4% of cases to hemoglobin-relevant bleeding. The old patients with significant comorbidities and a high HAS-BLED score were mainly affected. The female gender and presence of anemia independently predicted the occurrence of bleeding following TDA. Moreover, we introduced a new risk stratification tool by modifying the HAS-BLED score to assess the risk of bleeding in patients who are already on anticoagulants. Although the significance of the proposed tool is the matter of further investigations with larger sample sizes, our analyses suggest the consideration of prior anticoagulation as a parameter in addition to the HAS-BLED score lead to the prediction of the bleeding risk in TDA patients at a higher level of significance.\n\nAbbreviations\nTDAtherapeutic duplication of anticoagulants\n\nACanticoagulants,\n\nLMWHlow-molecular weight heparins\n\nDOACdirect oral anticoagulants\n\nVKAvitamin-K antagonists\n\nDVTdeep vein thrombosis\n\nIHDischemic heart disease\n\nVTEvenous thromboembolism\n\nAFatrial fibrillation\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nRR and ARS and PS devised the project, the main conceptual idea and proof outlines. RR and FC and CZ gathered the data. RR analyzed the data. RR took the lead in writing the manuscript and wrote it in consultation with other authors. RR and PS and ARS revised and proofed the final version of the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\nThis research work has been done without receiving any financial support.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nApproval was obtained from the local ethics committee named Ethikkommission Nordwest- und Zentralschweiz (EKNZ).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nHerein the authors declare that there’s not any conflict of interest with this research work.\n==== Refs\nReferences\n1. Institute for Safe Medication Practices Canada. ISMP List of High-Alert Medications in Acute Care Settings. Inst Safe Medicat Pract. 2014.\n2. 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Wang YP, Kehar R, Iansavitchene A, Lazo-Langner A. Bleeding risk in non-Valvular atrial fibrillation patients receiving direct Oral anticoagulants and warfarin: a systematic review and meta-analysis of observational studies. Blood. 2019;134(Supplement_1):3672.\n30. Lobraico-Fernandez J, Baksh S, Nemec E. Elderly bleeding risk of direct Oral anticoagulants in Nonvalvular atrial fibrillation: a systematic review and meta-analysis of cohort studies. Drugs in R and D. 2019;19(3):235–45.\n31. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.\n32. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105(2):91–9.\n33. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1 Suppl):108S–121S.\n34. 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Consult Pharm. 2015;30(7):395–402.\n\n", "fulltext_license": "CC BY", "issn_linking": "1477-9560", "issue": "18()", "journal": "Thrombosis journal", "keywords": "Anticoagulants; Direct Oral anticoagulants; HAS-BLED score; Medication error; Therapeutic duplication", "medline_ta": "Thromb J", "mesh_terms": null, "nlm_unique_id": "101170542", "other_id": null, "pages": "14", "pmc": null, "pmid": "32774174", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "16924087;18579811;23861122;8368229;27585515;25249791;21870978;21175312;28271315;28860793;30165484;21830957;9002493;11157645;18309033;9727814;21219407;21428778;30298305;27747717;30213217;28603628;23808982;19762550;22111719;16983130;31127504;22114827;27250070;23479259;26173191;24315724", "title": "Therapeutic duplication of anticoagulants: a retrospective study of frequency and consequences in a tertiary referral hospital.", "title_normalized": "therapeutic duplication of anticoagulants a retrospective study of frequency and consequences in a tertiary referral hospital" }	[ { "companynumb": "CH-TEVA-2020-CH-1858004", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DALTEPARIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTICOAGULANT THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2500", "drugstructuredosageunit": "025", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DALTEPARIN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076999", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "CLOPIDOGREL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "RIVAROXABAN" } ], "patientagegroup": "6", "patientonsetage": "98", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Subarachnoid haemorrhage", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Medication error", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RAHMANZADE R, CABRERA DIAZ F, ZAUGG C, SCHUETZ P, SALILI AR. 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CABRERA DIAZ F.? ZAUGG C.? SCHUETZ P.? SALILI A.R.. THERAPEUTIC DUPLICATION OF ANTICOAGULANTS: A RETROSPECTIVE STUDY OF FREQUENCY AND CONSEQUENCES IN A TERTIARY REFERRAL HOSPITAL. THROMBOSIS JOURNAL. 2020?18(14):1-9", "literaturereference_normalized": "therapeutic duplication of anticoagulants a retrospective study of frequency and consequences in a tertiary referral hospital", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "CH", "receiptdate": "20201106", "receivedate": "20201106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18471125, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210114" } ]
{ "abstract": "OBJECTIVE\nTo review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).\n\n\nMETHODS\nData were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer's postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (> or = 65 and > or = 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and alpha-blockers) and incorrect use.\n\n\nRESULTS\nSildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged > or = 65 years, and in those aged > or = 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.\n\n\nCONCLUSIONS\nThis collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.", "affiliations": "AP-HP, Neuro-Uro-Andrology, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France. [email protected]", "authors": "Giuliano\|F\|F\|;Jackson\|G\|G\|;Montorsi\|F\|F\|;Martin-Morales\|A\|A\|;Raillard\|P\|P\|", "chemical_list": "D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate", "country": "England", "delete": false, "doi": "10.1111/j.1742-1241.2009.02254.x", "fulltext": "\n==== Front\nInt J Clin PractijcpInternational Journal of Clinical Practice1368-50311742-1241Blackwell Publishing Ltd 10.1111/j.1742-1241.2009.02254.xReview ArticlesSafety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database Giuliano F 1Jackson G 2Montorsi F 3Martin-Morales A 4Raillard P 51 AP-HP, Neuro-Uro-Andrology, Department of Physical Medicine and Rehabilitation, Raymond Poincaré HospitalGarches, France2 Cardiac Department, St. Thomas’ HospitalLondon, UK3 Department of Urology, Università-Vita Salute San RaffaeleMilan, Italy4 Servicio de Urologia, Complejo, Hospitalario Carlos HayaMálaga, Spain5 Safety and Risk Management, Pfizer IncNew York, NY, USAFrançois Giuliano, Pr, MD, PhD, Raymond Poincaré Hospital, Physical Medicine and Rehabilitation, Neuro-Uro-Andrology, 104 Boulevard Raymond Poincaré, Garches 92380, France Tel.:+ 33 147107832 Fax:+ 33 147104443 Email:[email protected] François Giuliano is a consultant for Johnson & Johnson, Pfizer Inc, Bayer Schering Pharma, Sanofi-Aventis and Lilly; a meeting participant for Johnson & Johnson, Pfizer Inc and Lilly; and a study investigator for Pfizer Inc and Bayer. Graham Jackson is a consultant for Lilly and Pfizer Inc; and a meeting participant for Lilly, Pfizer Inc and Bayer. Francesco Montorsi is a consultant for Pfizer Inc, Bayer, GSK and AMS; and a study investigator for Astra, Pfizer Inc, Eli Lilly, GSK, MSD, Bayer, Novartis and Lilly ICOS. Antonio Martin-Morales is a consultant for Pfizer Inc, Bayer Schering Pharma, Lilly ICOS, Ipsen Pharma, Prostrakan, Pierre-Fabre and Johnson & Johnson; a meeting participant/lecturer for Pfizer Inc, Bayer Schering Pharma, Lilly ICOS, Ipsen Pharma, Johnson & Johnson and a scientific study/trial investigator for Pfizer Inc, Bayer Schering Pharma, Lilly ICOS, Johnson & Johnson and Prostrakan Pierre Raillard is an employee of Pfizer Inc.\n\nRe-use of this article is permitted in accordance with the Terms and Conditions set out at http://www3.interscience.wiley.com/authorresources/onlineopen.html\n\n1 2010 64 2 240 255 1 2009 10 2009 © 2009 Blackwell Publishing LtdRe-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.Aim:\nTo review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).\n\nMethods:\nData were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer’s postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (≥ 65 and ≥ 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and α-blockers) and incorrect use.\n\nResults:\nSildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged ≥ 65 years, and in those aged ≥ 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.\n\nConclusion:\nThis collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.\n==== Body\nReview Criteria\nUsing a database of 67 double-blind placebo-controlled trials conducted by the manufacturer and the manufacturer’s postmarketing safety database, we reviewed special safety topics and, for the most frequently prescribed doses (50 and 100 mg), conducted a comprehensive assessment of the tolerability of sildenafil overall and by age (i.e. stratifying cut-offs of ≥ 65 and ≥ 75 years).\n\nMessage for the Clinic\nSildenafil 50 and 100 mg were generally well tolerated, including by elderly men. There was no causal link with cardiovascular events. Furthermore, no new safety risks relating to priapism, non-arteritic anterior ischaemic optic neuropathy or incorrect use were detected. In addition, there were no unexpected adverse reactions from drug interactions, and a similar safety profile was present in men with or without moderate impairment of renal or hepatic function.\n\nIntroduction\nSildenafil citrate (VIAGRA®, Pfizer Limited, Sandwich, Kent, UK), approved by the United States Food and Drug Administration in March 1998 and by the European Medicines Agency in September 1998 for the on-demand treatment of erectile dysfunction (ED), was the first phosphodiesterase type 5 (PDE5) inhibitor licensed for this indication. Initial clinical trials of sildenafil were conducted in the United Kingdom (1), Europe (2) and the United States (3) and were followed by trials performed in Central and South America (4–6), Africa (7,8), Asia (9,10) and Australia (11). The effectiveness and safety of sildenafil for treating ED have been established in over 120 manufacturer-sponsored clinical trials with a cumulative exposure of more than 14,000 patient-years and in other independent studies (12,13). In most of the trials, sildenafil was administered on demand with a starting dose of 50 mg and subsequent adjustment to 25 mg or, more usually, 100 mg depending on toleration and efficacy, but it has also been studied in once-daily dosage (10, 25 and 50 mg) (14) and in single-doses up to 800 mg (15). Comprehensive reviews examining the efficacy and safety profile of sildenafil have been published (16,17). As of August 2008, sildenafil had been prescribed to more than 37 million men, and more than a billion tablets (averaging six per second) have been dispensed worldwide (18).\n\nTreatment-related adverse events with PDE5 inhibitors such as sildenafil, vardenafil (Levitra®, Bayer AG, Leverkusen, Germany) and tadalafil (Cialis®, Eli Lilly Nederland B.V., Houten, the Netherlands) are generally mild to moderate, showing minor differences across the PDE5 inhibitor class (19,20). Headache, facial flushing, nasal congestion and dyspepsia are the most common adverse events (19,21–23). Postmarketing surveillance of PDE5 inhibitors has provided additional data that, in general, indicate a safety profile consistent with that reported in premarketing clinical studies (24–30). However, there are some gaps in the knowledge base. For example, the safety of PDE5 inhibitor therapy has not previously been reported by age,1 despite an increased prevalence of ED in older men (31). Given the ageing populations of the developed and developing world, with an expected increase in the prevalence of ED to more than 300 million men worldwide by 2025 (32), this will become increasingly important.\n\nUsing a database of all 67 of the manufacturer’s double-blind placebo-controlled (DBPC) trials and the manufacturer’s postmarketing safety database, we conducted a comprehensive assessment of the tolerability of sildenafil overall, by dose and by age (cut-offs of ≥ 65 and ≥ 75 years). The objective of this collated review was to assess special safety topics and to document the tolerability by age of the most frequently prescribed doses (50 and 100 mg).2\n\nMethods\nDBPC database\nThe DBPC database contains all routine safety data and serious adverse event data for the 67 DBPC sildenafil trials for the indication of ED, which were completed by June 1, 2007. Appropriate Institutional Review Board approval and patient informed consent were obtained for all trials.\n\nAlthough sildenafil was studied in doses of up to 800 mg in phase I, single-dose, healthy volunteer studies (15), doses in the DBPC database ranged from 5 to 200 mg. However, most of the trials used the currently approved doses for the treatment of ED (25, 50 and 100 mg) and included a double-blind phase of 12 weeks (15). In 45 trials, the dose was flexible (most had dose adjustment at an interim visit according to efficacy and toleration while blinding was maintained), and in 22 trials, the dose was fixed. In most of the flexible-dose trials, the initial dose of sildenafil was 50 mg and most patients were titrated to 100 mg. In nearly all of the trials, sildenafil could be taken on demand approximately 1 h before sexual activity but not more than once daily. Many of the trials also included an open-label extension phase after the completion of the DBPC phase, in which most patients used sildenafil 100 mg.\n\nParticipants were generally required to have a documented history of ED of at least 3–6 months and to be in a stable sexual relationship. Trials that investigated conditions that contribute to the aetiology of ED generally required that the condition (e.g. diabetes mellitus) be stable or stable under treatment. Otherwise, the inclusion and exclusion criteria of the trials were broadly consistent with the Viagra prescribing information (15). In most of the trials, men receiving nitrate therapy and nitric oxide donors were excluded but, in some early trials, a few men randomised to sildenafil (n = 16) or placebo (n = 9) were taking glyceryl trinitrate ‘as required’. In some of the more recent trials, to avoid potential hypotension, any patient who was currently prescribed, taking, and/or likely to be treated with an α-blocker was either excluded from entering the trial or was not to take study medication within 4 h of dosing with the α-blocker.\n\nThere were no restrictions on other vasoactive and antihypertensive medications. Men with severe cardiac failure, unstable angina or a recent history (i.e. within 3–6 months) of stroke or myocardial infarction were excluded. Otherwise, efficacy and safety were assessed in men with a variety of comorbid conditions that share risk factors with ED, including diabetes mellitus, hypertension, cardiovascular disease (coronary artery disease, angina, myocardial infarction and stroke), radical prostatectomy, spinal cord injury and depression.\n\nPostmarketing safety database\nFrom first launch in 1998 through September 2007 (when the database was closed), > 35 million patients are estimated to have used sildenafil worldwide for the treatment of ED. In accordance with Pfizer Pharmacovigilance Standard Operating Procedures, the postmarketing safety database contains all cases of adverse events that were reported spontaneously to Pfizer by healthcare professionals, persons other than healthcare professionals, national or local registries (when applicable) and health authorities, or that are systematically identified from the medical literature. It excludes cases from the sildenafil clinical trials programme (except for cases of serious adverse events). It also excludes cases representative of sildenafil indications other than ED (i.e. pulmonary hypertension). For cases reporting a dose, the dose represents the first daily dose taken by the patient at the onset of an adverse event.\n\nAnalyses\nIn the clinical trials included in the DBPC database, the severity of each adverse event was categorised according to investigator judgment as mild (usually transient, required no special treatment and did not interfere with daily activities), moderate (low level of inconvenience and may have interfered with daily activities; usually ameliorated by simple therapeutic measures), or severe (interrupted daily activity and required systemic drug therapy or other medical treatment). A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Each event is presented using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (version 10.0) and with causality assessed by the trial investigator.\n\nUsing the DBPC database, incidence of adverse events, severe and serious adverse events and discontinuations were derived from the double-blind phase only. Data were analysed by dose (fixed-dose trials) and by modal flexible-dose (flexible-dose trials). Modal flexible-dose was defined as the dose the man was exposed to the longest during the trial period; if the exposure duration was equal for two different doses, the higher dose was selected as the modal dose. Data were also analysed by starting dosage (< 50, 50 and 100 mg) and by starting dose stratified by age groups. In this report, only the data for starting doses of 50 and 100 mg are considered. Death listings are reported for all phases of the study (e.g. including open-label extension).\n\nMost postmarketing adverse event reports are submitted voluntarily, causality is not assessed, clinical information may be missing or incomplete, follow-up information may not be available, the magnitude of underreporting is unknown and many factors influence reporting (i.e. length of time since marketing, market share of the drug, publicity or media reports about the drug or an adverse event, the seriousness of an adverse reaction, regulatory actions and awareness by healthcare professionals and consumers of adverse event reporting and litigation) (33,34). Furthermore, because the source of medication is usually not captured, reports related to non-genuine products can enter a database. For example, an estimated 44% of tablets labelled ‘Viagra’ and sold over the Internet is counterfeit (35). Counterfeit ED medications may contain none or an unknown quantity of the purported active ingredient, other possibly active ingredients of unknown efficacy and safety, or even toxic ingredients (36). Therefore, the spontaneous reporting system yields reporting rates, not incidence rates, and it is generally not appropriate to make comparisons between drugs in reporting rates. The most important role of the spontaneous reporting system is for signal detection (34).\n\nCommon adverse events were defined as those occurring in > 2% of men in ≥ 1 treatment or age group in the DBPC database, or at a reporting rate ≥ 1% in at least one of the two dosage groups in the postmarketing safety database.\n\nSpecial safety topics\nSeveral safety topics of special interest were selected for more detailed analysis, including certain adverse events [e.g. cardiovascular risk, priapism and non-arteritic anterior ischaemic optic neuropathy (NAION)] and events that might arise from intrinsic factors (e.g. impairment of renal and hepatic function), drug interactions [e.g. with nitrates, cytochrome P3A4 (CYP3A4) inhibitors, concomitant ED medications and α-blockers] or incorrect use (e.g. overdose and abuse). Some of these topics (cardiovascular risk and impaired renal and hepatic function) are medical history factors, which are not coded in the postmarketing safety database and therefore could not be searched in that database. Cardiovascular risk was assessed using the DBPC database, in men with cardiovascular disease, receiving antihypertensive medications, or with diabetes. Also using the DBPC database, baseline laboratory parameters were used to identify moderate renal impairment (defined as > 1.5 times the upper limit of normal blood urea nitrogen/urea and creatinine) and moderate hepatic impairment [defined as > 1.5 times the upper limit of normal for ≥ 2 tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin]. MedDRA-preferred terms were used to search for priapism, NAION, hearing loss and incorrect use [although cases having the intent to self-harm (e.g. suicide or suicide attempt) were excluded from the overdose analysis]. Comprehensive lists of α-blockers, nitrates, nitric oxide donors, CYP3A4 inhibitors and concomitant ED medications (37) were used to search for drug interactions.\n\nResults and discussion\nDatabases\nThe DBPC database contained more than 14,000 men, who were enrolled and received at least one dose of study drug. The mean age of sildenafil and placebo patients in the 54 parallel design trials was 55 years, with the majority aged ≥ 45 years; similar trends were observed for the 13 cross-over trials. Most of the men were white. At the time of enrolment ED had persisted, on average, for 4.5 years; it was most frequently organic in origin. The most common concomitant illnesses were of cardiovascular aetiology or associated with cardiovascular risk factors [i.e. hypertension, diabetes mellitus (non-insulin dependent), hyperlipidaemia, hypercholesterolaemia, coronary artery disease and a history of myocardial infarction] reflecting the age-related prevalence of these conditions. Benign prostatic hyperplasia and localised prostate cancer, treated with transurethral prostatectomy and radical prostatectomy, respectively, were also relatively common, as were conditions associated with an elderly or ageing population (e.g. osteoarthritis and visual disturbance).\n\nConsistent with a population of advancing age and with the underlying comorbidity frequently seen in patients with ED, the most common medications taken were those used to treat hypertension, hyperlipidaemia, diabetes mellitus, arthritic conditions and skeletal muscular injuries, and to prevent myocardial infarction. Thus, the DBPC database includes a heterogeneous ED population that is representative of the ED population as a whole.\n\nThe postmarketing safety database identified 39,277 sildenafil patients with adverse events through July 15, 2007. The vast majority of these were reported spontaneously by health or non-health professionals (Table 1). The first daily dose was identified in slightly less than half of the cases (i.e. > 25 and ≤ 50 mg, n = 12,843; > 50 and ≤ 100 mg, n = 5066). Demographical and case characteristics, where known, were comparable to those observed for the DBPC database, in that the majority of the population was ≥ 50 years of age and the majority of cases reported a first total daily dose of 25–100 mg. Most of the cases were non-serious (80.4%) and approximately half (54%; 21,334/39,277) of the men reported a case outcome. Of the cases with known case outcomes, nearly half (49%; 10,498/21,334) reported an outcome of recovered/recovering/recovering with sequelae, and very few reported a fatal outcome (6.1%; 1303/21,334). Medical history is not a coded search function in the postmarketing safety database, but concomitant medications were consistent with common concomitant medications used by men in the DBPC database.\n\nTable 1 Sources of cases populating the postmarketing safety database\n\nSource\tNumber (%)\t\nSpontaneous\t\nHealth professional\t15,894 (40.5)\t\nNon-health professional\t22,397 (57.0)\t\nTotal\t38,391 (97.5)\t\nHealth authority\t\nHealth professional\t658 (1.7)\t\nNon-health professional\t21 (0.1)\t\nTotal\t679 (1.7)\t\nPublished report\t307 (0.8)\t\nTotal\t39,277 (100)\t\nThe international literature is carefully screened daily to identify all relevant cases. Although an attempt is consistently made to avoid counting events twice, there may be a few duplicate cases, i.e. reported in observational studies published in the literature (e.g. the International Men’s Health Study (29) and Prescription Event Monitoring study (24)) and as spontaneous postmarketing cases.\n\nTolerability of 50 mg vs. 100 mg\nThe safety profile of sildenafil, based on data from the DBPC database that included more than 7500 men treated with sildenafil 50 or 100 mg (Tables 2–4), remained consistent with that presented in the original regulatory submissions from approximately 10 years ago. Very rare were the serious adverse events of priapism (n = 11 patients), NAION (n = 0 patients) and hearing loss (n = 1 patient of unilateral loss considered to be embolic in aetiology), which are discussed in detail in subsequent sections of this review. Common adverse events in men treated with sildenafil were those related to the pharmacology of PDE5 inhibition, such as headache, vasodilation and facial flushing. These were reported in a higher incidence of men treated with sildenafil than with placebo (Table 4) and in a comparable incidence to that documented in the Viagra product information leaflet (15). Previously reported data collated from 17 of the randomised, DBPC, flexible-dose trials showed that the rate of these common adverse events decreased markedly over a 16-week treatment period such that, during the first 4–6 weeks of treatment, the rate among sildenafil-treated patients was higher than that for placebo-treated patients but, by 8 weeks and thereafter, the rate was similar between sildenafil- and placebo-treated patients (Figure 1) (38).\n\nTable 4 Common treatment-related adverse events, stratified by dose and age, in 67 double-blind placebo-controlled trials\n\n\tEvent by disorder system, number (%) of patients with event [with severe event]\t\n\tEye\tGI\tNervous system\tRespiratory\tVascular\t\nTrial design dosage (n)† Age group (n)\tChromatopsia\tCyanopsia\tVisual disturbance\tDyspepsia\tDizziness\tHeadache\tNasal congestion\tFlushing\tHot flush\t\nFixed-dose\t\nSildenafil 50 mg (804)\t4 (0.5)\t1 (0.1)\t1 (0.1)\t35 (4.4) [3]\t14 (1.7) [1]\t116 (14.4) [9]\t15 (1.9) [1]\t107 (13.3) [1]\t27 (3.4) [1]\t\nSildenafil 100 mg (1373)\t17 (1.2) [1]\t19 (1.4)\t35 (2.5)\t64 (4.7) [6]\t18 (1.3)\t167 (12.2) [13]\t29 (2.1) [1]\t130 (9.5) [5]\t30 (2.2)\t\nPlacebo (1623)\t0\t1 (0.1)\t1 (0.1)\t7 (0.4)\t9 (0.6)\t39 (2.4) [1]\t2 (0.1)\t16 (1.0)\t3 (0.2)\t\nFlexible-dose\t\nSildenafil 50 mg (2060)\t8 (0.4)\t14 (0.7)\t12 (0.6)\t50 (2.4) [6]\t58 (2.8)\t264 (12.8) [21]\t42 (2.0) [3]\t205 (10.0) [2]\t28 (1.4) [1]\t\nSildenafil 100 mg (3479)\t13 (0.4)\t36 (1.0)\t23 (0.7)\t101 (2.9) [5]\t53 (1.5)\t305 (8.8) [19]\t65 (1.9) [3]\t271 (7.8) [4]\t12 (0.3)\t\nPlacebo (4979)\t2 (0)\t1 (0)\t5 (0.1)\t15 (0.3) [1]\t40 (0.8) [2]\t155 (3.1) [11]\t12 (0.2)\t65 (1.3) [1]\t7 (0.1)\t\nAll trials‡\t\nSildenafil 50 mg, initial dose\t\nAll ages (6207)\t24 (0.4)\t51 (0.8)\t35 (0.6)\t181 (2.9)\t127 (2.0)\t705 (11.4)\t125 (2.0)\t577 (9.3)\t56 (0.9)\t\n< 65 years (5003)\t21 (0.4)\t42 (0.8)\t27 (0.5)\t146 (2.9)\t103 (2.1)\t587 (11.7)\t107 (2.1)\t472 (9.4)\t47 (0.9)\t\n≥ 65 years (1203)\t3 (0.2)\t9 (0.7)\t8 (0.7)\t35 (2.9)\t24 (2.0)\t118 (9.8)\t18 (1.5)\t105 (8.7)\t9 (0.7)\t\n≥ 75 years (134)\t1 (0.7)\t0\t2 (1.5)\t9 (6.7)\t0\t13 (9.7)\t1 (0.7)\t13 (9.7)\t1 (0.7)\t\nSildenafil 100 mg, initial dose\t\nAll ages (1337)\t16 (1.2) [1]\t19 (1.4)\t35 (2.6)\t64 (4.8) [6]\t18 (1.3)\t163 (12.2) [13]\t28 (2.1) [1]\t124 (9.3) [5]\t23 (1.7)\t\n< 65 years (1026)\t10 (1.0) [1]\t15 (1.5)\t32 (3.1)\t49 (4.8) [4]\t12 (1.2)\t134 (13.1) [10]\t26 (2.5) [1]\t98 (9.6) [5]\t18 (1.8)\t\n≥ 65 years (308)\t6 (1.9)\t4 (1.3)\t3 (1.0)\t15 (4.9) [2]\t6 (1.9)\t29 (9.4) [3]\t2 (0.6)\t26 (8.4)\t5 (1.6)\t\n≥ 75 years (37)§\t1 (2.7)\t0\t1 (2.7)\t3 (8.1)\t1 (2.7)\t2 (5.4)\t0\t3 (8.1)\t1 (2.7)\t\nPlacebo\t\nAll ages (6602)\t2 (0)\t2 (0)\t6 (0.1)\t22 (0.3) [1]\t49 (0.7) [2]\t194 (2.9) [12]\t14 (0.2)\t81 (1.2) [1]\t10 (0.2)\t\n< 65 years (5294)\t2 (0)\t2 (0)\t3 (0.1)\t21 (0.4) [1]\t40 (0.8) [1]\t161 (3.0) [12]\t12 (0.2)\t63 (1.2) [1]\t9 (0.2)\t\n≥ 65 years (1303)\t0\t0\t3 (0.2)\t1 (0.1)\t9 (0.7) [1]\t33 (2.5)\t2 (0.2)\t18 (1.4)\t1 (0.1)\t\n≥ 75 years (128)\t0\t0\t0\t0\t0\t2 (1.6)\t0\t1 (0.8)\t0\t\nAE, adverse event; DC, discontinuation; GI, gastrointestinal.\n\n Events occurring in > 2% of men in ≥ 1 group. An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. Listed are DCs, dose reductions and temporary DCs that were caused by an AE. Severe events are shown only when ≥ 1 occurred. Because of the small number of severe events, percentages are not given.\n\n† In flexible-dose trials, dose is the modal dose, the dose that the patient was exposed to the longest during the study period. If the duration was the same for two different doses, the higher dose was selected as the modal dose of the patient.\n\n‡ Sum of patient numbers in the ‘< 65 years’ group plus the ‘≥ 65 years group’. do not total the numbers in the ‘All ages’ group because age was missing for one patient (50 mg) and three patients (100 mg).\n\n§ In addition to the tabulated events, there were also 1 (2.4%) case each of iris disorder (mild), abdominal discomfort (mild), diarrhoea haemorrhagic (moderate), gastroesophageal reflux (mild), nausea (mild), fatigue (moderate), heart rate increase (mild), musculoskeletal pain (moderate), pain in extremity (moderate) and hypoesthenia (mild).\n\nTable 2 Overview of adverse events and discontinuations stratified by dose, in 67 double-blind placebo-controlled trials\n\n\tFixed-dose trials\tFlexible-dose trials\t\n\tSildenafil dose\tModal sildenafil dose\t\nAdverse events†\t50 mg (N = 804)\t100 mg (N = 1373)\tPlacebo (N = 1623)\t50 mg (N = 2060)\t100 mg (N = 3479)\tPlacebo (N = 4979)\t\nAE, number of events\t\nAll causality\t1101\t1419\t769\t1807\t2768\t2491\t\nTreatment-related\t501\t781\t181\t1077\t1421\t668\t\nAE, number (%) of patients\t\nAll causality\t498 (61.9)\t655 (47.7)\t489 (30.1)\t951 (46.2)\t1549 (44.5)\t1572 (31.6)\t\nSevere\t51 (6.3)\t56 (4.1)\t41 (2.5)\t87 (4.2)\t102 (2.9)\t127 (2.6)\t\nSerious\t17 (2.1)\t19 (1.4)\t23 (1.4)\t37 (1.8)\t55 (2.6)\t67 (1.3)\t\nDC\t14 (1.7)\t20 (1.5)\t19 (1.2)\t50 (2.4)\t27 (0.8)\t49 (1.0)\t\nDose reduction or temporary DC\t20 (2.5)\t18 (1.3)\t17 (1.0)\t118 (5.7)\t59 (1.7)\t68 (1.4)\t\nTreatment-related\t295 (36.7)\t436 (31.8)\t136 (8.4)\t655 (32.3)\t885 (25.4)\t480 (9.6)\t\nSevere\t21 (2.6)\t19 (1.4)\t6 (0.4)\t35 (1.7)\t29 (0.8)\t19 (0.4)\t\nSerious\t1 (0.1)\t1 (0.1)\t1 (0.1)\t3 (0.1)\t5 (0.1)\t3 (0.1)\t\nDC\t8 (1.0)\t10 (0.7)\t7 (0.4)\t28 (1.4)\t10 (0.3)\t18 (0.4)\t\nDose reductions or temporary DC\t1 (0.1)\t8 (0.6)\t1 (0.1)\t102 (5.0)\t29 (0.8)\t32 (0.6)\t\nAE, adverse event; DC, discontinuation.\n\n Modal dose: dose the patient was exposed to the longest during the study period. If the duration was the same for two different doses, the higher dose was selected as the modal dose of the patient.\n\n† An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Listed are DCs, dose reductions and temporary DCs that were caused by an AE.\n\nFigure 1 Rate of treatment-related adverse events over time collated from 17 randomised, double-blind, placebo-controlled, flexible-dose trials (sildenafil 25–100 mg, n = 2362; placebo, n = 1986). Treatment periods of up to 4 months were divided into 2-week intervals; the number of patients who experienced any adverse event was recorded for each interval and divided by the total number of patients who received treatment during that interval (38)\n\nThe safety profiles of sildenafil 50 and 100 mg in the DBPC trials were comparable, in that there was no apparent increase in the incidence of men with all-causality or treatment-related adverse events among those receiving 100 mg as a fixed or flexible-dose compared with those receiving 50 mg as a fixed or flexible-dose (Tables 2 and 4). The exception to this was a known increased incidence of men with transient altered colour vision (chromatopsia and cyanopsia) at doses of ≥ 100 mg (15). Indeed, for some adverse events, the incidence was higher among those receiving 50 mg than among those receiving 100 mg. For example, headache [fixed-dose: 14.4% (50 mg) vs. 12.2% (100 mg); modal flexible-dose: 12.8% (50 mg) vs. 8.8% (100 mg)] and flushing [fixed-dose: 13.3% (50 mg) vs. 9.5% (100 mg); flexible-dose: 10.0% (50 mg) vs. 7.8% (100 mg)] (Table 4). It is likely that the differences between fixed-doses are clinically meaningless and that those between flexible-doses reflect enrichment of the 50-mg group with patients having tolerability issues that prevented dosage increase, such that their most frequent dose throughout the study was 50 mg.\n\nIn the population as a whole and in all subgroups stratified by age, the overall incidence of men with adverse events was similar in those initiating treatment with 100 mg vs. 50 mg, except for a slight dose-related increase in the incidence of treatment-related adverse events among older men (Table 3). Among the most common treatment-related adverse events, the incidence was generally similar with a starting dose of 100 mg vs. 50 mg (Table 4). The exception to this was headache in men aged ≥ 75 years, which occurred in 5.4% (2/37) of those starting with 100 mg and in 9.7% (13/134) of those starting with 50 mg. For most events, the incidence was also similar across age subgroups for each starting dose. Noteworthy exceptions to this were a higher incidence of men with dyspepsia in the subgroup of men aged ≥ 75 years, which was relatively small (50 mg, n = 134; 100 mg, n = 37), and a lower incidence of men with headache and nasal congestion in the subgroups of men aged ≥ 75 or ≥ 65 years.\n\nTable 3 Overview of adverse events and discontinuations stratified by starting dose and age, in 67 double-blind placebo-controlled trials\n\n\tOverall\t< 65 years\t≥ 65 years\t≥75 years\t\n\t50 mg\t100 mg\tPL\t50 mg\t100 mg\tPL\t50 mg\t100 mg\tPL\t50 mg\t100 mg\tPL\t\nAdverse events†\t(n = 6207)\t(n = 1337)\t(n = 6602)\t(n = 5003)\t(n = 1026)\t(n = 5294)\t(n = 1203)\t(n = 308)\t(n = 1303)\t(n = 134)\t(n = 37)\t(n = 128)\t\nAE, number of events\t\nAll causality\t5539\t1391\t3260\t4395\t1038\t2513\t1144\t353\t747\t123\t44\t75\t\nTreatment-related\t3011\t758\t849\t2476\t607\t692\t535\t151\t157\t61\t21\t10\t\nAE, number (%) of patients\t\nAll causality\t2935 (47.3)\t638 (47.7)\t2061 (31.2)\t2344 (46.9)\t487 (47.5)\t1610 (30.4)\t591 (49.1)\t151 (49.0)\t451 (34.6)\t67 (50.0)\t19 (51.4)\t42 (32.8)\t\nSevere\t229 (3.7)\t56 (4.2)\t168 (2.5)\t187 (3.7)\t41 (4.0)\t122 (2.3)\t42 (3.5)\t15 (4.9)\t46 (3.5)\t2 (1.5)\t0\t6 (4.7)\t\nSerious\t106 (1.7)\t19 (1.4)\t90 (1.4)\t78 (1.6)\t14 (1.4)\t60 (1.1)\t28 (2.3)\t5 (1.6)\t30 (2.3)\t4 (3.0)\t1 (2.7)\t5 (3.9)\t\nDC\t113 (1.8)\t25 (1.9)\t89 (1.3)\t88 (1.8)\t16 (1.6)\t64 (1.2)\t25 (2.1)\t9 (2.9)\t25 (1.9)\t5 (3.7)\t2 (5.4)\t3 (2.3)\t\nDose reduction or temporary DC\t237 (3.8)\t18 (1.3)\t85 (1.3)\t194 (3.9)\t12 (1.2)\t66 (1.2)\t43 (3.6)\t6 (1.9)\t19 (1.5)\t4 (3.0)\t2 (5.4)\t2 (1.6)\t\nTreatment-related\t1840 (29.6)\t422 (31.6)\t616 (9.3)\t1510 (30.2)\t329 (32.1)\t496 (9.4)\t330 (27.4)\t93 (30.2)\t120 (9.2)\t40 (29.9)\t13 (35.1)\t7 (5.5)\t\nSevere\t81 (1.3)\t19 (1.4)\t25 (0.4)\t68 (1.4)\t14 (1.4)\t23 (0.4)\t13 (1.1)\t5 (1.6)\t2 (0.2)\t0\t0\t0\t\nSerious\t9 (0.1)\t1 (0.1)\t4 (0.1)\t6 (0.1)\t1 (0.1)\t3 (0.1)\t3 (0.2)\t0\t1 (0.1)\t0\t0\t0\t\nDC\t54 (0.9)\t12 (0.9)\t29 (0.4)\t40 (0.8)\t9 (0.9)\t22 (0.4)\t14 (1.2)\t3 (1.0)\t7 (0.5)\t1 (0.7)\t1 (2.7)\t1 (0.8)\t\nDose reduction or temporary DC\t176 (2.8)\t8 (0.6)\t34 (0.5)\t150 (3.0)\t6 (0.6)\t28 (0.5)\t26 (2.2)\t2 (0.6)\t6 (0.5)\t3 (2.2)\t1 (2.7)\t0\t\nAE, adverse event; DC, discontinuation; NA, data not available; PL, placebo.\n\n Sum of patient numbers in the ‘< 65 years’ group plus the ‘≥ 65 years group’. do not total the numbers in the ‘All ages’ group because age was missing for one patient (50 mg) and three patients (100 mg).\n\n† An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Listed are DCs, dose reductions and temporary DCs that were caused by an AE.\n\nThe majority of adverse events included in the postmarketing safety database were known sildenafil adverse drug reactions, similar to those reported in DBPC trials. Overall, the onset of more of the adverse events occurred in association with a total daily dose of 50 mg [i.e. > 25–50 mg; 32.7% (12,843/39,277)] than with a total daily dose of 100 mg [i.e. > 50–100 mg; 12.9% (5066/39,277)]. The higher number of reports in association with a total daily dose of 50 mg likely reflects that most adverse event reports are generated in men newly on treatment and that 50 mg is the recommended sildenafil staring dose. For most types of events, the reporting rates were similar between the 50- and 100-mg dose (Table 5). Not listed in Table 5 are reports of drug ineffective [50 mg, n = 3803 (29.6%); 100 mg, n = 2038 (40.2%)], drug effect decreased [50 mg, n = 1090 (8.5%); 100 mg, n = 397 (7.8%)], or ED [50 mg, n = 1132 (8.8%); 100 mg, n = 449 (8.9%)] because the efficacy of sildenafil is well established (12,13), an increase in dose or second-line treatment should be considered in cases in which sildenafil is ineffective (39), and it is the role of the healthcare professional to establish realistic treatment goals and expectations. Most men in whom sildenafil treatment failed responded successfully after re-education and counselling, which included information on patient and partner expectations, how to properly take the drug, titration to maximum dose and a minimum trial of eight attempts (40).\n\nTable 5 In the postmarketing safety database, reporting rate of common adverse drug reactions for which the first total daily dose was 50 or 100 mg\n\n\tFirst total daily dose\t\nDisorder system Event, n (%)\t50 mg N = 12,843 reports†\t100 mg N = 5,066 reports†\t\nCardiac\t\nMyocardial infarction\t273 (2.1)\t95 (1.9)\t\nPalpitation\t236 (1.8)\t48 (0.9)\t\nTachycardia\t165 (1.3)\t36 (0.7)\t\nEye disorders\t\nCyanopsia\t233 (1.8)\t189 (3.7)\t\nVision blurred\t244 (1.9)\t89 (1.8)\t\nVisual disturbance\t149 (1.2)\t74 (1.5)\t\nGastrointestinal\t\nDyspepsia\t415 (3.2)\t174 (3.4)\t\nNausea\t276 (2.2)\t82 (1.6)\t\nGeneral and administration site\t\nChest pain\t220 (1.7)\t59 (1.2)\t\nDrug interaction\t248 (1.9)\t121 (2.4)\t\nFeeling hot\t202 (1.6)\t47 (0.9)\t\nMalaise\t130 (1.0)\t40 (0.8)\t\nInjury, poisoning and procedural complications\t\nIntentional drug misuse\t85 (0.7)\t66 (1.3)\t\nIntentional overdose\t153 (1.2)\t121 (2.4)\t\nOverdose\t154 (1.2)\t65 (1.3)\t\nNervous system\t\nDizziness\t502 (3.9)\t167 (3.3)\t\nHeadache\t1929 (15.0)\t574 (11.3)\t\nReproductive system\t\nPriapism and related events‡\t305 (2.4)\t132 (2.6)\t\nRespiratory\t\nDyspnoea\t163 (1.3)\t54 (1.1)\t\nNasal congestion\t530 (4.1)\t156 (3.1)\t\nSkin and subcutaneous tissue\t\nErythema\t304 (2.4)\t59 (1.2)\t\nVascular\t\nFlushing\t1367 (10.6)\t409 (8.1)\t\nHot flush\t183 (1.4)\t26 (0.5)\t\n Events constituting ≥ 1% of reported events in ≥ 1 of the two dosage groups are listed.\n\n† 50 mg = > 25–50 mg; 100 mg = > 50–100 mg.\n\n‡ Priapism and erection increased.\n\nIn the DBPC database, the safety profiles of sildenafil 50 and 100 mg were comparable in that there were no apparent dose-related increases in the incidence of men with severe adverse events, serious adverse events, discontinuations caused by adverse events or dose reductions caused by adverse events in the population as a whole (Table 3) and in either the fixed-dose trials or the flexible-dose trials (Table 2). Across subgroups stratified by starting dose and age, there was a low incidence of men with treatment-related serious events (< 1%), severe events (< 2%), discontinuations caused by adverse events (< 3%) and dose reductions or temporary discontinuations caused by adverse events (≤ 3%) (Table 3).\n\nThe overall frequency of death was low in the DBPC database and was comparable between men using sildenafil (13/8691, 0.15%) and placebo (7/6602, 0.11%). Most deaths were in men aged ≥ 50 years. Among the deaths were six men using 50 mg (mean age, 56.8 years), of whom two were ≥ 65 years and one was ≥ 75 years; five men using 100 mg (mean age, 62.4 years), of whom three were ≥ 65 years and one was ≥ 75 years; and seven men using placebo (mean age, 67.2 years), of whom six were ≥ 65 years and one was ≥ 75 years. None of the deaths was considered to be treatment related.\n\nIn the postmarketing safety database, approximately 20% (7683/39,277) of patients were considered serious and 3.3% of patients (1310/39,277) had an outcome of death. Of the 882 deaths for which age was reported, the majority of cases [79.4% (700/882)] involved patients aged > 50 years. For serious adverse events and deaths, the order of magnitude differences between the incidence rates of the DBPC database and the reporting rates of the postmarketing safety database reflects the vastly different natures of these metrics, as described in Methods section.\n\nCardiovascular risk\nThe prevalence of ED is increased in men at risk for cardiovascular disease (41–47). Further evidence for the relationship between ED and cardiovascular disease is that the most common organic cause of ED is vascular disease (31,48) and some of the most common comorbid diagnoses in men with ED are cardiovascular disease risk factors (i.e. hypertension, hyperlipidaemia and diabetes mellitus) (49). However, previous extensive study revealed no evidence that sildenafil use was associated with increased risk of adverse cardiovascular disease events (27,29,50–52).\n\nNot surprisingly, given the known association between ED and cardiovascular disease, and between age and cardiovascular disease, the most commonly reported adverse events that resulted in death in the DBPC database were cardiac related (i.e. myocardial infarction, cardiac arrest, cardiac failure and coronary artery disease), and most of these were in men aged ≥ 50 years. However, it should be noted that the deaths were not attributed to sildenafil and that the overall cardiovascular death rate was slightly higher in the placebo groups (3 of 7 deaths) than in the sildenafil groups (4 of 11 deaths). Similarly, the incidence of men with serious cardiovascular events was comparable and not significantly different in the sildenafil and placebo groups [i.e. acute myocardial infarction (4.1% vs. 4.5%), chest pain (3.0% vs. 2.3%), coronary artery disease (2.7% vs. 5.3%), myocardial infarction (2.5% vs. 3.8%) and cerebrovascular accident (2.5% vs. 2.3%)], and none of these serious cardiovascular events was related to sildenafil treatment.\n\nBased on available safety data, there is no evidence of a causal link between sildenafil and cardiovascular events. Safety data from the original regulatory submissions, postmarketing observational studies (24,29) and published literature demonstrate that sildenafil does not increase the rate of myocardial infarction or other serious cardiovascular events in men with ED. Furthermore, the safety profile of sildenafil in men with ED and diabetes mellitus (11,53,54), arterial hypertension (55) or cardiovascular conditions (56,57) is similar to that in men with ED without these conditions. The safety of sildenafil has not been studied in men with hypotension (blood pressure < 90/50 mmHg) or recent history of stroke or myocardial infarction, and its use is therefore currently contraindicated in men with these conditions (15).\n\nPriapism\nPriapism is a rare adverse drug reaction with sildenafil. In the DBPC database, the incidence of men with priapism or related events was 0.1% (11/8691) in sildenafil recipients and < 0.1% (2/6602) in placebo recipients. Most cases reported events that were considered mild in severity; none that was considered as severe or defined as serious; and most of which resolved with no action, intervention or reduction of dose. Eight of the cases were associated with sildenafil 50 mg, including two that were characterised by multiple events and two (one of which resolved with a dose reduction) that were characterised by a duration of > 1 day. Three of the cases were associated with sildenafil 100 mg, including two that were characterised by multiple events that resolved, and two that were characterised by a duration of > 1 day and resolved with no action.\n\nThe postmarketing safety database was searched for priapism-related events (coded in the MedDRA as ‘priapism’ and ‘erection increased’). Comparison of priapism-related events as reported by healthcare professionals and consumers, respectively, shows that, although the same pathological entity gets reported (in most cases as a serious event), reports of healthcare professionals tend to use the term ‘priapism,’ whereas those of consumers tend to use the term ‘erection increased.’ The reporting rate was 2.5% for sildenafil 50 mg (320/12,843 total patients) and 2.7% for sildenafil 100 mg (138/5066 total patients). In contrast to the DBPC database, for which none of the cases of priapism was considered by the investigator to be severe or fulfilled the definition for ‘serious’, 56% (180/320) of the reports in the postmarketing safety database that were associated with sildenafil 50 mg and 64% (89/138) of the reports in the postmarketing safety database that were associated with sildenafil 100 mg were reported as serious events. However, for most of the priapism cases, the reporter indicated that the case was not clinically severe. Also, for most of the priapism cases, the reporter indicated that the patient had recovered or was recovering without sequelae at the time of the report.\n\nThe risk of priapism appears to be increased in certain situations. For example, in cases of sildenafil overdose, priapism was reported at a rate more than twice that of the overall postmarketing safety database. Also, across all sildenafil doses, concomitant medication use was reported in 377 reports of priapism, in 27% (102/377) of which the concomitant medication(s) could have contributed to the priapism [i.e. other ED medications, alpha-adrenergic antagonists (phentolamine), psychotropics (amitriptyline, nortriptyline, trazodone, fluphenazine), amphetamines and cocaine]. In the subgroup of cases that reported concomitant use of another ED medication, alprostadil was used concomitantly with sildenafil in 74% (14/19) of the patients of priapism.\n\nAs priapism, although rare, is a potentially serious adverse event, the Viagra summary of product characteristics (SmPC) recommends use with caution in patients with anatomic deformation of the penis or in patients who have conditions that may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia) (15). Interestingly, sildenafil has been reported to be successful in relieving priapism in patients with sickle cell disease (58).\n\nNAION\nEvents suggestive of NAION were not discovered in the DBPC database. In the postmarketing safety database, the reporting rate for events suggestive of NAION was 0.8% (333/39,277). Nearly half (48%) of the cases for which medical history or concomitant medication information was available reported possible predisposing risk factors, including previous ocular disorders (n = 52), hypertension (n = 58), hyperlipidaemia (n = 47), diabetes mellitus and related conditions (n = 29), smoking (n = 36) and coronary artery disease (n = 21). More than half of the events suggestive of NAION were reported by attorneys rather than healthcare professionals and lack appropriate medical information.\n\nNo cases of NAION were discovered in a retrospective review of > 13,000 patients in the manufacturer’s clinical trials database or during 2935 patient-years of follow up in a prospective observational study of 3813 men (mean age, 57 years) (59). In another prospective observational study, one case of NAION was identified in a total of 35,569 patient-years of observation, representing an unadjusted NAION incidence estimated to be 2.8 patients per 100,000 patient-years of exposure to sildenafil, which is similar to or lower than estimates in general population samples (59).\n\nThe data cited herein do not suggest an increased incidence of NAION in men who took sildenafil for their ED. However, because a causal association between visual field defects and NAION has not been excluded, sildenafil is contraindicated in patients who have loss of vision in one eye because of NAION, regardless of whether this episode was related to previous exposure to a PDE5 inhibitor (15). Should a sudden visual defect occur, the patient should stop taking sildenafil and consult a physician immediately (15).\n\nHearing loss\nIn the DBPC database, events of hearing loss were limited to one case of severe unilateral deafness which is considered to be embolic in aetiology and unrelated to sildenafil treatment and a case of mild deafness that was related to sildenafil treatment. In the latter case, the event is reported as ‘exacerbation of hearing loss,’ implying a relevant medical history, and the patient had concurrent multiple sclerosis.\n\nIn the postmarketing safety database, reports were extremely rare, with a reporting rate of 0.01% (3/39,277) for sudden hearing loss and 0.07% (26/39,277) for impaired hearing. The one literature case report in a patient with ED indicated emergence of the event shortly after dosing. This report appears to be isolated, and critical information around dosing and patient characteristics is omitted (60).\n\nHearing loss is a prevalent condition in the general population and is associated with a number of underlying risk factors, including several drugs. The pharmacological action of sildenafil is not consistent with known ototoxic mechanisms, and there have been no cases that demonstrate the absence of known risk factors and clear evidence of sildenafil challenge/dechallenge or dosing in relation to onset.\n\nImpaired renal function and hepatic function\nMedical history is not a search function that is coded in the postmarketing safety database, but the DBPC database was searched for safety data in men with ED and moderate impairment of renal or hepatic function.\n\nSildenafil has a low renal clearance (< 2%) and excretion because of high tubular reabsorption in the kidney. Sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose) (61). In the DBPC database, the sildenafil safety profile in the 21 men with moderate impairment of renal function was similar to that in men with ED and no impairment of renal function. None had a worsening of blood urea nitrogen/urea or creatinine values, and only 2 of 7 (29%) randomised to sildenafil and 9 of 14 (64%) randomised to placebo had adverse events. The adverse events in the two sildenafil recipients (moderate abdominal pain and sciatica; mild peripheral oedema) were not related to sildenafil treatment. Furthermore, published literature suggests that sildenafil is well tolerated in men with ED and receiving dialysis (62), chronic dialysis (63), haemodialysis (64) and peritoneal dialysis (65); across these published trials, in which a total of 86 men received sildenafil, the most common adverse events were similar in frequency, nature and severity to those observed in patients without renal impairment (i.e. headache, flushing, visual disturbances, hypertension, nasal congestion and dyspepsia). Thus, results from approximately 100 men treated with sildenafil in the DBPC database and the published literature suggest that sildenafil is well tolerated in patients with moderate renal impairment. As sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 ml/min), a 25-mg initial dose should be considered; based on efficacy and toleration, the dose may be increased to 50 or 100 mg (15).\n\nSildenafil is extensively and rapidly metabolised by the liver, primarily by CYP3A4 enzymes (15). In men with moderate impairment of hepatic function, the DBPC database suggested a sildenafil safety profile that was similar to that in men with ED and no impairment of hepatic function. Of the 26 men in the DBPC database who had moderate hepatic impairment and were treated with sildenafil, 23% (6/25) experienced a worsening of their alkaline phosphatase, AST, ALT or total bilirubin values, none of which was attributed to sildenafil. Adverse events were experienced by 77% (20/26) of the sildenafil recipients with hepatic impairment compared with 37% (7/19) of the placebo patients with hepatic impairment. In these men, all of the adverse events that were attributed to sildenafil treatment were mild in severity. As sildenafil clearance is reduced in men with hepatic impairment (e.g. cirrhosis), a 25-mg initial dose should be considered; based on efficacy and toleration, the dose may be increased to 50 or 100 mg (15). The safety of sildenafil has not been studied in men with severe hepatic impairment, and its use is therefore contraindicated (15).\n\nDrug interactions\nAs sildenafil potentiates the hypotensive effects of nitrates, its concomitant administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated (15). Drug interaction studies have shown that concomitant administration of sildenafil and nitrates is associated with known sildenafil adverse drug reactions (mainly class effects associated with PDE5 inhibition) and consistent reductions in blood pressure (18). Very few men in the DBPC database took nitrates concomitantly with sildenafil (16/8691) or placebo (9/6602), and none of these reported hypotension as an adverse event. Treatment-related adverse events were limited to one man treated with 50 mg who had dyspepsia and one man treated with 100 mg who had periorbital swelling, severe headache and facial flushing. In the postmarketing safety database, concomitant nitrate use represented approximately 1% (478/39,277) of patients, and the most frequent associated adverse events were consistent with the underlying cardiovascular conditions treated by nitrates [e.g. myocardial infarction (18%) and chest pain (15%)] or were hypotensive events from the known pharmacodynamic interaction of sildenafil and nitrates (11%).\n\nSildenafil metabolism is principally mediated by the CYP450 isoforms 3A4 (major route) and 2C9 (minor route); sildenafil clearance is reduced when administered concomitantly with CYP3A4 inhibitors such as ketoconazole, erythromycin and cimetidine. Concomitant administration of a single 100 mg dose of sildenafil with ritonavir (an HIV protease inhibitor that is a highly potent P450 inhibitor) at steady state (500 mg twice daily) resulted in increases of 300% (4-fold) in the sildenafil maximum serum concentration and 1000% (11-fold) in the sildenafil area under the plasma concentration vs. time curve (15). In the DBPC database, a small number of men took a CYP3A4 inhibitor, most commonly erythromycin or cimetidine, concomitantly with sildenafil (67/8691) or placebo (43/6602). In this subgroup, treatment-related adverse events occurred in nine men taking sildenafil 50 mg and in 11 men taking sildenafil 100 mg, including one man who had treatment-related adverse events at each dose. Treatment-related adverse events were generally known sildenafil adverse drug reactions that occurred at a slightly higher incidence than in the placebo group or in the entire DBPC database. There were too few postmarketing cases (n = 19) of concomitant CYP3A4 inhibitor and sildenafil use to make an assessment. Although the Viagra SmPC advises against the concomitant administration of sildenafil with ritonavir and recommends considering a sildenafil starting dose of 25 mg when administered concomitantly with other CYP3A4 inhibitors (15), this collated data review suggests little difference in the safety profile of sildenafil across doses (25–100 mg) when administered concomitantly with CYP3A4 inhibitors.\n\nThe current Viagra SmPC advises that patients should be haemodynamically stable on α-blocker therapy before initiating sildenafil treatment, and that initiation of sildenafil at lower doses (25 mg) should be considered (to minimise the potential for developing postural hypotension) (15). The safety of sildenafil administered concomitantly with α-blockers was investigated in three randomised, double-blind, placebo-controlled, cross-over drug interaction trials summarised in the SmPC, in which administration of sildenafil to men with benign prostatic hyperplasia and stabilised on the non-selective α-blocker doxazosin (4 and 8 mg) was associated with mean additional supine blood pressure reductions of 7/7 mmHg (25 mg dose), 9/5 mmHg (50 mg dose) and 8/4 mmHg (100 mg dose) respectively, and with mean additional standing blood pressure reductions of 6/6 mmHg (25 mg dose), 11/4 mmHg (50 mg dose) and 4/5 mmHg (100 mg dose) respectively, but with infrequent reports of symptomatic postural hypotension, which included dizziness and light-headedness, but not syncope) (15). These trials assessed men aged 35–75 years who had documented benign prostatic hyperplasia, had been receiving doxazosin for at least 2 months and took sildenafil after they had taken doxazosin 4 mg once daily for 2 weeks (66). In the first trial, one of four men who took sildenafil 100 mg had a serious adverse event of postural hypotension that began 35 min postdose and lasted for 8 h, but none of the 17 men who took sildenafil 25 mg experienced symptomatic postural hypotension. In the second trial, one of 20 men discontinued prematurely because of hypotension after taking sildenafil 50 mg, but he was also taking minoxidil concomitantly; two other men experienced hypotension as a moderately severe adverse event, with onset 1 h after taking sildenafil 50 mg and resolution of hypotension after 7.5 h. In the third trial, one of 25 men screened with open-label sildenafil 50 mg was discontinued because of symptomatic hypotension (a moderately severe adverse event) 30 min postdose, but none of the 20 men who took sildenafil 100 mg during the trial had a severe adverse event related to blood pressure. In addition to these single-dose, drug interaction trials, several published reports of data from randomised, clinical trials have assessed the safety of sildenafil administered concomitantly with α-blocker therapy and found no evidence of symptomatic postural hypotension associated with concomitant tamsulosin (n = 93) or terazosin (n = 78) therapy (67), doxazosin therapy (n = 14) (68) or alfuzosin therapy (n = 21) (69).\n\nIn the DBPC database, concomitant α-blocker and study drug administration was uncommon, occurring in only 4.2% (368/8691) of sildenafil recipients and 5.0% (329/6602) of placebo patients. It was also infrequent in the postmarketing safety database, occurring in 4.1% (1600/39,277) of patients. In both databases, non-selective α-blocker use (e.g. doxazosin or terazosin) was reported in most cases. In the DBPC database, the most commonly reported adverse events in sildenafil recipients administered α-blockers concomitantly were dyspepsia, headache and flushing, which are known adverse drug reactions with sildenafil treatment. The incidence of events expected from a pharmacological interaction between sildenafil and an α-blocker (decreased blood pressure, orthostatic hypotension) was very low, and there were no cases of hypotension. Adverse events were similar between men using sildenafil 50 and 100 mg, except for a greater incidence of flushing, dyspepsia and nasopharyngitis in the latter. Of sildenafil recipients with adverse events, 46% (168/349) had treatment-related adverse events, mostly mild events [80% (134/168) mild; 1.8% (3/168) severe]. In comparison, 16.9% (32/189) of placebo patients who were taking an α-blocker had an adverse event that was treatment related, of which 9.4% (3/32) were severe. Overall, sildenafil appears to be well tolerated by men receiving concomitant α-blockers. This collated data review suggests little difference in the safety profile of sildenafil across doses (25–100 mg) with concomitant use of α-blockers.\n\nGuidelines on the treatment of ED recommend PDE5 inhibitors as a first-line treatment (39,70). Other treatments include apomorphine sulphate, vacuum devices, intracavernosal injection with prostaglandin E1 and intraurethral delivery of prostaglandin E1. The safety profile of sildenafil administered concomitantly with other ED treatments has not been investigated in clinical trials and, in the DBPC database, few men used other ED medications concomitantly with sildenafil (13/8691) or placebo (12/6602). Treatment-related events, all of which resolved, occurred in three of these men: mild dyspepsia (alprostadil concomitantly with sildenafil 25 mg), mild chromatopsia and headache (alprostadil concomitantly with sildenafil 50 mg and then 100 mg) and moderate atypical chest pain (sildenafil concomitantly with sildenafil 100 mg). In the postmarketing safety database, 1.7% (670/39,277) of all patients reported concomitant ED medications; approved PDE5 inhibitors in more than half and alprostadil in one-third. In the subgroup that reported concomitant ED medications, the adverse events that occurred at more than twice the rate found in the overall postmarketing safety database usually represented the known dose-related increase in visual effects associated with PDE5 inhibition (cyanopsia and visual disturbance) or a synergistic pharmacological effect on the penis (erection increased, penis disorder and priapism). In most (22/40; 55%) of the patients with visual effects, another PDE5 inhibitor was used concomitantly, and in most (14/19; 74%) of the patients with priapism, alprostadil was used concomitantly. Other events that occurred at more than twice the rate found in the overall postmarketing safety database were related to underlying medical conditions (e.g. pain, dyspnoea and increased blood cholesterol and blood pressure) or to alprostadil injection (e.g. pain). Although the concomitant use of sildenafil with other treatments for ED is advised against in the Viagra SmPC (15), this collated data review identified no unexpected adverse drug reactions, suggesting that the safety risk is likely to be low in the general ED population.\n\nOverdose\nOverdose results from intentionally or inadvertently exceeding the maximum recommended daily dose or dosing frequency of a drug, which for sildenafil is a daily dose of 100 mg and (even if the total daily dose does not exceed 100 mg) a dosing frequency of not more than once per day. Sildenafil has low general toxicity; no relevant reproductive toxicity, genotoxicity or carcinogenic properties; and a substantial safety margin (18,71). Clinical studies of doses higher than the approved maximum showed an increased frequency and severity of known adverse drug reactions, including a dose-related increase in the frequency of visual adverse events, but no clear relationship between dose and maximum decreases in blood pressure and no clinically significant changes in electrocardiograms (18). With administration more frequently than once a day, there was an increased frequency of muscular ache, which was transient and without evidence of muscular damage, and dyspepsia (15,18). In the DBPC database, there were no reports of sildenafil overdose. In the postmarketing safety database, excluding cases in conjunction with suicides or suicide attempts, the reporting rate for sildenafil overdose was 2.3% (884/39,203).\n\nAdverse events in the postmarketing cases of overdose were generally known sildenafil adverse drug reactions (i.e. headache and flushing), which were generally reported at a slightly higher frequency than in the overall postmarketing safety database. Priapism was reported at a rate more than twice that of the overall postmarketing safety database. Of the 884 patients with overdose identified in the postmarketing safety database, 165 reported a first total daily dose > 100 mg. In this subset, the reporting rate was more than twice that for the overall postmarketing safety database for acute myocardial infarction (3.0% vs. 0.7%), myocardial infarction (6.1% vs. 2.5%), tachycardia (2.4% vs. 1.0%), drug interaction (4.8% vs. 2.4%), malaise (2.4% vs. 1.0%), dyspnoea (2.4% vs. 1.0%) and hypotension (5.5% vs. 1.1%). Although a relationship with sildenafil overdose cannot be excluded in 4 of the 12 patients with myocardial infarction and in 14 of the 57 deaths, neither can a relationship between overdose and increased cardiac risk be assumed based on the small number of postmarketing cases. However, we recommend admission to hospital and cardiac monitoring, preferably in a coronary care unit, for 48 h. In this way, any cardiovascular complication can be addressed by experienced healthcare professionals. Standard supportive measures should be adopted as required, but renal dialysis is not expected to accelerate clearance because sildenafil is highly bound to plasma proteins and is not eliminated in the urine.\n\nThe highest first total daily dose reported was 2400 mg in a 33-year-old man who took 24 tablets of sildenafil 100 mg. He was diagnosed with annular scotoma, defective colour vision, vascular retinal dilatation, visual field defect and papilloedema. He recovered from all events except for visual field defect and annular scotoma.\n\nThus, the collated data review determined that overdose with sildenafil is rare in the ED population and identified no new safety issues or adverse reactions in conjunction with overdose. It is noteworthy that, in a parallel-group, double-blind, randomised trial and its long-term open-label extension study, the safety profile of sildenafil, in doses up to 240 mg/day for the treatment of pulmonary arterial hypertension, was unchanged compared with lower dosages (72). In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased (15).\n\nExtensive data (clinical trial data from > 13,000 patients (50,51), 7 years of international postmarketing data, observational studies of > 28,000 men in the United Kingdom (24) and 3813 men in the European Union (73)) was used to support the previously published conclusion that there are no special cardiovascular concerns when sildenafil is used in accordance with product labelling (27).\n\nAbuse\nAbuse can be classified as addiction/dependence (an involuntary compulsion, which is usually marked by tolerance to the effects and withdrawal symptoms when use is terminated), abuse (recreational use without medical rationale but without addiction or dependence) and misuse (intentional or unintentional incorrect use by a healthcare provider or patient). Unintentional misuse includes accidental exposure, drug administration error, incorrect dose administered and medication error. Events relating to addiction/dependence, abuse or misuse of sildenafil were not identified in the DBPC database, but were identified in the postmarketing safety database.\n\nThe mode of action of sildenafil is peripheral rather than central (71,74). Consequently, sildenafil lacks the libido-stimulating activity that classically defines an aphrodisiac agent. In addition, there is no evidence that men with ED develop physical dependence or tolerance to sildenafil. The absence of evidence of tolerance developing to the erectogenic effects of sildenafil is further supported by the results of a long-term study over 4 years (75). However, in the postmarketing safety database, sildenafil dependence was reported in a few [0.15% (58/39,277)] patients, mostly psychological dependence on sildenafil to achieve erection or insecurity in initiating intercourse without sildenafil.\n\nSildenafil abuse represented 0.11% (42/39,277) of all reported events, in 76% of which the patient did not have a diagnosis of ED. Intentional misuse was identified in 1.4% (535/39,277) of all patients, most commonly taking sildenafil for recreational purposes, without a prescription, and/or without a diagnosis of ED (n = 207) and adjusting the dose or route/form of administration without direction of a physician (n = 141). Unintentional misuse was identified in 0.91% (357/39,277) of patients, including patients who accidentally took the drug, accidentally took more of the drug than intended or altered their dose or dosing frequency without first consulting a physician.\n\nThus, in the postmarketing safety database, the predominant form of improper use was obtaining sildenafil without a prescription and/or taking sildenafil without a diagnosis of ED. Sildenafil is often obtained through uncontrolled channels outside of the healthcare system, a risky behaviour that is a medical concern that needs to be addressed (76–78). Also, some men take sildenafil for what they perceive as a better sexual performance, even though they do not have ED. No new safety signals or emerging trends were identified from this review of cases reporting sildenafil dependence, abuse and misuse.\n\nConclusions\nThis collated data review found that sildenafil was well tolerated at a dose of 50 or 100 mg, overall, in men who were aged ≥ 65 years and in those who were aged ≥ 75 years. No causal link was identified between sildenafil administered in accordance with product labelling and cardiovascular events, and further support was lent to the safety of sildenafil in men at risk for cardiovascular disease, in that no new safety risks relating to cardiovascular events were identified in patients with cardiovascular conditions, hypertension or diabetes mellitus. No new safety risks were identified with sildenafil relating to priapism or NAION. In the small number of men with ED and moderate impairment of renal function or hepatic function who have been treated with sildenafil in DBPC trials, the sildenafil safety profile was similar to that in men with ED and no impairment of renal or hepatic function. As sildenafil was well tolerated, has a relatively short half-life (4–5 h) and is administered as needed in a maximum of one dose per day, the safety risk from drug interactions is likely to be low in the general ED population. Indeed, no unexpected adverse drug reactions were identified from the concomitant use of sildenafil with nitrates, nitric oxide donors, CYP3A4 inhibitors, other ED medications or α-blockers. Overdose with sildenafil was rare in the ED population, and no new adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse. It can be concluded that sildenafil in all registered doses has a good safety profile.\n\n1 PubMed search: ‘erectile dysfunction’ (Mesh) and ‘drug toxicity’ (Mesh) and (sildenafil or vardenafil or tadalafil) and [‘age factors’ (Mesh) or ‘age groups’ (Mesh)].\n\n2 The recommended starting dose is 50 mg taken as needed approximately 1 h before sexual activity [VIAGRA® (sildenafil citrate) summary of product characteristics, http://www.emea.europa.eu/humandocs/PDFs/EPAR/viagra/H-202-PI-en.pdf]. Based on efficacy and toleration, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day.\n\nThe authors thank Gabriel Schnetzler, MD, Pfizer International Operations, Paris, France, for his assistance in reviewing the manuscript. All financial and material support for the preparation of this manuscript was provided by Pfizer Inc, which was involved in the data collection and analysis. Editorial support was provided by Deborah M. Campoli-Richards, BSPHA, RPh, of Complete Healthcare Communications, Inc. and was funded by Pfizer Inc.\n\nAuthor contributions\nFrançois Giuliano, Graham Jackson, Francesco Montorsi, Antonio Martin-Morales and Pierre Raillard were involved in data interpretation and in the drafting, critical revision and approval of the manuscript.\n==== Refs\nReferences\n1 Dinsmore WW Hodges M Hargreaves C Sildenafil citrate (VIAGRA) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects Urology 1999 53 800 5 10197860 \n2 Montorsi F McDermott TED Morgan R Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies Urology 1999 53 1011 8 10223498 \n3 Goldstein I Lue TF Padma-Nathan H Oral sildenafil in the treatment of erectile dysfunction N Engl J Med 1998 338 1397 404 9580646 \n4 Becher E Tejada Noriega A Gomez R Decia R Sildenafil citrate (Viagra) in the treatment of men with erectile dysfunction in southern Latin America: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, flexible-dose escalation study Int J Impot Res 2002 14 Suppl. 2 S33 41 12161766 \n5 Glina S Bertero E Claro J Efficacy and safety of flexible-dose oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction in Brazilian and Mexican men Int J Impot Res 2002 14 Suppl. 2 S27 32 12161765 \n6 Gomez F Davila H Costa A Efficacy and safety of oral sildenafil citrate (Viagra) in the treatment of male erectile dysfunction in Colombia, Ecuador, and Venezuela: a double-blind, multicenter, placebo-controlled study Int J Impot Res 2002 14 Suppl. 2 S42 7 12161767 \n7 Levinson IP Khalaf IM Shaeer KZ Smart DO Efficacy and safety of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in Egypt and South Africa Int J Impot Res 2003 15 Suppl. 1 S25 9 12825106 \n8 Osegbe DN Shittu OB Aghaji AE Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in Nigerian men Int J Impot Res 2003 15 Suppl. 1 S15 8 12825104 \n9 Tan HM Moh CL Mendoza JB Asian sildenafil efficacy and safety study (ASSESS-1): a double-blind, placebo-controlled, flexible-dose study of oral sildenafil in Malaysian, Singaporean, and Filipino men with erectile dysfunction. 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RIVM report 2005. http://www.rivm.nl/bibliotheek/rapporten/267041001.pdf [Accessed 28 November 2007] \n37 WHO Drug Dictionary 2002 Uppsala, Sweden Uppsala Monitoring Centre 2nd Quarter \n38 Carson C Siegel R Orazem J Sildenafil citrate treatment for erectile dysfunction: rate of adverse events decreases over time J Urol 2002 167 Suppl. 179 \n39 Wespes E Amar E Hatzichristou D EAU guidelines on erectile dysfunction: an update Eur Urol 2006 49 806 15 16530932 \n40 McCullough AR Barada JH Fawzy A Achieving treatment optimization with sildenafil citrate (Viagra®) in patients with erectile dysfunction Urology 2002 60 28 38 12414331 \n41 Bacon CG Mittleman MA Kawachi I A prospective study of risk factors for erectile dysfunction J Urol 2006 176 217 21 16753404 \n42 Kupelian V Link CL McKinlay JB Association between smoking, passive smoking, and erectile dysfunction: results from the Boston Area Community Health (BACH) Survey Eur Urol 2007 52 416 22 17383811 \n43 Kupelian V Shabsigh R Araujo AB Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study J Urol 2006 176 222 6 16753405 \n44 Millett C Wen LM Rissel C Smoking and erectile dysfunction: findings from a representative sample of Australian men Tob Control 2006 15 136 9 16565463 \n45 Ponholzer A Temml C Mock K Prevalence and risk factors for erectile dysfunction in 2869 men using a validated questionnaire Eur Urol 2005 47 80 5 15582253 \n46 Riedner CE Rhoden EL Ribeiro EP Fuchs SC Central obesity is an independent predictor of erectile dysfunction in older men J Urol 2006 176 1519 23 16952671 \n47 Selvin E Burnett AL Platz EA Prevalence and risk factors for erectile dysfunction in the US Am J Med 2007 120 151 7 17275456 \n48 Feldman HA Johannes CB Derby CA Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study Prev Med 2000 30 328 38 10731462 \n49 Seftel AD Sun P Swindle R The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction J Urol 2004 171 2341 5 15126817 \n50 Mittleman MA Maclure M Glasser DB Evaluation of acute risk for myocardial infarction in men treated with sildenafil citrate Am J Cardiol 2005 96 443 6 16054479 \n51 Mittleman MA Glasser DB Orazem J Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo Int J Clin Pract 2003 57 597 600 14529061 \n52 Blonde L Sildenafil citrate for erectile dysfunction in men with diabetes and cardiovascular risk factors: a retrospective analysis of pooled data from placebo-controlled trials Curr Med Res Opin 2006 22 2111 20 17076971 \n53 Boulton AJ Selam JL Sweeney M Ziegler D Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus Diabetologia 2001 44 1296 301 11692178 \n54 Buranakitjaroen P Mangklabruks A Leungwattanakij S Efficacy and safety of sildenafil in Asian males with erectile dysfunction and cardiovascular risk J Med Assoc Thai 2007 90 1100 8 17624203 \n55 Pickering TG Shepherd AM Puddey IB Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial Am J Hypertens 2004 17 1135 42 15607620 \n56 Katz SD Parker JD Glasser DB Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure Am J Cardiol 2005 95 36 42 15619391 \n57 Olsson AM Persson CA Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in men with cardiovascular disease Int J Clin Pract 2001 55 171 6 11351770 \n58 Bialecki ES Bridges KR Sildenafil relieves priapism in patients with sickle cell disease Am J Med 2002 113 252 12208390 \n59 Gorkin L Hvidsten K Sobel RE Siegel R Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neuropathy Int J Clin Pract 2006 60 500 3 16620369 \n60 Mukherjee B Shivakumar T A case of sensorineural deafness following ingestion of sildenafil J Laryngol Otol 2007 121 395 7 17166328 \n61 Muirhead GJ Rance DJ Walker DK Wastall P Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil Br J Clin Pharmacol 2002 53 Suppl. 1 13S 20S 11879255 \n62 Rosas SE Wasserstein A Kobrin S Feldman HI Preliminary observations of sildenafil treatment for erectile dysfunction in dialysis patients Am J Kidney Dis 2001 37 134 7 11136178 \n63 Chen J Mabjeesh NJ Greenstein A Clinical efficacy of sildenafil in patients on chronic dialysis J Urol 2001 165 819 21 11176477 \n64 Seibel I Poli De Figueiredo CE Teloken C Moraes JF Efficacy of oral sildenafil in hemodialysis patients with erectile dysfunction J Am Soc Nephrol 2002 13 2770 5 12397048 \n65 Mahon A Sidhu PS Muir G Macdougall IC The efficacy of sildenafil for the treatment of erectile dysfunction in male peritoneal dialysis patients Am J Kidney Dis 2005 45 381 7 15685517 \n66 Kloner RA Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions Am J Cardiol 2005 96 42M 6M 15979430 \n67 Narayan P Gagnier P Doyle C Concomitant use of sildenafil with tamsulosin or terazosin: a retrospective safety evaluation (abstract) J Urol 2004 171 Suppl. 4 357 14665927 \n68 De Rose AF Giglio M Traverso P Combined oral therapy with sildenafil and doxazosin for the treatment of non-organic erectile dysfunction refractory to sildenafil monotherapy Int J Impot Res 2002 14 50 3 11896478 \n69 Kaplan SA Gonzalez RR Te AE Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction Eur Urol 2007 51 1717 23 17258855 \n70 Lue TF Giuliano F Montorsi F Summary of the recommendations on sexual dysfunctions in men J Sex Med 2004 1 6 23 16422979 \n71 European Medicines Agency VIAGRA European Public Assessment Report (EPAR), revision 11 European Public Assessment Reports (EPAR) for authorised medicinal products for human use 03/09/2008. http://www.emea.europa.eu/humandocs/Humans/EPAR/viagra/viagra.htm [Accessed 19 September 2008] \n72 Galie N Ghofrani HA Torbicki A Sildenafil citrate therapy for pulmonary arterial hypertension N Engl J Med 2005 353 2148 57 16291984 \n73 Giuliano F Porst H Hedelin H Cardiovascular safety of Viagra® (sildenafil citrate): results of the international men’s health study Eur Urol 2005 4 Suppl. 3 137 \n74 Boolell M Allen MJ Ballard SA Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction Int J Impot Res 1996 8 47 52 8858389 \n75 McMurray JG Feldman RA Auerbach SM Long-term safety and effectiveness of sildenafil citrate in men with erectile dysfunction Ther Clin Risk Manag 2007 3 975 81 18516312 \n76 Smith KM Romanelli F Recreational use and misuse of phosphodiesterase 5 inhibitors J Am Pharm Assoc 2005 45 63 72 \n77 Romanelli F Smith KM Recreational use of sildenafil by HIV-positive and -negative homosexual/bisexual males Ann Pharmacother 2004 38 1024 30 15113986 \n78 Sugar SJ Reply to ‘Viagra: the risks of recreational use’ Am J Med 2006 119 92 3 16431206\n\n", "fulltext_license": "CC BY", "issn_linking": "1368-5031", "issue": "64(2)", "journal": "International journal of clinical practice", "keywords": null, "medline_ta": "Int J Clin Pract", "mesh_terms": "D000368:Aged; D002318:Cardiovascular Diseases; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D062787:Drug Overdose; D007172:Erectile Dysfunction; D006311:Hearing Disorders; D006801:Humans; D007674:Kidney Diseases; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011317:Priapism; D011358:Product Surveillance, Postmarketing; D011687:Purines; D016032:Randomized Controlled Trials as Topic; D000068677:Sildenafil Citrate; D013450:Sulfones; D016896:Treatment Outcome", "nlm_unique_id": "9712381", "other_id": null, "pages": "240-55", "pmc": null, "pmid": "19900167", "pubdate": "2010-01", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": "16431206;11018621;12208390;16952671;12352386;10197860;15582253;12161765;12825104;11176477;17087804;8858389;17011375;16753405;16620369;15730119;11692178;11220982;12161767;11494079;18261073;18507892;12414335;12435622;17313426;12399521;12657355;18516312;15766322;12397048;12161766;15126817;9580646;17258855;16565463;11136178;16422979;15938595;8254833;15685517;16530932;12414330;10223498;15049992;16753404;11896478;15113986;11879255;12547849;15619391;16409214;15983284;16387566;17383811;10731462;12825106;12414331;10444124;17076971;17287834;16291984;15607620;11351770;16054479;17275456;17166328;12841917;14529061;17624203", "title": "Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database.", "title_normalized": "safety of sildenafil citrate review of 67 double blind placebo controlled trials and the postmarketing safety database" }	[ { "companynumb": "FR-ALKEM LABORATORIES LIMITED-FR-ALKEM-2022-03147", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SILDENAFIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "212440", "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, 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Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. 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SAFETY OF SILDENAFIL CITRATE: REVIEW OF 67 DOUBLE-BLIND PLACEBO-CONTROLLED TRIALS AND THE POSTMARKETING SAFETY DATABASE. JOURNAL OF SEXUAL MEDICINE. 2014?11 (4):885-887", "literaturereference_normalized": "safety of sildenafil citrate review of 67 double blind placebo controlled trials and the postmarketing safety database", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "JP", "receiptdate": "20201026", "receivedate": "20140418", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10086912, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]
{ "abstract": "Pulmonary sarcomatoid carcinoma is a rare, poorly differentiated, and highly aggressive type of non-small cell lung cancer. High tumor mutational burden and PD-L1 overexpression make it an excellent candidate for immunotherapy.\nWe presented the case of a patient who underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for an infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV pulmonary sarcomatoid carcinoma. He received first- and second-line chemotherapy without any benefit. Since March 2016, he has been treated with the anti-PD1 agent nivolumab with a dramatic improvement of symptoms, disappearance of a brain lesion, and partial response on other metastatic sites. He tolerated the treatment well and is still responding after 22 months from the beginning.\nIn very lethal non-small cell lung cancer subtypes such as the sarcomatoid variants, high tumor burden and deteriorated general conditions should not preclude, at least in some cases, the use of immunotherapy. Anti-PD1 may also have a reliable role in disease control in the brain. Lastly, the strong rationale behind sarcomatoid histology should further prompt trials exploring immunotherapeutic approaches in this subset of non-small cell lung cancer.", "affiliations": "Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.;Pathology Unit, Azienda AUSL Romagna, Regional Hospital Ravenna, Ravenna, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.", "authors": "Salati\|Massimiliano\|M\|;Baldessari\|Cinzia\|C\|;Calabrese\|Fiorella\|F\|;Rossi\|Giulio\|G\|;Pettorelli\|Elisa\|E\|;Grizzi\|Giulia\|G\|;Dominici\|Massimo\|M\|;Barbieri\|Fausto\|F\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000492666", "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] 10.1159/000492666cro-0011-0615Case ReportNivolumab-Induced Impressive Response of Refractory Pulmonary Sarcomatoid Carcinoma with Brain Metastasis Salati Massimiliano aBaldessari Cinzia aCalabrese Fiorella bRossi Giulio cPettorelli Elisa aGrizzi Giulia aDominici Massimo aBarbieri Fausto aaDepartment of Oncology, University of Modena and Reggio Emilia – Policlinico of Modena, Modena, ItalybDepartment of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, ItalycPathology Unit, Azienda AUSL Romagna, Regional Hospital Ravenna, Ravenna, ItalyCinzia Baldessari, Department of Oncology, University of Modena and Reggio Emilia – Policlinico of Modena, Via del Pozzo 71, IT-41124 Modena (Italy), E-Mail [email protected] Salati and Cinzia Baldessari contributed equally to this work.\n\nSep-Dec 2018 7 9 2018 7 9 2018 11 3 615 621 31 7 2018 3 8 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Background\nPulmonary sarcomatoid carcinoma is a rare, poorly differentiated, and highly aggressive type of non-small cell lung cancer. High tumor mutational burden and PD-L1 overexpression make it an excellent candidate for immunotherapy.\n\nObjectives and Method\nWe presented the case of a patient who underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for an infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV pulmonary sarcomatoid carcinoma. He received first- and second-line chemotherapy without any benefit. Since March 2016, he has been treated with the anti-PD1 agent nivolumab with a dramatic improvement of symptoms, disappearance of a brain lesion, and partial response on other metastatic sites. He tolerated the treatment well and is still responding after 22 months from the beginning.\n\nResults and Conclusions\nIn very lethal non-small cell lung cancer subtypes such as the sarcomatoid variants, high tumor burden and deteriorated general conditions should not preclude, at least in some cases, the use of immunotherapy. Anti-PD1 may also have a reliable role in disease control in the brain. Lastly, the strong rationale behind sarcomatoid histology should further prompt trials exploring immunotherapeutic approaches in this subset of non-small cell lung cancer.\n\nKeywords\nImmunotherapyLung cancerPulmonary sarcomatoid carcinomaBrain metastasis\n==== Body\nIntroduction\nPulmonary sarcomatoid carcinoma (PSC) is a rare, poorly differentiated, and highly aggressive tumor entity accounting for less than 3% of non-small cell lung cancer (NSCLC) [1]. Early metastatic dissemination and resistance to conventional therapies result in a prognosis usually poorer than other lung cancers [2]. Recently, the targeting of immunologic checkpoints turned out to be a major breakthrough in oncology. Nivolumab is a fully human IgG4 PD-1 blocking antibody approved for previously treated advanced NSCLC [3, 4]. High tumor mutational burden and PD-L1 overexpression make PSC an excellent candidate for immunotherapy [5]. However, only anecdotal case reports on anti-PD1 efficacy in PSC have been described so far [6].\n\nCase Report\nOn November 2015, a 74-year-old male with ECOG PS 0 and no smoking history underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for a large infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV PSC (Table 1). Medical history also reports HCV-related hepatitis successfully treated with PEG interferon in 2005 and a melanoma of the scalp surgically removed in 2013.\n\nAt histology, the tumor was characterized by mixed non-small cell carcinoma and sarcoma. The epithelial component showed highly pleomorphic tumor cells with striking nuclear atypia, including atypical mitoses and large area of necrosis and moderate reactive inflammation. Sarcoma-like elements (spindle and giant cells) were present in about half of neoplasia. A large panel of antibodies was used in order to well characterize the tumor and rule out other tumors, firstly melanoma, given his past medical history (Table 1). Tumor samples were analyzed by 30-gene next-generation sequencing, but no mutations were detected. ALK (D5F3 clone) and ROS1 rearrangements (D4D6 clone) and MET investigated either by immunohistochemistry or fluorescence in situ hybridization were also negative. Interestingly, immunohistochemistry for PDL-1 (clones SP263 by Ventana Medical System and E1L3N by Cell Signaling) showed a strong expression both in tumoral cells (tumor proportion score ≥50%) and in inflammatory cells (Fig. 1).\n\nOn January 2016, following surgery, the patient initiated a first-line chemotherapy regimen consisting of carboplatin/pemetrexed at conventional doses. After cycle 1, he experienced grade 2 nausea and vomiting and complained of abdominal right-sided pain. A computed tomography (CT) scan was then performed showing progressive disease with the appearance of lung, adrenal, liver, and lymph node metastases. A second-line chemotherapy with weekly docetaxel was then started, although the patient's general health conditions rapidly deteriorated and diffuse pain worsened requiring opioids.\n\nAfter 2 cycles with docetaxel, a CT scan demonstrated the appearance of a brain lesion and an increase in size of lung, hepatic, and right paravertebral muscle lesions.\n\nIn March, the patient started receiving the anti-PD1 agent nivolumab at the recommended dose of 3 mg/kg every 2 weeks within an expanded access program. After only one administration, he experienced a dramatic improvement of symptoms associated with a rapid decrease of LDH and a progressive tapering of opioids therapy until discontinuation. A subsequent reassessment by CT scan showed disappearance of the brain lesion and partial response on other sites (Fig. 2). Since December 2016, according to the patient's request, nivolumab administration has been modified to a 3-weekly schedule. Treatment was well tolerated, except for grade 1 transient cutaneous rash, vitiligo on the hands, and a slow recovery from pneumonia successfully treated by the combination of oral steroids (prednisone maximum dose 50 mg for no more than 10 days) and antibiotics on July 2017 (Fig. 3). Currently, at the end of July 2018, 28 months after the initiation of the anti-PD1, the patient is still on therapy and further responding.\n\nDiscussion and Conclusion\nTo our knowledge, the case presented herein is adding valuable insights into the use of a checkpoint inhibitor in very lethal NSCLC subtypes, such as the sarcomatoid variants. Firstly, high tumor burden and deteriorated general conditions should not preclude the use of immunotherapy as, at least in some cases, it may result in rapid tumor shrinkage together with profound and lasting response. Secondly, anti-PD1 may have a reliable role in disease control also in the brain, despite earlier concerns about its capability of crossing the blood-brain barrier. Lastly, the strong rationale behind sarcomatoid histology should further prompt trials exploring immunotherapeutic approaches in this subset of NSCLC.\n\nOther open questions remain to be answered. For instance, whether the prior therapy with PEG interferon could have acted as trigger for T cells thus boosting nivolumab activity and, again, whether changing the treatment schedule to 3-weekly could be a safe, effective, and cost-saving way to deliver immune checkpoint inhibitors while improving patients' distress.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nAuthor Contributions\nMassimiliano Salati, Cinzia Baldessari, Giulia Grizzi, Stefano Cascinu, Massimo Dominici, and Fausto Barbieri: medical oncologists in charge of the patient; Fiorella Calabrese and Giulio Rossi: pathologists in charge of the tumor specimen analyses; Elisa Pettorelli: data manager.\n\nAcknowledgement\nBristol-Myers-Squibb Italy for providing nivolumab.\n\nFig. 1. Immunohistochemistry for PDL-1 (clones SP263 by Ventana Medical System and E1L3N by Cell Signaling) showing a strong expression in both tumoral cells (a, tumor proportion score ≥50%; original magnification ×200) and inflammatory cells inside an area of tumor necrosis (b, macrophages and lymphocytes with arrows; original magnification ×100).\n\nFig. 2. Abdomen and brain CT scans. T0 images are related to the clinical status before nivolumab (March 21, 2016), T2 images refer to the situation after 2 months (May 20, 2016), and T20 images describe the tumor after 20 months (November 16, 2017). In the left column, images refer to the CT follow-up on the hepatic lesion (arrow), then the adrenal gland lesions (arrow), and the lesion of right paravertebral muscle (arrow). In the right column, images refer to the CNS lesion (arrow) before nivolumab therapy (T0), after 4 cycles (T2), and after 34 cycles (T20).\n\nFig. 3. Pulmonary CT scans. Images refer to the slow recovery from pneumonia from May 11 to July 17 to November 16, 2017 (from left to right).\n\nTable 1 Histopathological and molecular features of the lung cancer biopsy\n\nFeature/biomarker\tResults\t\nMNF-116\t–/+\t\nAE1/AE3\t–/+\t\nEMA\t–/+\t\nCK7\t–\t\nTTF1\t–\t\nVimentin\t+ (mainly in sarcomatoid component)\t\nP63\t–\t\nNapsin\t–\t\nCalretinin\t–/+\t\nD240\t–\t\nWT1\t–/+\t\nHMB45\t–\t\nS100\t–\t\nKi67\t40%\t\nALK (D5F3 clone)\tnegative\t\nROS1 rearrangements (clone D4D6)\tnegative\t\nMET IHC and FISH\tnegative\t\n30-gene next-generation sequencing\tno mutations detected\n==== Refs\nReferences\n1 Yendamuri S Caty L Pine M Adem S Bogner P Miller A Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis Surgery 2012 9 152 (3) 397 402 22739072 \n2 Shum E Stuart M Borczuk A Wang F Cheng H Halmos B Recent advances in the management of pulmonary sarcomatoid carcinoma Expert Rev Respir Med 2016 3 10 (4) 1 10 26567613 \n3 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer N Engl J Med 2015 10 373 (17) 1627 39 26412456 \n4 Brahmer J Reckamp KL Baas P Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer N Engl J Med 2015 373 (2) 123 35 26028407 \n5 Schrock AB Li SD Frampton GM Suh J Braun E Mehra R Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling J Thorac Oncol 2017 6 12 (6) 932 42 28315738 \n6 Gounant V Brosseau S Naltet C Opsomer MA Antoine M Danel C Nivolumab-induced organizing pneumonitis in a patient with lung sarcomatoid carcinoma Lung Cancer 2016 9 99 162 5 27565934\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "11(3)", "journal": "Case reports in oncology", "keywords": "Brain metastasis; Immunotherapy; Lung cancer; Pulmonary sarcomatoid carcinoma", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "615-621", "pmc": null, "pmid": "30323751", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "26412456;27565934;28315738;26028407;22739072", "title": "Nivolumab-Induced Impressive Response of Refractory Pulmonary Sarcomatoid Carcinoma with Brain Metastasis.", "title_normalized": "nivolumab induced impressive response of refractory pulmonary sarcomatoid carcinoma with brain metastasis" }	[ { "companynumb": "IT-ACCORD-104250", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201195", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONVENTIONAL DOSES, (3 Q 4 W)", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "SARCOMATOID CARCINOMA OF THE LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "35", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOCETAXEL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "CONVENTIONAL DOSES", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "SARCOMATOID CARCINOMA OF THE LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201601", "drugstartdateformat": "610", "drugstructuredosagenumb": "500", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PEMETREXED." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206775", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CONCENTRATE FOR CUTANEOUS SOLUTION", "drugdosagetext": "CONVENTIONAL DOSES", "drugenddate": "2016", "drugenddateformat": "602", "drugindication": "SARCOMATOID CARCINOMA OF THE LUNG", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201601", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201601" } }, "primarysource": { "literaturereference": "SALATI M, BALDESSARI C, CALABRESE F, ROSSI G, PETTORELLI E, GRIZZI G ET AL. 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{ "abstract": "Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.\n\n\n\nWe conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.\n\n\n\nOf the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).\n\n\n\nA chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).", "affiliations": "From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.", "authors": "Foà\|Robin\|R\|;Bassan\|Renato\|R\|;Vitale\|Antonella\|A\|;Elia\|Loredana\|L\|;Piciocchi\|Alfonso\|A\|;Puzzolo\|Maria-Cristina\|MC\|;Canichella\|Martina\|M\|;Viero\|Piera\|P\|;Ferrara\|Felicetto\|F\|;Lunghi\|Monia\|M\|;Fabbiano\|Francesco\|F\|;Bonifacio\|Massimiliano\|M\|0000-0003-0716-1686;Fracchiolla\|Nicola\|N\|;Di Bartolomeo\|Paolo\|P\|;Mancino\|Alessandra\|A\|;De Propris\|Maria-Stefania\|MS\|;Vignetti\|Marco\|M\|;Guarini\|Anna\|A\|;Rambaldi\|Alessandro\|A\|;Chiaretti\|Sabina\|S\|;\|\|\|", "chemical_list": "D018033:Antibodies, Bispecific; C510808:blinatumomab; D000069439:Dasatinib", "country": "United States", "delete": false, "doi": "10.1056/NEJMoa2016272", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-4793", "issue": "383(17)", "journal": "The New England journal of medicine", "keywords": null, "medline_ta": "N Engl J Med", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts; D018033:Antibodies, Bispecific; D000971:Antineoplastic Combined Chemotherapy Protocols; D060830:Consolidation Chemotherapy; D000069439:Dasatinib; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "0255562", "other_id": null, "pages": "1613-1623", "pmc": null, "pmid": "33085860", "pubdate": "2020-10-22", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults.", "title_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults" }	[ { "companynumb": "IT-AMGEN-ITASP2019157218", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "28 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "B PRECURSOR TYPE ACUTE LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "28", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLINATUMOMAB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "125557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "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": "BLINATUMOMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DASATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "140 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "140", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DASATINIB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "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, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DEXAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Acute lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FOA R.? 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"reactionmeddrapt": "Venoocclusive disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rash maculovesicular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage intracranial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Central nervous system leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Testicular pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gamma-glutamyltransferase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary 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extramedullary", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aphasia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute graft versus host disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic function abnormal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bradyphrenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypogammaglobulinaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, 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CHIARETTI S.? FERRARA F. ET AL.. DASATINIB-BLINATUMOMAB FOR PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS. THE NEW ENGLAND JOURNAL OF MEDICINE. 2020?383 (17):1613-1623", "literaturereference_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201104", "receivedate": "20201104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18463649, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "IT-AMGEN-ITASP2020004632", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "28 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "B PRECURSOR TYPE ACUTE LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "28", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLINATUMOMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DASATINIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "140 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "140", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DASATINIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLINATUMOMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Central nervous system leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FOA R.? CHIARETTI S.? FERRARA F. ET AL.. DASATINIB-BLINATUMOMAB FOR PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS. NEW ENGLAND JOURNAL OF MEDICINE. 2020?383 (17):1613-1623", "literaturereference_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201104", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17278060, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" }, { "companynumb": "IT-AMGEN-ITASP2019157222", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": null, 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"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": "BLINATUMOMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "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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CHIARETTI S.? FERRARA F. ET AL.. DASATINIB-BLINATUMOMAB FOR PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS. THE NEW ENGLAND JOURNAL OF MEDICINE. 2020?383 (17):1613-1623", "literaturereference_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201104", "receivedate": "20190926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16857775, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]
{ "abstract": "A 24-year-old pregnant woman (29.4 weeks of gestation) with A (H1N1) influenza-associated adult respiratory distress syndrome was admitted to the intensive care unit. The patient was connected to femoral-jugular veno-venous extracorporeal membrane oxygenation (ECMO) 8 hours after admission. On the 7(th) day of ECMO support, due to the increasing threat to the life of the mother and the fetus, a decision was made to carry out a cesarean section (CS) without discontinuing the ECMO support. The CS was performed uneventfully under general anesthesia, 5 hours after the discontinuation of heparin infusion. A live, premature 1200 g female neonate was delivered. No complications occurred in the perioperative period. On the 17(th) day, the patient was successfully weaned off the ECMO and discharged 10 days later. The newborn was discharged from the hospital in good health 41 days after the delivery.", "affiliations": "Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland.;Department of General and Pediatric Radiology, Medical University of Wroclaw, Poland.;1 Department and Clinic of Gynecology and Obstetrics, Medical University of Wroclaw, Poland.;Department and Clinic of Cardiac Surgery, Medical University of Wroclaw, Poland.;Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland.;Department and Clinic of Cardiac Surgery, Medical University of Wroclaw, Poland.;Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland.", "authors": "Łysenko\|Lidia\|L\|;Zaleska-Dorobisz\|Urszula\|U\|;Blok\|Radosław\|R\|;Dumański\|Andrzej\|A\|;Zielińska\|Marzena\|M\|;Kustrzycki\|Wojciech\|W\|;Durek\|Grażyna\|G\|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.5114/kitp.2014.43855", "fulltext": "\n==== Front\nKardiochir Torakochirurgia PolKardiochir Torakochirurgia PolKITPKardiochirurgia i Torakochirurgia Polska = Polish Journal of Cardio-Thoracic Surgery1731-55301897-4252Termedia Publishing House 2308710.5114/kitp.2014.43855Case ReportsA successful cesarean section in a pregnant woman with A (H1N1) influenza requiring ECMO support Łysenko Lidia 1Zaleska-Dorobisz Urszula 2Blok Radosław 3Dumański Andrzej 4Zielińska Marzena 1Kustrzycki Wojciech 4Durek Grażyna 11 Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland2 Department of General and Pediatric Radiology, Medical University of Wroclaw, Poland3 1st Department and Clinic of Gynecology and Obstetrics, Medical University of Wroclaw, Poland4 Department and Clinic of Cardiac Surgery, Medical University of Wroclaw, PolandAddress for correspondence: Lidia Łysenko, MD, PhD, Department and First Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Chałubińskiego 1a, 50-368 Wrocław, Poland29 6 2014 6 2014 11 2 216 219 08 10 2013 14 10 2013 04 4 2014 Copyright © 20142014This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A 24-year-old pregnant woman (29.4 weeks of gestation) with A (H1N1) influenza-associated adult respiratory distress syndrome was admitted to the intensive care unit. The patient was connected to femoral-jugular veno-venous extracorporeal membrane oxygenation (ECMO) 8 hours after admission. On the 7th day of ECMO support, due to the increasing threat to the life of the mother and the fetus, a decision was made to carry out a cesarean section (CS) without discontinuing the ECMO support. The CS was performed uneventfully under general anesthesia, 5 hours after the discontinuation of heparin infusion. A live, premature 1200 g female neonate was delivered. No complications occurred in the perioperative period. On the 17th day, the patient was successfully weaned off the ECMO and discharged 10 days later. The newborn was discharged from the hospital in good health 41 days after the delivery.\n\nCiężarna, lat 24, w 29,4 tygodniu ciąży z objawami ostrej niewydolności oddechowej dorosłych w przebiegu zakażenia wirusem grypy A (H1N1) została przyjęta na oddział intensywnej terapii. Osiem godzin po przyjęciu chorej rozpoczęto udowo-szyjne, żylno-żylne przezmembranowe natlenianie pozaustrojowe (ECMO). W 7. dobie leczenia, w związku z narastającym zagro-żeniem życia matki i płodu, podjęto decyzję o wykonaniu cięcia cesarskiego (CS) bez wyłączania ECMO. Odstawiono wlew heparyny i po 5 godzinach, w znieczuleniu ogólnym, wykonano CS. Urodziła się dziewczynka, żywa, niedonoszona, o wadze 1200 g. W okresie okołooperacyjnym nie obserwowano powikłań. W 17. dobie leczenia pacjentka została z sukcesem odłączona od ECMO, a 10 dni później wypisana do domu. Dziecko w dobrym stanie ogólnym zostało wypisane do domu 41 dni po urodzeniu.\n\ninfluenzapregnancyECMOcesarean section\n==== Body\nIntroduction\nThe influenza A (H1N1) virus was identified as the cause of the pandemic of 2009. As is the case with seasonal influenza, the pandemic virus A (H1N1) carried the risks of serious complications requiring treatment in an intensive care unit (ICU); pregnant and postpartum women were included in the risk group [1]. Pregnancy is associated with immunological changes, such as increased ventilatory demand as well as decreased functional residual capacity and oncotic pressure, which constitute predisposing factors for serious complications in pregnant and postpartum women when exposed to respiratory infection caused by an influenza virus [1, 2]. Primary viral pneumonia, which leads to the development of adult respiratory distress syndrome (ARDS), is the most serious complication of influenza. The treatment of ARDS should be comprehensive and include a pharmacological strategy (anti-viral and antibiotic treatment), a non-pharmacological strategy (lung protective strategy, recruitment maneuvers, prone position ventilation), and verification of the diagnosis with a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay, as well as a therapy adjunctive to mechanical ventilation – nitric oxide, extracorporeal membrane oxygenation (ECMO), arterial venous carbon dioxide removal, and high-frequency oscillatory ventilation. The following report describes the case of a pregnant woman who developed ARDS as a complication resulting from influenza A (H1N1) and was successfully treated with ECMO, during which an emergency cesarean section (CS) was performed.\n\nCase report\nIn March 2011, a 24-year-old pregnant woman (29.4 weeks of gestation), primigravida, was admitted to the ICU of a teaching hospital with symptoms of acute respiratory failure, having been transferred from the department of internal medicine of a district hospital. In anamnesis, the patient had been ill for the previous 5 days, exhibiting signs of acute upper respiratory tract infection, for which she had been treated on an outpatient basis with antibiotics and antipyretic medication. On admission to the ICU, the patient was in a critical condition, under analgosedation, intubated, and on mechanical ventilation. The mechanical ventilation settings were: controlled mandatory ventilation, volume control, fraction of inspired oxygen (FiO2) – 1.0, positive end-expiratory pressure (PEEP) – 5.0 cmH2O, tidal volume (TV) – 550 mL, respiratory rate (RR) – 22 per minute, with plateau pressure in the respiratory tract (Pplat) – 34 cmH2O, and compliance – 19 mL/cmH2O. Blood pressure was 120/75 mmHg (without catecholamines), sinus tachycardia was 140 beats per minute (bpm), diuresis – 80-100 mL per hour, and body temperature – 36.6°C. Extensive crackling could be heard over both lung fields. Arterial blood gas (ABG) showed profound hypoxia with an oxygenation index PaO2/FiO2 of 48.1, pH of 7.317, and normocapnia. The patient's plain chest PA X-ray image taken on admission to the ICU showed diffuse, almost homogeneous opacity of both lungs (Fig. 1).\n\nFig. 1 Plain chest PA X-ray on admission to the ICU shows diffuse, almost homogeneous opacity of both lungs\n\nLung injury score was established at 3.25 points, which indicated a diagnosis of ARDS. Laboratory tests showed elevated levels of inflammatory response (C-reactive protein, CRP – 195.3 mg/L, N: < 10 mg/L) and infection parameters (procalcitonin, PCT – 0.49 ng/mL, N: < 0.05 ng/mL). The consulting gynecologist found no signs of threatened premature delivery. A decision was made to delay the delivery. Pneumonia was suspected as a complication resulting from the influenza A (H1N1) virus; treatment with oseltamivir, empiric piperacillin/tazobactam, and azithromycin was started. A virological examination was performed using the RT-PCR assay, giving a positive result for the presence of the influenza A (H1N1) virus. Although the parameters of mechanical ventilation were modified (TV of approximately 6 ml/kg), high Pplat (37 cmH2O) and low compliance (17.7 mL/cmH2O) were observed. The ABG (FiO2 1.0) showed PaO2 of 48 mmHg, paCO2 of 48.7 mmHg, and pH of 7.304. A decision was made to place the patient on femoral-jugular veno-venous ECMO, which was commenced 8 hours after admitting the patient to the ICU. Once the ECMO was started, the patient required systemic heparinization. The ECMO flow was kept at 5.4 L/min (cardiac index – 4.56 l/min/m2) with 4500 revolutions per minute; protective lung ventilation was applied (pressure-controlled ventilation) with FiO2 – 0.3, Pplat – 20 cmH2O, RR – 10 per minute, PEEP – 10 cmH2O, and PaO2 kept at 70 mmHg. On the first day of ECMO support, the patient developed symptoms of acute kidney insufficiency, and renal replacement therapy with the use of continuous veno-venous hemodiafiltration was started and maintained for three days until normal diuresis was observed. The values of inflammation and infection parameters gradually dropped. The patient received two 12 mg doses of dexamethasone separated by a one-day interval to accelerate fetal lung maturity. Fetal heart rate (FHR) monitoring was carried out every 2 hours, while cardiotocography (CTG) recordings were performed 2 times a day. On day 6 of ECMO support, an elevation in body temperature (38.8°C) and an increase in inflammation and infection parameters occurred (CRP – 131 mg/L, PCT – 0.46 ng/mL). The results of microbiological tests were negative. The antibiotic therapy was modified – piperacillin/tazobactam and azithromycin were discontinued, and empiric linezolid, cilastatin/imipenem, and fluconazole were commenced. The CTG recordings detected silent oscillation and FHR of 180 bpm. On day 7, the FHR was 190 bpm. A decision was made to perform a cesarean section (CS) without disconnecting the ECMO. The CS (30.3 weeks of gestation) was uneventfully performed under general anesthesia after a five-hour discontinuation of heparin infusion. A female neonate was delivered with Apgar scores of 2 and 5 (respectively at 1, and 5 minutes of life) and a weight of 1200 g. Endotracheal intubation and mechanical ventilation of the newborn were started immediately after delivery. The neonate was transferred to the pediatric ICU for further treatment. Heparin infusion was restarted 14 hours after completing the CS. No bleeding or thromboembolic events within the ECMO circuit were reported. On day 8, the test for the influenza A (H1N1) virus using an RT-PCR assay was repeated; the result was positive. For this reason, oseltamivir was discontinued and zanamivir inhalation was started. On day 10 of ECMO support, the patient's fever subsided. On day 14, a plain chest PA X-ray demonstrated increased aeration in the middle and upper parts of both lung fields with a regression of intra-alveolar changes. Inflammation and infection parameters returned to normal. A 15-day follow-up test was performed with the RT-PCR assay for the presence of the influenza A (H1N1) virus. The result was negative and zanamivir was discontinued. On day 17, the patient was successfully weaned off the ECMO. After two more days, the patient was extubated, and empirical antibiotic therapy was discontinued. On day 23, computed tomography (CT) of the chest was performed, confirming the presence of bilateral multi-lobar infiltrates and radiological symptoms of ARDS (Fig. 2).\n\nFig. 2 CT of the lungs on the 23rd day of treatment shows bilateral multilobar infiltrates and radiological symptoms of ARDS\n\nOn day 27, the patient was discharged in good health. The newborn, having reached a weight of 2000 g, was discharged from the hospital in good health after 41 days. Three months after discharge from the hospital, the mother underwent a follow-up CT chest scan and spirometry. The CT scan revealed regression of the changes in the lungs after treatment (Fig. 3). The spirometry tests did not indicate any abnormalities.\n\nFig. 3 CT of the lungs 3 months after hospital discharge shows the regression of the changes in the lungs after treatment\n\nDiscussion\nInfluenza A (H1N1) infection during pregnancy carries risks for the mother and the fetus. The rate of hospital admission for pregnant women with influenza A (H1N1) is higher than for non-pregnant women. During the 2009 flu pandemic caused by the A (H1N1) virus, studies showed that pregnant women were 7.2 times more likely to be hospitalized and 4.3 times more likely to be admitted to an ICU than non-pregnant women [3]. Mortality among pregnant women with influenza A (H1N1) who had required treatment in the ICU varied according to different sources from 8 to 17.6% [1, 2, 4]. In one group of patients, which included pregnant women, the conventional treatment for ARDS that developed as a result of influenza A (H1N1) was ineffective, and it was then necessary to use ECMO as a rescue therapy [4–6]. This paper presents the use of ECMO on a pregnant woman suffering from ARDS that developed as a result of influenza A (H1N1) infection. In a case such as this, starting ECMO saves the life of the mother, but exposes the fetus to complications associated with systemic heparinization and extracorporeal circulation. Using the quickest possible intervention to deliver the fetus may shorten the ECMO use. It is, however, best to take the risk of starting ECMO, so that the child can reach a later gestational age, which increases the chance of survival. In the case described in this study, a CS was successfully performed using ECMO, and the decision to do this was taken due to the increasing threat to the life of the mother and the fetus. Previously, only one other similar case of performing a CS while using ECMO was mentioned in the scientific literature [7]. In other cases of pregnant women with influenza A (H1N1) requiring the use of ECMO that have been described to date, CS was performed either before starting ECMO or after its discontinuation [4]. The decision to perform a CS while the patient was on ECMO was not easy due to the increased risk of thrombosis from the required duration of heparin discontinuation. Major operations have been successfully performed under urgent conditions with temporary discontinuation of heparin infusion during the use of ECMO [8–10]. The case presented in this article ended with complete success for both the mother and the child. It seems that, while keeping the pros and cons fully in mind, it is worthwhile in certain situations to take the risk of performing a CS while ECMO is being administered. Certainly, the new generation of equipment for ECMO reduces the risk of complications from bleeding or thromboembolic events and makes the procedure safer.\n==== Refs\nReferences\n1 Louie JK Acosta M Jamieson DJ Honein MA Severe 2009 H1N1 influenza in pregnant and postpartum Women in California NEJM 2012 362 27 35 20032319 \n2 Jamieson DJ Honein MA Rasmussen SA Williams JL Swerdlow DL Biggerstaff MS Lindstrom S Louie JK Christ CM Bohm SR Fonseca VP Ritger KA Kuhles DJ Eggers P Bruce H Davidson HA Lutterloh E Harris ML Burke C Cocoros N Finelli L MacFarlane KF Shu B Olsen SJ H1N1 2009 influenza virus infection during pregnancy in the USA Lancet 2009 374 451 458 19643469 \n3 Creanga AA Johnson TF Graitcer SB Hartman LK Al-Samarrai T Schwarz AG Chu SY Sackoff JE Jamieson DJ Fine AD Shapiro-Mendoza CK Jones LE Uyeki TM Balter S Bish C Finelli L Honein MA Severity of 2009 pandemic influenza A (N1N1) virus infection in pregnant women: New York City, May-June 2009 Obstet Gynecol 2010 115 717 726 20308830 \n4 Fine A Dentinger C Johnson TF Kossowski A Steiner-Sichel L Schwarz AG Hartman LK Honein MA Jamieson D Uyeki T Al-Samarrai T Creanga AA Graitcer SB 2009 pandemic influenza A (HH1N1) in pregnant women requiring intensive care – New York City, 2009 MMWR 2010 59 321 326 20339343 \n5 Critical Care Services and 2009 H1N1 influenza in Australia and New Zealand The ANZIC Influenza Investigators N Engl J Med 2009 361 1925 1934 19815860 \n6 Grasselli G Foti G Patroniti N Giuffrida A Cortinovis B Zanella A Pagni F Mergoni M Pesci A Pesenti A A case of ARDS associated with influenza A-H1N1 infection treated with extracorporeal respiratory support Minerva Anestesiol 2009 5 741 745 19940827 \n7 Panarello G Ancona GD Capitanio G Occhipinti G Attardo G Bertani A Arcadipane A Cesarean section during ECMO support Minerva Anestesiol 2011 77 654 657 21525834 \n8 Noorani A Vuylsteke A Lewis C Parameshwar J Catarino P A moribund athlete Lancet 2012 380 74 22770460 \n9 Huang PM Ko WJ Tsai PR Kuo SW Hsu HH Chen JS Lee JM Lee YC Aggressive management of massive hemothorax in patients on extracorporeal membrane oxygenation Asian J Surg 2012 35 16 22 22726559 \n10 Lamb K Cowan S Evans N Pitcher H Moritz T Lazar M Hirose H Cavarocchi N Successful management of bleeding complications in patients supported with extracorporeal membrane oxygenation with primary respiratory failure Perfusion 2012 28 125 131 23104582\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1731-5530", "issue": "11(2)", "journal": "Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery", "keywords": "ECMO; cesarean section; influenza; pregnancy", "medline_ta": "Kardiochir Torakochirurgia Pol", "mesh_terms": null, "nlm_unique_id": "101279148", "other_id": null, "pages": "216-9", "pmc": null, "pmid": "26336425", "pubdate": "2014-06", "publication_types": "D002363:Case Reports", "references": "19643469;22726559;23104582;20032319;19940827;20308830;19815860;21525834;22770460", "title": "A successful cesarean section in a pregnant woman with A (H1N1) influenza requiring ECMO support.", "title_normalized": "a successful cesarean section in a pregnant woman with a h1n1 influenza requiring ecmo support" }	[ { "companynumb": "PL-PFIZER INC-2014202125", "fulfillexpeditecriteria": "1", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "HEPARIN 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, 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A SUCCESSFUL CESAREAN SECTION IN A PREGNANT WOMAN WITH A (H1N1) INFLUENZA REQUIRING ECMO SUPPORT. KARDIOCHIRURGIA I TORAKOCHIRURGIA POLSKA. 2014;11 (2):216-219", "literaturereference_normalized": "a successful cesarean section in a pregnant woman with a h1n1 influenza requiring ecmo support", "qualification": "1", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20140724", "receivedate": "20140724", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10340673, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]
{ "abstract": "BACKGROUND\nPost-transplant lymphoproliferative disorders (PTLDs) represent a spectrum of heterogenetic lymphoid proliferations. PTLD is a serious complication that affects the long-term survival of kidney transplant patients. Imaging examination is an important method for detecting and diagnosing PTLD. Contrast-enhanced ultrasonography (CEUS) and CEUS-guided biopsy are important modalities for tumor detection and diagnosis. In this case, we describe a 69 years old man in whom a native kidney PTLD was confirmed by CEUS.\n\n\nMETHODS\nA 69-year-old male patient who had a kidney transplant 1 year earlier presented with 3 months of progressive myasthenia of both lower limbs associated with amyotrophy and weight loss. Although positron emission tomography/computed tomography (PET-CT) showed a high metabolic lesion in the untransplanted kidney, abdominal contrast enhanced computed tomography cannot detect the lesion in the atrophic left kidney. The above examinations showed that the transplanted kidney was normal. CEUS can detect a homogeneously enhanced lesion in the same location as PET-CT. Subsequently, a biopsy was performed under CEUS guidance, and the final pathological diagnosis was diffuse large B-cell lymphoma. The patient then received the R-CHOP treatment. Unfortunately, pulmonary thromboembolism occurred 2 weeks later, and the patient's condition was not alleviated through active treatment. Finally, the patient's family gave up treatment, and the patient was discharged.\n\n\nCONCLUSIONS\nThe case suggested that CEUS was a valuable imaging method for patient with renal transplantation to detect and diagnose of PTLD.", "affiliations": "Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Guangdong Second People's Hospital, Haizhu District, Guangzhou, 510317, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China. [email protected].", "authors": "Zhang\|Jian-Chao\|JC\|http://orcid.org/0000-0003-0685-2311;Lan\|Hui-Xia\|HX\|;Zhao\|Hui-Juan\|HJ\|;Lei\|Yang-Yang\|YY\|;Ma\|Li\|L\|;Xie\|Xiao-Yan\|XY\|;Lu\|Ming-de\|MD\|;Wang\|Wei\|W\|http://orcid.org/0000-0002-9485-583X", "chemical_list": "D003287:Contrast Media; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1186/s12885-019-6355-0", "fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 635510.1186/s12885-019-6355-0Case ReportApplication of contrast-enhanced ultrasonography in the diagnosis of post-kidney transplant lymphoproliferative disorder in native kidney- a case report http://orcid.org/0000-0003-0685-2311Zhang Jian-Chao [email protected] 1Lan Hui-Xia [email protected] 1Zhao Hui-Juan [email protected] 1Lei Yang-Yang [email protected] 1Ma Li [email protected] 2Xie Xiao-Yan [email protected] 1Lu Ming-de [email protected] 1http://orcid.org/0000-0002-9485-583XWang Wei [email protected] 11 grid.412615.5Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080 People’s Republic of China 2 Department of Medical Ultrasonics, Guangdong Second People’s Hospital, Haizhu District, Guangzhou, 510317 People’s Republic of China 21 11 2019 21 11 2019 2019 19 11352 5 2019 11 11 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\nPost-transplant lymphoproliferative disorders (PTLDs) represent a spectrum of heterogenetic lymphoid proliferations. PTLD is a serious complication that affects the long-term survival of kidney transplant patients. Imaging examination is an important method for detecting and diagnosing PTLD. Contrast-enhanced ultrasonography (CEUS) and CEUS-guided biopsy are important modalities for tumor detection and diagnosis. In this case, we describe a 69 years old man in whom a native kidney PTLD was confirmed by CEUS.\n\nCase presentation\nA 69-year-old male patient who had a kidney transplant 1 year earlier presented with 3 months of progressive myasthenia of both lower limbs associated with amyotrophy and weight loss. Although positron emission tomography/computed tomography (PET-CT) showed a high metabolic lesion in the untransplanted kidney, abdominal contrast enhanced computed tomography cannot detect the lesion in the atrophic left kidney. The above examinations showed that the transplanted kidney was normal. CEUS can detect a homogeneously enhanced lesion in the same location as PET-CT. Subsequently, a biopsy was performed under CEUS guidance, and the final pathological diagnosis was diffuse large B-cell lymphoma. The patient then received the R-CHOP treatment. Unfortunately, pulmonary thromboembolism occurred 2 weeks later, and the patient’s condition was not alleviated through active treatment. Finally, the patient’s family gave up treatment, and the patient was discharged.\n\nConclusion\nThe case suggested that CEUS was a valuable imaging method for patient with renal transplantation to detect and diagnose of PTLD.\n\nKeywords\nContrast-enhanced ultrasonographyBiopsyPost transplantation lymphoproliferativeKidney transplantationNational Natural Science Foundation of ChinaNO.81701701Wang Wei Natural Science Foundation of Guangdong ProvinceNO.2016A030310143Wang Wei Department of Finance of Guangdong ProvinceNo.20160904Wang Wei issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nPost-transplant lymphoproliferative disorders (PTLDs) represent a group of heterogenetic lymphoid proliferations ranging from polyclonal lymphoid proliferation to lymphomas. PTLD occurs after solid organ transplantation and is associated with administration of immunosuppressive agents [1]. Prompt diagnosis of PTLD is critical to prognosis, to prevent the further development of malignant lymphoma [2]. Imaging examination is an important method to detect and diagnose PTLD, including conventional ultrasonography (US), Doppler ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) are important image modalities for characterizing PTLD [3, 4]. However both the iodinated contrast agent for CE-CT and the gadolinium for MRI have potentially nephrotoxic, restricting their use in patients with impaired renal function [5]. Compared with CE-MRI and CE-CT, the contrast agents used for contrast-enhanced ultrasonography (CEUS) are no nephrotoxic and can be safety applied to patients with renal dysfunction. CEUS can also provide real-time visualization of contrast-enhanced patterns, which can be used for differential diagnosis of renal lesions [6]. In addition, the exact real-time aspect of CEUS makes it uniquely suited for interventions [7]. CEUS therefore has gradually become the preferred method to detect and diagnose renal tumors in chronic kidney disease and post-transplant patients in recent years [8, 9]. We report a case of a 69 year old man with a native renal lymphoma associated with PTLD. We describe the contrast-enhanced features of the tumor and the application of a CEUS guided biopsy on the tumor, which is not well visualized using US. To the best of our knowledge this is the first report on CEUS manifestations of native renal lymphoma following renal transplantation.\n\nCase presentation\nA 69-year-old male patient with kidney transplantation was submitted to our hospital for further evaluation and treatment of a left native kidney mass. The patient had chronic kidney disease for 2 years and had undergone dialysis for 10 months before kidney transplantation. The patient had a 20 years history of hypertension (the highest blood pressure: 170/106 mmHg) without diabetes. The patient underwent kidney transplantation 11 months prior to our study, and maintained a triple immunosuppressive regimen that consisted of tacrolimus, mycophenolatemofetil and prednisolone after transplantation. Two months prior, the patient was submitted to the local hospital for progressive myasthenia both lower limbs and weight loss. Routine laboratory tests showed the following: creatinine and urea were normal, but Epstein-Barr virus (EBV) and cytomegalovirus (CMV) IgG antibodies were positive. An MRI of the lumbar showed multiple vertebral bone destruction. A positron emission tomography/computed tomography (PET-CT) scan was then performed for further information, showing an intense FDG accumulation lesion (approximately 1.4 cm, standardized uptake values max: 4.7) in the medial portion of the left untransplanted kidney (Fig. 1a). PET-CT then proposed possible diagnosis of a renal malignant tumor and bone metastasis, but it could not confirm diagnosis. CE-CT was performed with following scanning parameters: tube voltage, 120 kV; tube current, 250 mA; and slice thicknesses, 1 mm and 10 mm. CE-CT (Fig. 1b) and US detect multiple cysts only and cannot find a solid lesion proposed by PET-CT. PET-CT and CE-CT did not reveal any abnormalities in transplanted kidney. To further evaluate the tumor and definite diagnosis, the patient was sent to our department.\nFig. 1 Positron emission tomography/computed tomography (PET-CT) and computed tomography (CT) images of the outer hospital. a PET-CT revealed a 1.4 cm intense FDG uptake (Standardize Uptake Values max: 4.7) lesion (wide arrow) at the medial portion of the left native kidney; b AS the same level of PET-CT, contrast-enhanced CT did not detect any solid lesion in the left native kidney (narrow arrow)\n\n\n\nUltrasonography was performed using the Aplio500 (Toshiba Medical Systems, Tokyo, Japan) equipped with a 375BT convex transducer (frequency range 3.0–6.0 MHz). The transplanted kidney was located in the right iliac fossa, and showed no abnormalities in conventional B-mode and Doppler ultrasonography. Only atrophic untransplanted kidneys with multiple cystic lesions were observed in US (Fig. 2a). Then a bolus of 2.4 ml of SonoVue (Bracco, Milan, Italy) was administered intravenously and flushed by 5.0 ml of 0.9% saline was performed. The examination was performed at a low mechanical index of 0.09. CEUS revealed a completely homogeneously enhancement lesion (approximately 1.3 × 1.1 cm) in the medial portion of the left untransplanted kidney in 33 s post-injected of contrast agent. Enhancement had progressed from the periphery towards the center of the lesion at 20 s post-injection (Fig. 2b). The lesion exhibited completely enhancement at 33 s (Fig. 2c) and was slightly higher enhanced than the surrounding parenchymal. The lesion gradually turned to hypo-enhancement at 90 s (Fig. 2d). These features of CEUS suggested a diagnosis of renal malignancy. Subsequently a biopsy was performed under CEUS –guidance because of poor differentiation between the target and adjacent cysts in US. Then a further bolus of agent was injected, and a BARD automatic biopsy gun with an 18G percutaneous core needle biopsy was repeated under CEUS guidance to enhanced lesion (Fig. 3). Two tissue core samples with 2 cm in length were obtained from the targeted area (Fig. 4a). Histological examination of the specimen provided a diagnosis of diffuse large B-cell lymphoma (DLBCL) (Fig. 4b, c) with immunohistochemistry staining showing positive results for CD20, CD79, Bcl-2 and Bcl-6. Finally, clinical diagnosis was non-Hodgkin’s lymphoma (diffuse large cell, stage III B). Clinicians consider the prognosis very poor and communicate effectively with patients and their families. The patient consented to accepted chemotherapy consisting of rituximab and cyclophosphamide, hydroxydaunomycin, oncovin and prednisolone at the standard dose. Unfortunately, the patient developed deep vein thrombosis in the right side of his lower limb and pulmonary thromboembolism 2 weeks after one cycle chemotherapy. Despite active treatment, the patient’s condition has not been alleviated. Finally, the patient’s family gave up treatment and the patient was discharged.\nFig. 2 The contrast-enhanced ultrasonography features of the tumor in native left kidney .a the tumor (arrow) and cysts (asterisk) are presenting hypoechoic lesions in conventional ultrasonography which is difficult to differentiate from surrounding cysts. b. After injection of contrast agent, the edge of tumor (wide arrow) start enhancing at 20 s, showing hypo-enhancement as surrounding parenchyma. c The lesion achieved peak-enhancement at 33 s, more intense than surrounding kidney parenchyma (narrow arrow). d The lesion gradually turned to hypo-enhancement at 90 s, showing hypo-enhancement in comparison to surrounding parenchyma .The cyst (asterisk) around the lesion still non-enhancing during whole examination\n\n\nFig. 3 Contrast-enhanced ultrasonography guided biopsy of the mass. The needle tip (wide arrow) has correctly been inserted into the completely enhanced mass (narrow arrow)\n\n\nFig. 4 Histological findings of the core needle biopsy specimen from the mass. a The core needle biopsy specimen from the mass; b, c Hematoxylin and eosin staining of specimen from the mass revealed diffuse infiltration of atypical lymphoid cells. (B 10×,C 40×)\n\n\n\nDiscussion and conclusions\nThe incidence of PTLD in kidney transplant patients is approximately 1–10%, and it occurs most frequently during the first year after transplantation. Immunosuppression and EBV infection, are two major factors associated with the progression of PTLD [2] .The Gastrointestinal tract, allograft kidney and abdominal cavity are common sites of PTLD, but it is rare in the native kidney, which has been described in only three studies [10–12]. In previous reports, both US and CE-CT can clearly show the tumor and be used to characterize the tumor. The tumors showed persistent hypo-enhancement throughout the examination with CE-CT. The enhancement pattern of the tumor is the main difference from clear cell renal cell carcinoma, which present avid early hyper-enhancement and early wash-out throughout the examination [13, 14].\n\nIn our case, the tumor showed avid early hyper enhancement on CEUS; however, this was not visible on US and CE-CT. There are three possible explanations for this difference in our case: First, since the microvasculature of the atrophic renal parenchyma was reduced compared to a normal kidney, less iodine contrast agent entered the renal parenchyma [13]. In addition, the tumor was small in size, and there was much less iodine contrast agent entering the tumor. As a result, the tumor presented no enhancement on CE-CT, which caused a failure to distinguish tumors from surrounding cysts. Second, because CEUS contrast material is purely intravascular, it better correlates with the microvessel density of a tumor. Therefore, CEUS is even more sensitive for detection of hypovascular lesions than contrast-enhanced CT [15]. Although the native kidney perfusion reduced in our case, the microvascular density of the tumor is relatively more abundant than the peripheral renal parenchyma. As a result, the tumor appeared hyper enhanced compare to the surrounding renal parenchyma on CEUS. Third, the CE-CT scan often started at 35 s after the beginning of the injection, but the lesion showed peak enhancement at 33 s during CEUS examination. This may result in missing the peak enhancement phase of the tumor on CE-CT. In contrast, real-time CEUS can continually provide information about blood perfusion for the renal lesion after injection, which can offer more diagnostic clues to differential the tumor from adjacent cysts.\n\nUS-guided biopsy is a common clinical method to obtain tissue specimens for histopathological analysis [16]. However, this technique may be unsuccessful when the tumor is poorly differentiated from adjacent structures. CEUS is well placed to address this problem because of its capacity to differentiate between the altered vascularization of a tumor and surrounding structures. CEUS could help further confirm the tumor border and guide the needle to the target area. CEUS also can be used to differentiate enhanced active area from non-enhanced necrotic area. By directing the biopsy needle toward enhanced areas of the lesion, the sample from necrotic parts of the lesion can be reduced [17]. In a previous report, using the contrast agent, the lesion detection rate was increased from 77.3% with US to 92.0% with CEUS during the biopsy, with a 95.2% success rate for CEUS-guided biopsies of these lesions [18, 19]. According to these finding, we performed the biopsy in our patient under the guidance of CEUS. Finally, the pathology of the biopsy specimen confirmed the diagnosis of diffuse large B cell lymphoma.\n\nIn summary, CEUS can provide more useful information than CE-CT to detect and diagnose PTLDs derived from atrophic native kidneys; CEUS-guided biopsy can improve the diagnostic accuracy and success rate of percutaneous biopsy. We believe that CEUS and CEUS-guided biopsy may be an effective method for early screening and diagnosis of native kidney PTLD in kidney transplant patients.\n\nAbbreviations\nCE-CTContrast-enhanced computed tomography\n\nCE-MRIMagnetic resonance imaging\n\nCEUSContrast-enhanced ultrasonography\n\nCMVCytomegalovirus\n\nDLBCLDiffuse large B-cell lymphoma\n\nEBVEpstein-Barr virus\n\nFDGFluorodeoxyglucose F18\n\nPET-CTPositron emission tomography/computed tomography\n\nPTLDPost-transplant lymphoproliferative disorders\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\nDescription\nOur report described the imaging feature of native kidney lymphoma on contrast-enhanced ultrasonography (CEUS) in a post-kidney transplant patient. We found that the lymphoma showed different enhanced pattern in atrophic kidney from the normal kidney. Then, we performed the tumor biopsy under the guidance of CEUS\n\nPublication of clinical datasets\nNot applicable.\n\nAuthors’ contributions\nJCZ design the study and drafting of the manuscript; HXL, HJZ, YYL acquisition the data and images; LM designed and generated all of the submitted Figs; XYX and MDL analysis the data and images; WW interacted with the patient; made substantial contributions to the content and design of the study; critical revision of the manuscript and take accountable for all aspects of the work to ensure the reliability and accuracy of the data. All authors and all authors have made significant contribution to the content of this paper. All authors read and approved the final manuscript.\n\nFunding\nOur work is supported by National Natural Science Foundation of China (No.81701701) (to W.W), Natural Science Foundation of Guangdong Province (No.2016A030310143) (to W.W) and Department of Finance of Guangdong Province (No.20160904) (to W.W). All of the above funding was used to conduct laboratory analyses and cover publication fees.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nThe patient provided written informed consent to publish this report and associated images. We have de-identified demographic information and other specific information of the patient.\n\nCompeting interests\nOur manuscript has been read and approved by all authors and there are no any financial or other interests in the subject matter of the manuscript.\n==== Refs\nReferences\n1. Caillard S Dharnidharka V Agodoa L Bohen E Abbott K Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression Transplantation 2005 80 9 1233 1243 10.1097/01.tp.0000179639.98338.39 16314791 \n2. Opelz G Döhler B Lymphomas after solid organ transplantation: a collaborative transplant study report Am J Transplant 2004 4 2 222 230 10.1046/j.1600-6143.2003.00325.x 14974943 \n3. Ginat DT Purakal A Pytel P Susceptibility-weighted imaging and diffusion-weighted imaging findings in central nervous system monomorphic B cell post-transplant lymphoproliferative disorder before and after treatment and comparison with primary B cell central nervous system lymphoma J Neuro-Oncol 2015 125 2 297 305 10.1007/s11060-015-1903-1 \n4. Pickhardt PJ Siegel MJ Posttransplantation lymphoproliferative disorder of the abdomen: CT evaluation in 51 patients Radiology 1999 213 1 73 78 10.1148/radiology.213.1.r99oc2173 10540643 \n5. Abu JB Leonard AC Sharma Y Katipally S Shields AR Alloway RR Woodle ES Thakar CV Contrast-induced nephropathy in renal transplant recipients: a single center experience Front Med (Lausanne) 2017 4 64 28603715 \n6. Sparchez Z Radu P Sparchez M Crisan N Kacso G Petrut B Contrast enhanced ultrasound of renal masses. A reappraisal of EFSUMB recommendations and possible emerging applications Med Ultrason 2015 17 2 219 226 10.11152/mu.2013.2066.172.fsum 26052574 \n7. Liu BX Huang GL Xie XH Zhuang BW Xie XY Lu MD Contrast-enhanced US-assisted percutaneous nephrostomy: a technique to increase success rate for patients with nondilated renal collecting system Radiology 2017 285 1 293 301 10.1148/radiol.2017161604 28467143 \n8. Chang EH Chong WK Kasoji SK Fielding JR Altun E Mullin LB Kim JI Fine JP Dayton PA Rathmell WK Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease BMC Nephrol 2017 18 1 266 10.1186/s12882-017-0681-8 28793871 \n9. Stock K, Kubler H, Maurer T, Slotta-Huspenina J, Holzapfel K. CEUS-diagnosis of solid renal tumors. Der Radiologe. 2018;58(6):553–62.\n10. Schultz TD Zepeda N Moore RB Post-transplant lymphoproliferative disorder and management of residual mass post chemotherapy: case report Int J Surg Case Rep 2017 38 115 118 10.1016/j.ijscr.2017.07.003 28756359 \n11. Lee M Kim SK Chung YE Choi JY Park MS Lim JS Kim MJ Kim H Necrotic lymphoma in a patient with post-transplantation lymphoproliferative disorder: ultrasonography and CT findings with pathologic correlation Ultrasonography 2015 34 2 148 152 10.14366/usg.14050 25541069 \n12. Chandra A Kaul A Aggarwal V Srivastava D Native kidney posttransplant lymphoproliferative disorder in a renal transplant recipient Saudi J Kidney Dis Transpl 2017 28 4 942 944 28748904 \n13. Ferda J Hora M Hes O Reischig T Kreuzberg B Mirka H Ferdova E Ohlidalova K Baxa J Urge T Computed tomography of renal cell carcinoma in patients with terminal renal impairment Eur J Radiol 2007 63 2 295 301 10.1016/j.ejrad.2007.01.027 17324547 \n14. Trenker C Neesse A Gorg C Sonographic patterns of renal lymphoma in B-mode imaging and in contrast-enhanced ultrasound (CEUS)--a retrospective evaluation Eur J Radiol 2015 84 5 807 810 10.1016/j.ejrad.2014.12.027 25650333 \n15. Quaia E Bertolotto M Cioffi V Rossi A Baratella E Pizzolato R Cov MA Comparison of contrast-enhanced sonography with unenhanced sonography and contrast-enhanced CT in the diagnosis of malignancy in complex cystic renal masses AJR Am J Roentgenol 2008 191 4 1239 1249 10.2214/AJR.07.3546 18806171 \n16. Sheafor DH Paulson EK Simmons CM DeLong DM Nelson RC Abdominal percutaneous interventional procedures: comparison of CT and US guidance Radiology 1998 207 3 705 710 10.1148/radiology.207.3.9609893 9609893 \n17. Partovi S Lu Z Kessner R Yu A Ahmed Y Patel IJ Nakamoto DA Azar N Contrast enhanced ultrasound guided biopsies of liver lesions not visualized on standard B-mode ultrasound-preliminary experience J Gastrointest Oncol 2017 8 6 1056 1064 10.21037/jgo.2017.08.17 29299367 \n18. Nolsoe CP Nolsoe AB Klubien J Pommergaard HC Rosenberg J Meloni MF Lorentzen T Use of ultrasound contrast agents in relation to percutaneous interventional procedures: a systematic review and pictorial essay J Ultrasound Med 2018 37 6 1305 1324 10.1002/jum.14498 29230842 \n19. Sparchez Z Radu P Kacso G Sparchez M Zaharia T Al HN Prospective comparison between real time contrast enhanced and conventional ultrasound guidance in percutaneous biopsies of liver tumors Med Ultrason 2015 17 4 456 463 26649339\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "19(1)", "journal": "BMC cancer", "keywords": "Biopsy; Contrast-enhanced ultrasonography; Kidney transplantation; Post transplantation lymphoproliferative", "medline_ta": "BMC Cancer", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003287:Contrast Media; D003520:Cyclophosphamide; D004317:Doxorubicin; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D006801:Humans; D016030:Kidney Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D008232:Lymphoproliferative Disorders; D008297:Male; D011241:Prednisone; D011655:Pulmonary Embolism; D000069283:Rituximab; D014750:Vincristine", "nlm_unique_id": "100967800", "other_id": null, "pages": "1135", "pmc": null, "pmid": "31752767", "pubdate": "2019-11-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9609893;25650333;17324547;28793871;26341369;29299367;28756359;29230842;26649339;10540643;25541069;18806171;28467143;29767316;16314791;28748904;14974943;26052574;28603715", "title": "Application of contrast-enhanced ultrasonography in the diagnosis of post-kidney transplant lymphoproliferative disorder in native kidney- a case report.", "title_normalized": "application of contrast enhanced ultrasonography in the diagnosis of post kidney transplant lymphoproliferative disorder in native kidney a case report" }	[ { "companynumb": "CN-HEALTHCARE PHARMACEUTICALS LTD.-2083736", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": 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null, "reaction": [ { "reactionmeddrapt": "Deep vein thrombosis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WANG W, ZHANG J, LAN H, ZHAO H, LEI Y, MA L, ET AL. 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{ "abstract": "BACKGROUND\nThere are several regimens used in hematopoietic stem cell (HSC) mobilization in multiple myeloma (MM). Cyclophosphamide (Cy) is one of the most commonly used agents, although it does not always result in collecting adequate number of CD34+ cells. Recently, cytarabine (Ara-C) has been proposed as potentially efficient and safe option.\n\n\nOBJECTIVE\nSince the data regarding Ara-C in HSC mobilization is limited, the aim of our study was to compare retrospectively the efficiency and toxicity of G-CSF combined with either Ara-C or Cy in MM patients.\n\n\nMETHODS\nOf a total of 89 patients, 43 received low or intermediate doses of Cy, and 46 were treated with 800 mg/m2 /day of Ara-C administered for two days.\n\n\nRESULTS\nThe mean peak of CD34+ cells/ul in peripheral blood was 132 (range, 84-202) in Ara-C and 51 (range, 29-69) in Cy cohort (p < 0.001). The median number of collected CD34+ cells (×106/kg) was 10.3 (range, 4.2-17.9) vs 4.5 (range, 2.7-8.9), respectively (p < 0.001). Mobilization failure was observed in one patient in Ara-C cohort (2%) and in 8 patients treated with Cy (19%) (p = 0.013). In the Ara-C group 98% of patients obtained more than 4×106 CD34+ cells/kg required for tandem transplantation. Moreover, we observed a trend toward increased paraprotein levels measured at transplant compared to before HSC mobilization in Ara-C cohort and significantly higher transfusion rates in that group.\n\n\nCONCLUSIONS\nOur findings confirm higher HSC mobilization efficacy of Ara-C compared to Cy in MM patients. However, lower transfusions rate and better disease control of Cy may justify its use in some cases.", "affiliations": "Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.", "authors": "Bogucka-Fedorczuk\|Aleksandra\|A\|https://orcid.org/0000-0002-9322-354X;Czyz\|Anna\|A\|;Kalicińska\|Elżbieta\|E\|;Sawicki\|Mateusz\|M\|;Laszkowska-Lewko\|Magdalena\|M\|;Wicherska-Pawłowska\|Katarzyna\|K\|https://orcid.org/0000-0001-6021-1123;Rybka\|Justyna\|J\|;Szeremet\|Agnieszka\|A\|;Prajs\|Iwona\|I\|;Szymczak\|Donata\|D\|;Wróbel\|Tomasz\|T\|", "chemical_list": "D018952:Antigens, CD34; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide", "country": "United States", "delete": false, "doi": "10.1002/jca.21784", "fulltext": null, "fulltext_license": null, "issn_linking": "0733-2459", "issue": "35(4)", "journal": "Journal of clinical apheresis", "keywords": "chemomobilization; cyclophosphamide; cytarabine; hematopoietic stem cells mobilization; hematopoietic stem cells transplantation; multiple myeloma", "medline_ta": "J Clin Apher", "mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001781:Blood Component Removal; D003520:Cyclophosphamide; D003561:Cytarabine; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D012074:Remission Induction; D012189:Retrospective Studies; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "8216305", "other_id": null, "pages": "246-254", "pmc": null, "pmid": "32298020", "pubdate": "2020-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Higher efficacy of intermediate dose cytarabine + G-CSF compared to cyclophosphamide + G-CSF in hematopoietic stem cell mobilization in patients with multiple myeloma.", "title_normalized": "higher efficacy of intermediate dose cytarabine g csf compared to cyclophosphamide g csf in hematopoietic stem cell mobilization in patients with multiple myeloma" }	[ { "companynumb": "PL-AMGEN-POLSP2020142366", "fulfillexpeditecriteria": "2", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "5 MICROGRAM/KILOGRAM, BID, ON THE FIFTH DAY AFTER CHEMOTHERAPY TILL THE LAST APHERESIS DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 TO 2 OR 2 TO 4.5 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "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": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM/SQ. METER, BID (FOR TWO SUBSEQUENT DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KALICINSKA, E. HIGHER EFFICACY OF INTERMEDIATE DOSE CYTARABINE + G?CSF COMPARED TO CYCLOPHOSPHAMIDE + G?CSF IN HEMATOPOIETIC STEM CELL MOBILIZATION IN PATIENTS WITH MULTIPLE MYELOMA. JOURNAL OF CLINICAL APHERESIS. 2020?35(4):246?254", "literaturereference_normalized": "higher efficacy of intermediate dose cytarabine g csf compared to cyclophosphamide g csf in hematopoietic stem cell mobilization in patients with multiple myeloma", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200911", "receivedate": "20200907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18237083, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]
{ "abstract": "Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC), which was previously treated with non-steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2-MBC patients who received Exe-Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the 'everyday clinical practice' population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow-up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe-Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow-up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe-Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long-term survival. Overall, Exe-Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe-Eve is an active and safe therapeutic option for endocrine-sensitive MBC patients in a real-world clinical setting, regardless of treatment lines.", "affiliations": "Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy.;Medical Oncology, San Giuseppe Moscati Hospital, I-83100 Avellino, Italy.;Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', I-80131 Naples, Italy.;Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy.;Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy.;Medical Oncology, Department of Clinical Medicine and Surgery, University of Naples Federico II, I-80131 Naples, Italy.;Medical Oncology, Sacro Cuore di Gesù Fatebenefratelli Hospital, I-82100 Benevento, Italy.;Breast Cancer Unit, Cancer Institute G. Pascale Foundation, I-80131 Naples, Italy.;Medical Oncology, Frattamaggiore Hospital, I-80027 Frattamaggiore, Italy.;Medical Oncology, Santa Maria della Pietà Hospital, I-80035 Nola, Italy.;Medical Oncology, ASL Napoli 2 Nord Hospital, I-80014 Giugliano, Italy.;Medical Oncology, Department of Clinical Medicine and Surgery, University of Naples Federico II, I-80131 Naples, Italy.;Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', I-80131 Naples, Italy.;Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', I-80131 Naples, Italy.", "authors": "Riccardi\|Ferdinando\|F\|;Colantuoni\|Giuseppe\|G\|;Diana\|Anna\|A\|;Mocerino\|Carmela\|C\|;Cartenì\|Giacomo\|G\|;Lauria\|Rossella\|R\|;Febbraro\|Antonio\|A\|;Nuzzo\|Francesco\|F\|;Addeo\|Raffaele\|R\|;Marano\|Ombretta\|O\|;Incoronato\|Pasquale\|P\|;De Placido\|Sabino\|S\|;Ciardiello\|Fortunato\|F\|;Orditura\|Michele\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2018.1672", "fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2018.1672MCO-0-0-1672ArticlesExemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety Riccardi Ferdinando 1Colantuoni Giuseppe 2Diana Anna 3Mocerino Carmela 1Cartenì Giacomo 1Lauria Rossella 4Febbraro Antonio 5Nuzzo Francesco 6Addeo Raffaele 7Marano Ombretta 8Incoronato Pasquale 9De Placido Sabino 4Ciardiello Fortunato 3Orditura Michele 31 Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy2 Medical Oncology, San Giuseppe Moscati Hospital, I-83100 Avellino, Italy3 Division of Medical Oncology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, I-80131 Naples, Italy4 Medical Oncology, Department of Clinical Medicine and Surgery, University of Naples Federico II, I-80131 Naples, Italy5 Medical Oncology, Sacro Cuore di Gesù Fatebenefratelli Hospital, I-82100 Benevento, Italy6 Breast Cancer Unit, Cancer Institute G. Pascale Foundation, I-80131 Naples, Italy7 Medical Oncology, Frattamaggiore Hospital, I-80027 Frattamaggiore, Italy8 Medical Oncology, Santa Maria della Pietà Hospital, I-80035 Nola, Italy9 Medical Oncology, ASL Napoli 2 Nord Hospital, I-80014 Giugliano, ItalyCorrespondence to: Dr Anna Diana, Division of Medical Oncology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 5 Sergio Pansini Street, I-80131 Naples, Italy, E-mail: [email protected] 2018 16 7 2018 16 7 2018 9 3 255 263 29 1 2018 05 6 2018 Copyright: © Riccardi et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC), which was previously treated with non-steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2-MBC patients who received Exe-Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow-up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe-Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow-up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe-Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long-term survival. Overall, Exe-Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe-Eve is an active and safe therapeutic option for endocrine-sensitive MBC patients in a real-world clinical setting, regardless of treatment lines.\n\nendocrine therapyeverolimusmetastatic breast cancerreal-life experience\n==== Body\nIntroduction\nBreast cancer (BC) is the most common malignancy and the leading cause of cancer death in women worldwide. Approximately 75% of BCs are hormone receptor positive (HR+), HER2-negative (HER2-); systemic therapy with endocrine agents represents the mainstay of treatment both in the early and advanced stages of disease (1,2).\n\nConsidering the efficacy and the favorable safety profile of endocrine-directed agents, sequential lines of endocrine therapy (ET) should be the preferred treatment strategy in the advanced setting, except in the case of immediate life-threatening disease or rapid visceral recurrence during adjuvant ET (3,4).\n\nDespite the effectiveness of ET in HR+ advanced BC, disease progression occurs in the majority of patients due to primary or acquired ET resistance.\n\nIn the last two decades, loss of estrogen receptor (ER) expression, ER mutations, alterations in co-regulatory proteins, and the upregulation of different signal transduction pathways have been identified as mechanisms leading to ET failure (5).\n\nAmong these mechanisms of resistance, cross-talk between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mTOR axis and ER signaling plays a key role in BC proliferation and progression and confers endocrine insensitivity to ET.\n\nPreclinical and clinical studies have shown that co-targeting downstream elements of this pathway using mammalian target of rapamycin (mTOR) inhibitors may synergistically increase the antitumoral activity of ET and overcome anti-hormone therapy resistance in BCs (6–8).\n\nEverolimus (Eve) is a mTOR inhibitor which induces apoptosis by blocking S6K1 and 4E-BP1 activation and inhibits cell growth, proliferation, and G1-S transition. Eve in combination with Exemestane (Exe), a steroidal aromatase inhibitor (SAI), was approved in 2012 based on the results of the pivotal BOLERO-2 trial. In this study, dual-blockade significantly improved progression-free survival (PFS), as compared with Exe alone, in non-steroidal AI (NSAI)-pretreated post-menopausal patients affected by HR+/HER2-MBC, while maintaining health-related quality of life (HRQoL) (9–11).\n\nOver the past two years, a new class of drugs, namely, CDK4/6 inhibitors, in combination with letrozole or fulvestrant as first or second-line therapy, respectively, has increasingly been used in the treatment of luminal MBC disease. Despite the impressive results from recently published studies reporting a significant PFS benefit with CDK4-6 inhibitors (palbociclib, ribociclib, abemaciclib) in combination with ET compared with ET alone, overall survival (OS) data are still awaited and the optimal sequence of ET, as monotherapy or in combination with targeted agents, is still not well established (12–15). However, combination of CDK4-6 inhibitors and letrozole is reasonably expected to become the new gold standard as first-line therapy in post-menopausal patients with HR+/HER2-endocrine sensitive MBC.\n\nNevertheless, it is crucial to acquire data about long-term outcomes and toxicity profile of therapeutic options currently used in everyday clinical practice in order to define the best therapeutic strategy in HR+/HER2-advanced breast cancer (ABC). Of note, the ongoing phase III randomized trial GIM-16 FEVEX (EudraCT n. 2014-004035-38), where MBCs have been randomized to receive Exe-Eve, followed, in case of progression disease, by fulvestrant or vice versa, should define the best therapeutic sequence in second and third line.\n\nIn our multicenter observational study, we retrospectively analyzed data from 264 HR+/HER2-MBC patients who received Exe-Eve combination, following NSAI failure, in different lines of hormonal treatment to evaluate the efficacy and tolerability of this combination in the ‘real world’ setting.\n\nPatients and methods\nThe main aim of our retrospective study was the analysis of activity, efficacy, and safety of Exe-Eve treatment according to the line of therapy. From January 2012 to January 2017, 264 patients with HR+/HER-MBC who received Exe-Eve as first or further line of ET, were eligible for the final analysis. For all patients, inclusion criteria were histologically confirmed diagnosis of HR+ and HER-locally advanced or MBC, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, basal screening for hepatitis B and C, administration of at least one cycle of Exe-Eve until disease progression, unacceptable toxicity or patient refusal, availability of clinical-pathological, radiologic, and laboratory parameters before Exe-Eve treatment, response evaluation, and survival data.\n\nFurthermore, prior therapy with AI was permitted if recurrence had occurred during or within 12 months of completion of adjuvant therapy, or in case of progression during treatment for advanced stage disease; likewise, previous chemotherapy for metastatic disease and palliative radiotherapy on bone and/or brain were permitted. Eve starting dose was 10 mg once a day orally; a dose reduction (5 mg) was chosen by the caring physician in some instances. Supportive measures were allowed and implemented according to individual daily practice. Toxicity data were collected monthly at each patient visit and were classified according to the National Cancer Institute Common Criteria for Adverse Events (NCI-CTCAE), version 4 (16).\n\nAccordingly, in case of toxicity, dose adjustments or temporary interruptions of therapy as well as timing and modality of evaluation were independently implemented by each investigator (as a general rule, Eve dose was reduced for toxicity of grade 2 or higher, while temporary interruption of treatment was proposed for mild toxicities; tumor assessment was carried out every 3 months). Data were retrieved after an anonymization procedure from a centralized database at the Breast Unit of Cardarelli Hospital. Four patients were lost to follow-up, and the study was completed by January 31, 2017. All patients provided written informed consent about the use of their data for future medical research. The Institutional Review Board at ‘F. Magrassi’ Department of Clinical and Experimental Medicine of ‘Luigi Vanvitelli’ University of Campania, Naples (Italy) approved the study.\n\n\nStatistical analysis\nAll continuous data were expressed as mean ± SD, range and median value; frequencies and percentages were reported for categorical variables. Fisher's exact test was used to analyze associations with categorical variables. Survival distribution was estimated by the Kaplan-Meier method with 95% confidence interval (CI) (17). Progression Free Survival (PFS) was defined as the time elapsed between the first Exe-Eve dose to the detection of disease progression or death for any cause. Patients who died of causes other than breast cancer-without experiencing tumor progression-were regarded as censored events at the date of death when computing the PFS rate. Differences in PFS according to clinical parameters or line of treatment were evaluated by the log-rank test and described by the Kaplan-Meier method. For final analysis, the PFS status of all patients was updated within 1 month of January 2017 deadline. Overall survival (OS) was defined as the time from the first cycle of therapy with Exe-Eve to the date of death or last contact. Cox proportional-hazards model was applied to multivariate survival analysis, and P-values and hazard ratios (HRs) with 95% CI were obtained. All significant variables in the univariate model were used to build the multivariate model of survival. Statistical Package for the Social Sciences (SPSS) 20.0 software, (Chicago, IL, USA) was used for statistical analysis and integrated with Medcalc software V.9.4.2.0 (Mariakerke, Belgium). In all analyses, the significance level was specified as P<0.05.\n\nResults\n\nEfficacy\nExe-Eve combination was used as first, second, or third line of ET in 45 (17%), 115 (43.6%), and 104 (39.4%) patients with MBC (total: 264; median age 56 years, range 49-64), respectively. Of these, 192 (72.7%) and 229 (86.7%) received adjuvant chemotherapy and ET, respectively. Furthermore, 128 patients (48.5%) treated with chemotherapy as first line treatment for metastatic disease subsequently received Exe-Eve combination as first (3 patients), second (56 patients), or third (69 patients) hormonal line. The main characteristics of the series are reported in Table I. At the end of the study, 104 patients (39.4%) had died and 156 patients (59.1%) were still alive, while 4 (1.5%) patients were lost to follow-up; thus, 260 patients (43, 114, and 103 in first, second, or third line of treatment, respectively) were eventually considered for survival analysis.\n\nExe-Eve combination was shown to be active in all lines of therapy. Particularly, although no complete response was observed, 105 (39.8%) partial responses, 88 (33.3%) disease stabilizations, and 71 (26.9%) disease progressions were recorded. The overall Disease Control Rate (DCR) was 73.1%, with no statistically significant difference between the different settings (73.3, 79.2 and 66.3% in first, second and third-line therapy, respectively; P=0.105).\n\nAt the time of data censoring, 4.1% of patients were receiving Exe-Eve without evidence of disease progression; median PFS was 9.1 months (95% CI 7.4-10.2) (Fig. 1). At a median follow-up of 42 months, median PFS was 11.6 (95% CI 5.8-17.3), 9.7 (95% CI7.7-10.8), and 7.5 (95% CI 6.0-9.8) months for patients treated with Exe-Eve as first, second, or third line of treatment, respectively, with a statistically significant correlation on univariate analysis with younger age (P=0.024), no previous adjuvant chemotherapy (P=0.028), no previous adjuvant ET (P=0.030), adjuvant ET duration ≥36 months (P=0.013), involvement of liver and/or lung (P=0.054), no previous chemotherapy for metastatic disease (P=0.0050), PS=0 at the start of treatment (P<0.0001). The risk of disease progression between the different subgroups was not statistically significant (log-rank P-value=0.218) (Fig. 2).\n\nOn multivariate analysis, previous adjuvant ET (P=0.001; HR=2.78; 95% CI: 1.68-4.60), previous chemotherapy for advanced disease (P=0.0027; HR=1.39; 95% CI: 1.03-1.89), and poor PS (P=0.002; HR=2.70; 95% CI: 1.67-4.37) were shown to be independent prognostic factors related to poor recurrence rate. Conversely, the risk of progression was significantly lower in patients treated with hormonal drugs for 36 months or longer (HR=0.48; 95% CI: 0.34-0.68) in the adjuvant setting.\n\nMedian OS was 33.0 months (95% CI 25.2-41.2) (Fig. 3); at a median follow-up of 67 months, median OS was 43.1 months (95% CI 23.1-53.2), 31.7 months (95% CI 23.5-44.1) and 27.9 months (95% CI 22.7-38.9) for patients treated with Exe-Eve as first, second, or third line of treatment, respectively (the difference between the different OS medians was not statistically significant, P=0.538) (Fig. 4). On univariate analysis, the variables related to better survival were younger age (≤48 years) (P=0.041), Ki67 ≤20% (P=0.032), duration of adjuvant ET ≥36 months (P=0.028), disease-free interval ≥45 months (P=0.010), no previous chemotherapy for metastatic disease (P=0.001), ECOG PS=0 (P=0.032), duration of treatment with Exe-Eve longer than 6.3 months (P=0.012), partial response (P=0.009), presence of stomatitis (P=0.049), and absence of diabetes during the treatment (P=0.001). Finally, on multivariate analysis, the variables related to a worse outcome were diabetes [P=0.001; HR=2.35; 95% CI 1.52-3.58)] and previous chemotherapy for metastatic disease (P=0.032; HR=1.58; 95% CI 0.92-2.26); conversely, the presence of mucositis correlated with long-term survival (P=0.042; HR=0.64; 95% CI 0.30-0.82).\n\nToxicity\nOverall, Exe-Eve was fairly well tolerated, most toxicities being G1 or 2, while treatment discontinuation was required in 15 patients (5.7%) due to unacceptable toxicity. Particularly, one patient who received Exe-Eve as first line treatment suffered from G4 diarrhea and refused the treatment, 3 patients developed interstitial lung disease requiring hospitalization, and 1 case of persistent G4 neutropenia was registered among second line patients. Finally, in patients subjected to a third line of therapy, 3 cases of G3 pneumonitis, 3 cases of G4 diarrhea, 1 case of persistently increased hepatic transaminases, 1 case of hyperglycemia requiring insulin therapy and a brief hospitalization, and 2 cases of G4 stomatitis were recorded.\n\nTwo hundred and fifty patients were started on full dose Eve, while 16 patients (6%) began treatment with half dose per physician choice; due to toxicities, Eve dosage was reduced to 5 mg in 25 patients (9.45%).\n\nOverall, hematologic toxicity was mild and no G4 events were recorded, with the exception of the neutropenic patient described above. Of note, a significant difference among the three groups of patients was recorded in terms of incidence of G1-3 thrombocytopenia and neutropenia, which occurred more frequently in second and third line, respectively (Table II).\n\nThe most commonly reported extra-hematologic toxicities (all grades) were stomatitis (54.8%), fatigue (39.3%), rash (33.3%), and diarrhea (33.2%), which occurred in more than one third of patients (Table II). Nausea and decreased appetite were recorded in 28.7 and 27.6% of patients, respectively, even if G3-4 adverse events (AEs) were rare (about 1-2%). Elevated serum transaminases, cough, hyperglycemia, pneumonitis/interstitial lung disease were also observed and the majority of G3-4 toxicities occurred in patients treated with Exe-Eve as third line therapy.\n\nDiscussion\nThe outcome of MBC patients is continuously improving because of the availability of new active therapeutic options. The challenge for clinicians is to balance treatment-related toxicity with the likelihood of benefit and cancer-related symptom relief deriving from therapy. For this reason, current clinical guidelines advocate the use of ET as the preferred treatment for HR+, HER2-MBC, unless visceral crisis or concern/proof of endocrine resistance is observed.\n\nRecently, the introduction of CDK4/6 inhibitors in combination with endocrine agents resulted in a significant PFS benefit, however, overall survival data are still missing and there is no consensus on the optimal sequence of ET, that is, as monotherapy or in combination with targeted agents (12–15).\n\nCurrently, the combination of Eve and Exe is a widely used regimen for treatment of endocrine sensitive postmenopausal MBC patients progressing after NSAIs therapy. However, current international guidelines suggest taking into account the relevant class-effect AEs of this regimen with regard to the decision to treat, which nonetheless should be made on a case by case basis.\n\nFor this purpose, more experience has to be collected on toxicity profile and efficacy in different subsets of patients (i.e., differing in metastatic sites, performance status, number of prior therapies etc.) in order to help physicians to optimize the therapeutic strategy for each patient.\n\nThe main aim of our observational study was to explore the efficacy and tolerability of Eve-Exe combination, according to the line of therapy, in an unselected population from nine Cancer Centers in Campania region (South Italy). The hypothesis of the association between the onset of side effects and efficacy was also addressed in our analysis.\n\nThe pivotal phase III BOLERO-2 trial showed that dual-blockade based on the association of Eve plus Exe doubled the median PFS compared to Exe alone (7.8 vs. 3.2 by investigator review and 11 vs. 4.1 months by central review, respectively) in patients with HR+, HER2-MBC progressing after prior NSAIs. The clinical benefit rate (CBR), defined as CR+PR+SD ≥24 months, was also better in the Eve-Exe arm with respect to Exe alone arm (51.3% vs. 26.4%, respectively).\n\nOS was a secondary endpoint but did not meet statistical significance despite it was shown to increase (4.4 months) following addition of Eve to Exe (31.0 months in the experimental arm vs. 26.6 months in patients receiving Exe alone) (9–10,18).\n\nThe lack of a statistically significant survival gain could be due to the fact that BOLERO-2 trial was powered to detect only an eight-month OS improvement. Furthermore, the small imbalance in post-study salvage chemotherapy use (63 vs. 53%, control vs. experimental arm, respectively) has probably influenced OS results leading to a reduction in the survival gap between the two groups.\n\nIn our retrospective analysis, Exe-Eve combination was shown to be active in all lines of therapy. Particularly, although no complete response was observed, DCR was 73.1%, with no statistically significant difference between the different settings. At a median follow-up of 42 months, median PFS was 11.6, 9.7, and 7.5 months for patients treated with Exe-Eve as first, second, or third line of treatment, respectively. Median OS was 33.0 months; at a median follow-up of 67 months, median OS was 43.1, 31.7, and 27.9 months for patients treated with Exe-Eve as first, second or third line of treatment, respectively. No statistically significant difference in terms of PFS and OS between the different subgroups was detected. Our results confirmed the considerable activity and efficacy of Eve-Exe observed in BOLERO-2, although the safety profile of this combination remains debated. In the BOLERO-2 trial, the most commonly reported AEs, affecting at least one-third of patients in the Eve-Exe arm, were stomatitis, rash, fatigue, diarrhea, nausea, decreased appetite, and pneumonitis. While most AEs were low grade (G1-2), one-half of patients in the Eve-Exe arm experienced grade 3-4 toxicities vs. 27% of patients in the placebo plus Exe arm. The discontinuation rate due to AEs was higher with Eve-Exe (9%) compared with the control arm (3%); the most common toxiticies leading to treatment discontinuation in the experimental group included pneumonitis, stomatitis, dyspnea, and fatigue (19). Consistent with BOLERO-2 results, in our analysis, the most frequently described toxicities (all grades) were stomatitis (54.8%), fatigue (39.3%), rash (33.3%), and diarrhea (33.2%), which occurred in more than one third of patients. Treatment discontinuation was registered only in 5.7% of patients and the most common AEs leading to treatment discontinuation were pneumonitis, stomatitis, and diarrhea. In the Italian expanded-access, multicenter BALLET trial, permanent treatment discontinuation due to side effects was reported to be more frequent (17.1% of patients) with respect to our series and was mainly caused by non infectious pneumonitis (NIP), stomatitis, asthenia, and dyspnea. The majority of these toxicities occurred within the first 12 weeks of start of therapy, consistently across all clinical trials (20). Since 2012 approval, several retrospective trials have been carried out to assess the role of Eve-Exe combination in daily clinical practice, providing clinicians with valuable additional data to guide treatment decisions. To our knowledge, five large observational studies have strengthened the role of this combination in patients with HR+, HER2-MBC. With the exception of the Italian trial by Moscetti et al (21), the remaining studies were only presented as abstracts at scientific international conferences on breast cancer.\n\nThe Austrian non-interventional phase 4 STEPAUT study aimed at evaluating efficacy and safety of Eve-Exe according to clinical routine. The second interim analysis on 225 out of 300 enrolled patients was recently presented at San Antonio Breast Cancer Symposium in 2016. Overall, median PFS was 9.5 months, in line with our PFS data (9.1 months). A subgroup analysis was also performed according to Eve dosing and, interestingly, PFS was lower for the 5 mg-group compared to the 10-mg group (6.5 vs. 9.1 months, respectively). However, it should be noted that patients receiving the 5 mg starting dose had unfavorable prognostic factors as well as worse ECOG PS and more prior therapies. The safety profile was consistent with data previously reported in BOLERO-2 trial and, noteworthy, in accordance with our findings, occurrence of stomatitis did not negatively affect PFS. The EVEREXES phase IIIb trial investigated safety and tolerability profiles as primary endpoints and efficacy as a secondary objective. In this trial, 232 post-menopausal women affected by HR+, HER2-MBC were recruited in Eastern countries. The planned interim analysis presented at San Antonio Breast Cancer Symposium by Im et al in December 2015 showed a median PFS of 9.45 months, which is also consistent with our results. The majority of AEs were grade 1-2 and the most common G3-4 toxicities, as expected, included stomatitis, fatigue, hyperglycemia, and NIP. Therefore, this trial confirmed the role of Eve-Exe combination even for the treatment of patients from Asia, Africa and middle Est, a population poorly represented in BOLERO-2 (<10% of all series). Furthermore, a large, multicenter, non interventional study from Germany (BRAWO trial) including 3,000 patients provided data on the routine clinical use of Eve-Exe therapy. The second interim analysis of BRAWO, presented at the European Society of Medical Oncology (ESMO) in September 2014 by Fasching et al was carried out on 500 patients: A median PFS of 8 months was recorded, with a higher median PFS (10.1 months) for patients treated with Exe-Eve in the first-line setting. These data are still in accordance with our results as an increased PFS of 11.6 months was observed in patients receiving Eve-Exe as first line treatment, even though no statistically significant correlation in terms of risk of disease progression between the different lines of treatment was found. Of note, the third interim analysis of BRAWO study, presented at ESMO in 2015, showed a significantly longer duration of treatment in patients with younger age, better ECOG performance status, and no comorbidities. 4EVER is another German phase IIIb study evaluating the efficacy and safety of Eve-Exe in a broader patient population than that of BOLERO-2. The final efficacy analysis, calculated on 281 patients, was presented at the San Antonio Breast Cancer Symposium in 2015. Efficacy data were poorer compared with those from BOLERO-2, being the median PFS equal to 5.6 months. This may be due to the different patient population enrolled in this trial. In fact, unlike the BOLERO-2 trial, there were less limitations in enrollment criteria, including the number of previous CT lines, the prior use of Exe, or the time to progression after NSAI therapy. Finally, Moscetti et al (21) recently published an Italian retrospective trial assessing the safety of Eve-Exe combination and the possible association between toxicities and previous treatments in 181 unselected patients. On multivariate analysis, no association between the number of prior therapies and toxic events was found, which is in line with the real-life data of the Italian BALLETT-related cohort (20). In this study, a switch from 10 mg Eve starting dose to 5 mg, due to AEs, was reported in 27% of patients, which is a figure quite similar to that reported in BOLERO-2 and EAP. Conversely, in our series, Eve dosage was reduced to 5 mg in about 10% of patients only, perhaps due to the wide use of prophylactic measures and therapeutic interventions for stomatitis management.\n\nAnother important aspect to focus on is the correlation between adverse events and patient characteristics and response to treatment. In this regard, our multivariate analysis showed diabetes and previous chemotherapy for metastatic disease as the variables related to a worse outcome; conversely, the presence of mucositis correlated with long-term survival. Recently, a meta-analysis of data from seven randomized phase III trials of Eve assessing the clinical impact of stomatitis on efficacy in different solid tumors was published (22). Specifically, in BOLERO-2 study, the median PFS was 8.5 vs. 6.9 months for patients receiving Eve with or without stomatitis within 8 weeks, respectively. These results and those of the above mentioned STEPAUT trial are in accordance with our findings and suggest a careful and close monitoring of patients in the first weeks of treatment in order to better manage and prevent stomatitis. In this scenario, the SWISH trial demonstrated that a prophylactic use of a commercially available, non-expensive oral dexamethasone mouthwash resulted in a marked reduction in the incidence and severity of stomatitis in patients receiving Eve-Exe combination for treatment of HR+, HER2-MBC, when compared with data from BOLERO-2. On the basis of these findings, this measure can be considered as a new standard of oral care for BC patients receiving Eve and Exe therapy (23).\n\nIn conclusion, with the limitations due to the observational nature of our findings, addition of Eve to Exe is an effective therapeutic option for HR+, HER2-MBC patients after failure of NSAI therapy in the real word scenario. Patient characteristics, costs, and side effects have to be integrated in the treatment decision making process.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors' contributions\nFR and MO conceived and designed the study. GiuC, AD, CM, GiaC, RL, AF, FN, RA, OM and PI collected the data from the source. Analysis and interpretation of data was performed by FR. AD wrote the first draft for the manuscript. FC and SD performed data collection and critical revision of the article for important intellectual content. All authors approved the final manuscript.\n\nEthics approval and consent to participate\nThe Institutional Review Board at ‘F. Magrassi’ Department of Clinical and Experimental Medicine of ‘Luigi Vanvitelli’ University of Campania, Naples (Italy) approved the study. All patients provided written informed consent for the use of their data.\n\nPatient consent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. mPFS in the overall population. The mPFS in the overall population treated with Everolimus-Exemestane in combination was 9.1 months (95% confidence interval, 7.4-10.2). mPFS, median progression-free survival.\n\nFigure 2. mPFS according to the line of treatment. The mPFS was 11.6 (95% CI, 5.8-17.3), 9.7 (95% CI, 7.7-10.8) and 7.5 (95% CI, 6.0-9.8) months for patients treated with Exe-Eve as first, second or third line of treatment, respectively. mPFS, median progression-free survival; Eve-Exe, Everolimus-Exemestane; CI, confidence interval.\n\nFigure 3. mOS in the overall population. The mOS in the overall population treated with Everolimus-Exemestane in combination was 33.0 months (95% confidence interval 25.2-41.2) mOS, median overall survival.\n\nFigure 4. mOS according to the line of treatment. The mOS was 43.1 (95% CI, 23.1-53.2), 31.7 (95% CI, 23.5-44.1), and 27.9 months (95% CI, 22.7-38.9) for patients treated with Exe-Eve at first, second or third line of treatment, respectively. mOS, median overall survival; Eve-Exe, Everolimus-Exemestane; CI, confidence interval.\n\nTable I. Patient characteristics.\n\nCharacteristic\tExe-Eve as I line of ET (%)\tExe-Eve as II line of ET (%)\tExe-Eve as III line of ET (%)\tTotal (%)\tP-value\t\nTotal\t45\t115\t104\t264\t\t\nAge (years)\t\t\t\t\t0.091\t\n ≤48\t6 (13.3)\t31 (27.0)\t28 (26.9)\t65 (24.6)\t\t\n 49-64\t25 (53.3)\t65 (56.5)\t58 (55.8)\t147 (55.7)\t\t\n ≥65\t15 (33.3)\t19 (16.5)\t18 (17.3)\t52 (19.7)\t\t\nECOG PS\t\t\t\t\t0.724\t\n 0\t37 (82.2)\t100 (87.0)\t90 (86.5)\t227 (86)\t\t\n 1-2\t8 (17.8)\t15 (13.0)\t14 (13.5)\t37 (14.0)\t\t\nSurgery (primary tumor)\t\t\t\t\t0.082\t\n Quadrantectomy\t28 (62.2)\t56 (48.7)\t44 (42.3)\t128 (48.5)\t\t\n Mastectomy/biopsy\t17 (37.8)\t59 (51.3)\t60 (57.7)\t136 (51.5)\t\t\npT\t\t\t\t\t0.082\t\n 1.2\t17 (37.8)\t91 (79.1)\t72 (69.2)\t201 (76.1)\t\t\n 3.4.x\t7 (15.6)\t24 (20.9)\t32 (30.8)\t63 (23.9)\t\t\npN\t\t\t\t\t0.211\t\n 0\t18 (40.0)\t24 (20.8)\t18 (17.3)\t60 (22.7)\t\t\n 1\t10 (22.2)\t26 (22.6)\t26 (25.0)\t62 (23.5)\t\t\n 2\t8 (17.8)\t34 (29.5)\t29 (27.8)\t71 (26.9)\t\t\n 3\t5 (11.1)\t21 (18.2)\t20 (19.2)\t46 (17.4)\t\t\n X\t4 (8.8)\t10 (8.6)\t11 (6.7)\t25 (9.5)\t\t\nGrading\t\t\t\t\t0.510\t\n G1-G2\t17 (37.8)\t52 (45.2)\t50 (48.1)\t119 (45.1)\t\t\n G3\t28 (62.2)\t63 (54.8)\t54 (51.9)\t145 (54.9)\t\t\nER, median (IQR)\t80 (70-90)\t80 (70-90)\t80 (60-90)\t80 (70-90)\t0.252\t\nPgR, median (IQR)\t60 (30-80)\t60 (30-80)\t60 (20-80)\t60 (30-80)\t0.804\t\nKI67\t\t\t\t\t0.852\t\n ≤20%\t22 (48.9)\t56 (48.7)\t47 (45.2)\t125 (47.4)\t\t\n >20%\t23 (51.1)\t59 (51.3)\t57 (54.8)\t139 (52.7)\t\t\nAdjuvant chemotherapy\t\t\t\t\t0.641\t\n Yes\t35 (77.8)\t81 (70.4)\t76 (73.1)\t192 (72.7)\t\t\n No\t10 (22.2)\t34 (29.6)\t28 (26.9)\t72 (27.3)\t\t\nAdjuvant radiotherapy\t\t\t\t\t0.002\t\n Yes\t38 (84.4)\t64 (60)\t56 (53.9)\t163 (61.7)\t\t\n No\t7 (15.6)\t46 (40)\t48 (46.2)\t101 (38.3)\t\t\nAdjuvant ET\t\t\t\t\t0.015\t\n Yes\t45 (100)\t96 (83.5)\t88 (84.6)\t229 (86.7)\t\t\n No\t0 (0)\t19 (16.5)\t16 (15.4)\t35 (13.3)\t\t\nMedian duration of adjuvant ET, months (IQR)\t42 (21-60)\t38 (12-60)\t35.5 (16-60)\t36 (15-60)\t0.711\t\nDisease free interval (from surgery)\t42 (25-93)\t44 (18-84)\t48.5 (22-84)\t45 (21-85)\t0.710\t\n1st site of metastases\t\t\t\t\t0.005\t\n Liver/lung\t11 (24.4)\t13 (11.3)\t10 (9.6)\t34 (12.9)\t\t\n Skin/lymph nodes/peritoneo/pleura\t4 (8.9)\t21 (18.3)\t32 (30.8)\t57 (21.6)\t\t\n Bone\t30 (66.7)\t81 (70.4)\t62 (59.6)\t173 (65.5)\t\t\n2 site of metastases\t\t\t\t\t0.406\t\n No\t20 (44.4)\t61 (53.0)\t56 (53.9)\t137 (51.9)\t\t\n Liver, lung\t13 (28.9)\t20 (17.4)\t16 (15.4)\t49 (18.6)\t\t\n Other\t12 (26.7)\t34 (29.6)\t32 (30.8)\t78 (29.6)\t\t\n3 site of metastases\t\t\t\t\t0.999\t\n No\t41 (91.1)\t105 (91.3)\t95 (91.4)\t241 (91.3)\t\t\n Yes\t4 (8.9)\t10 (8.7)\t9 (8.7)\t23 (8.7)\t\t\n1st line CT for metastatic disease\t\t\t\t\t<0.001\t\n Yes\t3 (6.7)\t56 (48.7)\t69 (66.4)\t128 (48.5)\t\t\n No\t42 (93.3)\t59 (51.3)\t35 (33.7)\t136 (51.5)\t\t\nER, estrogen receptor; PgR, progesterone receptor; CT, computed tomography; ET, endocrine therapy; PS, performance status; IQR, interquartile range.\n\nTable II. Haematological and non-haematological toxicities.\n\nHaematological toxicities\tAll patients (%)\tFirst line (%)\tSecond line (%)\tThird line (%)\tP-valuea\t\nNeutropenia\t\t\t\t\t0.002\t\n G1-2\t36 (13.6)\t2 (4.4)\t12 (10.4)\t22 (21.1)\t\t\n G3-4\t6 (2.2)\t–\t2 (1.7)\t4 (3.8)\t\t\nAnemia\t\t\t\t\t0.788\t\n G1-2\t65 (24.6)\t13 (28.9)\t28 (24.3)\t24 (23.0)\t\t\n G3-G4\t13 (4.9)\t2 (4.4)\t4 (3.5)\t7 (6.7)\t\t\nThrombocytopenia\t\t\t\t\t0.010\t\n G1-2\t32 (12.1)\t–\t18 (15.6)\t14 (13.5)\t\t\n G3-4\t6 (2.28)\t–\t3 (2.6)\t3 (2.9)\t\t\nNon-haematological toxicities\t\t\t\t\t\t\nStomatitis\t\t\t\t\t0.828\t\n G1-2\t120 (45.4)\t15 (33.3)\t55 (47.8)\t50 (48.0)\t\t\n G3-4\t25 (9.5)\t4 (8.9)\t10 (8.7)\t11 (10.6)\t\t\nFatigue\t\t\t\t\t0.279\t\n G1-2\t95 (36.0)\t15 (33.3)\t39 (34.0)\t41 (39.4)\t\t\n G3-4\t9 (3.4)\t–\t3 (2.6)\t6 (5.8)\t\t\nRash\t\t\t\t\t0.778\t\n G1-2\t84 (31.8)\t16 (35)\t36 (31.3)\t32 (30.8)\t\t\n G3-G4\t4 (1.5)\t1 (2.2)\t1 (<0.1)\t2 (1.9)\t\t\nDiarrhea\t\t\t\t\t0.876\t\n G1-2\t76 (28.8)\t15 (33.3)\t29 (25.2)\t32 (30.7)\t\t\n G3-4\t12 (4.5)\t2 (4.0)\t4 (3.5)\t6 (5.7)\t\t\nNausea\t\t\t\t\t0.627\t\n G1-2\t76 (28.7)\t12 (26.7)\t32 (27.8)\t32 (30.8)\t\t\n G3-G4\t3 (1.1)\t–\t1 (<0.1)\t2 (1.9)\t\t\nDecreased appetite\t\t\t\t\t0.727\t\n G1-2\t73 (27.6)\t10 (22.2)\t28 (24.3)\t35 (33.6)\t\t\n G3-G4\t3 (1.1)\t–\t1 (<0.1)\t2 (1.9)\t\t\nAST increase\t\t\t\t\t0.781\t\n G1-2\t28 (10.6)\t5 (11.1)\t11 (9.6)\t12 (11.5)\t\t\n G3-4\t9 (3.4)\t1 (2.2)\t3 (2.6)\t5 (4.8)\t\t\nCough\t\t\t\t\t0.192\t\n G1-2\t31 (11.7)\t5 (11.1)\t12 (10.4)\t14 (13.5)\t\t\n G3-G4\t3 (1.1)\t–\t–\t3 (2.9)\t\t\nALT increase\t\t\t\t\t0.375\t\n G1-2\t24 (9.1)\t5 (11.1)\t10 (8.7)\t9 (8.6)\t\t\n G3-4\t7 (2.6)\t–\t3 (2.6)\t4 (3.8)\t\t\nHyperglicemia\t\t\t\t\t0.472\t\n G1-2\t17 (6.4)\t3 (6.7)\t8 (6.9)\t6 (5.8)\t\t\n G3-4\t5 (1.8)\t–\t2 (1.7)\t3 (2.9)\t\t\nPneumonitis/interstitial lung disease\t\t\t\t\t0.592\t\n G1-2\t13 (4.9)\t2 (4.4)\t4 (3.5)\t7 (6.7)\t\t\n G3-G4\t6 (2.3)\t–\t2 (1.7)\t4 (3.8)\t\t\na Assessed by the chi-squared test. ALT, alanine aminotransferase; AST, aspartate aminotransferase.\n==== Refs\nReferences\n1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D Bray F Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 136 E359 E386 2015 10.1002/ijc.29210 25220842 \n2 Anderson WF Chatterjee N Ershler WB Brawley OW Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database Breast Cancer Res Treat 76 27 36 2002 10.1023/A:1020299707510 12408373 \n3 Cardoso F Costa A Senkus E Aapro M André F Barrios CH Bergh J Bhattacharyya G Biganzoli L Cardoso MJ 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3) Ann Oncol 28 16 33 2017 10.1093/annonc/mdx036 28177437 \n4 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology Breast Cancer Version 1.2018 https://www.nccn.org/professional/physician_gls/pdf/breast.pdf 4 6 2018 \n5 Osborne CK Schiff R Mechanisms of endocrine resistance in breast cancer Annu Rev Med 62 233 247 2011 10.1146/annurev-med-070909-182917 20887199 \n6 Bachelot T Bourgier C Cropet C Ray-Coquard I Ferrero JM Freyer G Abadie-Lacourtoisie S Eymard JC Debled M Spaëth D Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study J Clin Oncol 30 2718 2724 2012 10.1200/JCO.2011.39.0708 22565002 \n7 Baselga J Semiglazov V van Dam P Manikhas A Bellet M Mayordomo J Campone M Kubista E Greil R Bianchi G Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer J Clin Oncol 27 2630 2637 2009 10.1200/JCO.2008.18.8391 19380449 \n8 Boulay A Rudloff J Ye J Zumstein-Mecker S O'Reilly T Evans DB Chen S Lane HA Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer Clin Cancer Res 11 5319 5328 2005 10.1158/1078-0432.CCR-04-2402 16033851 \n9 Baselga J Campone M Piccart M Burris HA III Rugo HS Sahmoud T Noguchi S Gnant M Pritchard KI Lebrun F Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer N Engl J Med 366 520 529 2012 10.1056/NEJMoa1109653 22149876 \n10 Yardley DA Noguchi S Pritchard KI Burris HA III Baselga J Gnant M Hortobagyi GN Campone M Pistilli B Piccart M Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis Adv Ther 30 870 884 2013 10.1007/s12325-013-0060-1 24158787 \n11 Burris HA III Lebrun F Rugo HS Beck JT Piccart M Neven P Baselga J Petrakova K Hortobagyi GN Komorowski A Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial Cancer 119 1908 1915 2013 10.1002/cncr.28010 23504821 \n12 Turner NC Ro J André F Loi S Verma S Iwata H Harbeck N Loibl S Huang Bartlett C Zhang K Palbociclib in hormone-receptor-positive advanced breast cancer N Engl J Med 373 209 219 2015 10.1056/NEJMoa1505270 26030518 \n13 Cristofanilli M Turner NC Bondarenko I Ro J Im SA Masuda N Colleoni M De Michele A Loi S Verma S Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol 17 425 439 2016 10.1016/S1470-2045(15)00613-0 26947331 \n14 Hortobagyi GN Stemmer SM Burris HA Yap YS Sonke GS Paluch-Shimon S Campone M Blackwell KL André F Winer EP Ribociclib as first-line therapy for HR-positive, advanced breast cancer N Engl J Med 375 1738 1748 2016 10.1056/NEJMoa1609709 27717303 \n15 Sledge GW Jr Toi M Neven P Sohn J Inoue K Pivot X Burdaeva O Okera M Masuda N Kaufman PA MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 35 2875 2884 2017 10.1200/JCO.2017.73.7585 28580882 \n16 Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 6 14 2010 US Department of Health and Human Services. National Institutes of Health National Cancer Institute http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_Quick Reference_5×7.pdf 10 8 2017 \n17 Kaplan EL Meier P Nonparametric estimation from incomplete observations J Am Stat Assoc 53 457 481 1958 10.1080/01621459.1958.10501452 \n18 Piccart M Hortobagyi GN Campone M Pritchard KI Lebrun F Ito Y Noguchi S Perez A Rugo HS Deleu I Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Overall survival results from BOLERO-2 Ann Oncol 25 2357 2362 2014 10.1093/annonc/mdu456 25231953 \n19 Rugo HS Pritchard KI Gnant M Noguchi S Piccart M Hortobagyi G Baselga J Perez A Geberth M Csoszi T Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: Insights from BOLERO-2 Ann Oncol 25 808 815 2014 10.1093/annonc/mdu009 24615500 \n20 Jerusalem G Mariani G Ciruelos EM Martin M Tjan-Heijnen VC Neven P Gavila JG Michelotti A Montemurro F Generali D Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: Primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET) Ann Oncol 27 1719 1725 2016 10.1093/annonc/mdw249 27358383 \n21 Moscetti L Vici P Gamucci T Natoli C Cortesi E Marchetti P Santini D Giuliani R Sperduti I Mauri M Safety analysis, association with response and previous treatments of everolimus and exemestane in 181 metastatic breast cancer patients: A multicenter Italian experience Breast 29 96 101 2016 10.1016/j.breast.2016.07.005 27476084 \n22 Rugo HS Hortobagyi GN Yao J Pavel M Ravaud A Franz D Ringeisen F Gallo J Rouyrre N Anak O Motzer R Meta-analysis of stomatitis in clinical studies of everolimus: Incidence and relationship with efficacy Ann Oncol 27 519 525 2016 10.1093/annonc/mdv595 26759276 \n23 Rugo HS Seneviratne L Beck JT Glaspy JA Peguero JA Pluard TJ Dhillon N Hwang LC Nangia C Mayer IA Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): A single-arm, phase 2 trial Lancet Oncol 18 654 662 2017 10.1016/S1470-2045(17)30109-2 28314691\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2049-9450", "issue": "9(3)", "journal": "Molecular and clinical oncology", "keywords": "endocrine therapy; everolimus; metastatic breast cancer; real-life experience", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "255-263", "pmc": null, "pmid": "30155246", "pubdate": "2018-09", "publication_types": "D016428:Journal Article", "references": "25220842;27358383;24158787;22149876;28314691;27476084;27717303;19380449;26759276;12408373;26947331;25231953;28580882;26030518;28177437;23504821;16033851;20887199;24615500;22565002", "title": "Exemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety.", "title_normalized": "exemestane and everolimus combination treatment of hormone receptor positive her2 negative metastatic breast cancer a retrospective study of 9 cancer centers in the campania region southern italy focused on activity efficacy and safety" }	[ { "companynumb": "IT-MYLANLABS-2018M1067006", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203315", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RICCARDI F, COLANTUONI G, DIANA A, MOCERINO C, CARTENI G, LAURIA R, ET AL. EXEMESTANE AND EVEROLIMUS COMBINATION TREATMENT OF HORMONE RECEPTOR POSITIVE, HER2 NEGATIVE METASTATIC BREAST CANCER: A RETROSPECTIVE STUDY OF 9 CANCER CENTERS IN THE CAMPANIA REGION (SOUTHERN ITALY) FOCUSED ON ACTIVITY, EFFICACY AND SAFETY. MOL?CLIN?ONCOL 2018?9(3):255?263.", "literaturereference_normalized": "exemestane and everolimus combination treatment of hormone receptor positive her2 negative metastatic breast cancer a retrospective study of 9 cancer centers in the campania region southern italy focused on activity efficacy and safety", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180912", "receivedate": "20180912", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15374516, "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" } ]
{ "abstract": "Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log¹⁰ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.", "affiliations": "Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine, University of Basel Internal Medicine, University Hospital of Basel, Switzerland.", "authors": "Egli\|A\|A\|;Helmersen\|D S\|DS\|;Taub\|K\|K\|;Hirsch\|H H\|HH\|;Johnson\|A\|A\|", "chemical_list": "D007555:Isoxazoles; D063065:Organophosphonates; D003596:Cytosine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077339:Leflunomide; D009173:Mycophenolic Acid; D000077404:Cidofovir; D011241:Prednisone; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1111/j.1600-6143.2010.03265.x", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "10(10)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": null, "medline_ta": "Am J Transplant", "mesh_terms": "D000328:Adult; D000368:Aged; D000077404:Cidofovir; D003596:Cytosine; D005260:Female; D006801:Humans; D007555:Isoxazoles; D007674:Kidney Diseases; D000077339:Leflunomide; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D063065:Organophosphonates; D027601:Polyomavirus Infections; D011241:Prednisone; D051437:Renal Insufficiency; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus", "nlm_unique_id": "100968638", "other_id": null, "pages": "2324-30", "pmc": null, "pmid": "20840474", "pubdate": "2010-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Renal failure five years after lung transplantation due to polyomavirus BK-associated nephropathy.", "title_normalized": "renal failure five years after lung transplantation due to polyomavirus bk associated nephropathy" }	[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2019-08051", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "BK virus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EGLI A, HELMERSEN DS, TAUB K, HIRSCH HH, ET AL.. RENAL FAILURE FIVE YEARS AFTER LUNG TRANSPLANTATION DUE TO POLYOMAVIRUS BK-ASSOCIATED NEPHROPATHY. AMERICAN JOURNAL OF TRANSPLANTATION. 2010?10(10):2324-2330", "literaturereference_normalized": "renal failure five years after lung transplantation due to polyomavirus bk associated nephropathy", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "JP", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17205892, "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": "BACKGROUND\nEpidural steroid injections are frequently used to treat back and extremity pain. The procedure is generally safe, with a low rate of adverse events, including intrathecal entry, pneumocephalus, and chemical meningitis.\n\n\nMETHODS\nWe report a case of a 45-year-old woman who presented to the emergency department (ED) with headache, nausea, vomiting, and photophobia after a lumbar epidural steroid injection. She was afebrile and had an elevated white blood cell count. A non-contrast computed tomography scan of the head revealed pneumocephalus within the subarachnoid space and lateral ventricles. The patient was admitted to the ED observation unit for pain control and subsequently developed a marked leukocytosis and worsening meningismus. A lumbar puncture was performed yielding cerebrospinal fluid (CSF) consistent with meningitis (1,000 total nucleated cells, 89% neutrophils, 85 mg/dL total protein, and no red blood cells). Gram stain revealed no bacteria. The patient was admitted on empiric vancomycin and ceftriaxone. Antibiotics were discontinued at 48 h when CSF cultures remained negative and the patient was clinically asymptomatic. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should consider intrathecal entry and pneumocephalus in patients who present with a headache after an epidural intervention. The management of pneumocephalus includes supportive therapies, appropriate positioning, and supplemental oxygen. These symptoms can be accompanied by fever, leukocytosis, and markedly inflammatory CSF findings consistent with bacterial or chemical meningitis. Empiric treatment with broad-spectrum antibiotics should be initiated until CSF culture results are available.", "affiliations": "Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Anesthesiology, Penn State Milton S. Hershey Medical Center and Penn State College of Medicine, Hershey, Pennsylvania.;Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.", "authors": "Shah\|Aakash Kaushik\|AK\|;Bilko\|Andrey\|A\|;Takayesu\|James Kimo\|JK\|", "chemical_list": "D013256:Steroids", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0736-4679", "issue": "51(3)", "journal": "The Journal of emergency medicine", "keywords": "chemical meningitis; epidural intervention; epidural steroid injection; headache; intrathecal injection; pneumocephalus", "medline_ta": "J Emerg Med", "mesh_terms": "D005260:Female; D006801:Humans; D007268:Injections, Epidural; D007278:Injections, Spinal; D008581:Meningitis; D008875:Middle Aged; D011007:Pneumocephalus; D013256:Steroids", "nlm_unique_id": "8412174", "other_id": null, "pages": "265-8", "pmc": null, "pmid": "27381953", "pubdate": "2016-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epidural Steroid Injection Complicated by Intrathecal Entry, Pneumocephalus, and Chemical Meningitis.", "title_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis" }	[ { "companynumb": "US-MYLANLABS-2016M1058741", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "091058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "091058", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "0.5%, 2ML", "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": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "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": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. J-EMERG-MED 2016;51(3):265-268.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13088867, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-B. BRAUN MEDICAL INC.-1062847", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "008", "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": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "040", "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": "1", "drugstructuredosageunit": "011", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NORMAL SALINE" }, { "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": null, "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": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "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": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "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": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "019830", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ODANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE SULFATE" }, "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE SULFATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "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, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HCL" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Photophobia", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "19.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO, A AND TAKAYESU, JK. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS AND CHEMICAL MENINGITIS. THE JOURNAL OF EMERGENCY MEDICINE, VOL. 51, NO. 3, PP. 265-268, 2016", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170207", "receivedate": "20170207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13194090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-TEVA-726860USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5%, 2ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "88497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. J-EMERG-MED 2016;51(3):265-268.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170106", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13093930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-PFIZER INC-2016456906", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "011856", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "80 MG, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE SODIUM SUCCINATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO MILLILITERS OF A 0.5%", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH, A.. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS.. JOURNAL OF EMERGENCY MEDICINE. 2016;51 (3):265-268", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171027", "receivedate": "20161003", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12804140, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180320" }, { "companynumb": "PHHY2016US179288", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "12 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "40719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSPENSION FOR INJECTION", "drugdosagetext": "80 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "2 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK.. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. JOURNAL OF EMERGENCY MEDICINE. 2016;51(3):265-8.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170104", "receivedate": "20170104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13086135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-FRESENIUS KABI-FK201700200", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADICULAR PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "006488", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADICULAR PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "040583", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADICULAR PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis aseptic", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Procedural complication", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH A,BILKO A,TAKAYESU J. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. THE JOURNAL OF EMERGENCY MEDICINE 2016;3:265-268.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170106", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13093935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK026061", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 L, BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "011", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALINE /00075401/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO ML MILLILITERS OF A 0.5% LIDOCAINE SOLUTION CONTAINING 80 MG METHYLPREDNISOLONE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "SALINE /00075401/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "TWO ML MILLILITERS OF A 0.5% LIDOCAINE SOLUTION CONTAINING 80 MG METHYLPREDNISOLONE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "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": "BETAMETHASONE DIPROPIONATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "078930", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE DIPROPIONATE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK.. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS.. JOURNAL OF EMERGENCY MEDICINE. 2016;51(3):265-268", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170130", "receivedate": "20170130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13162531, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]
{ "abstract": "BACKGROUND\nA single injection of pegfilgrastim has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, whereas the experiences with pegfilgrastim in mobilization of peripheral blood progenitor cells (PBPCs) are limited.\n\n\nMETHODS\nForty unselected patients with lymphoma or multiple myeloma were treated with different chemotherapy regimens followed by 6 mg of pegfilgrastim for mobilization of autologous PBPCs. Patients with an inadequate mobilization (blood CD34+ cells <or= 10/microL after nadir) were given additional daily doses of 10 microg per kg unconjugated filgrastim.\n\n\nRESULTS\nA median blood CD34+ peak concentration of 81 per microL (range, 10-565/microL) was found in 30 patients, who had only received pegfilgrastim, compared to 13 per microL (median, range 4-71/microL; p < 0.001) in 10 poor mobilizing patients with additional filgrastim. The median yield of CD34+ cells was 9.8 x 10(6) per kg (range, 1.5-88.1) after pegfilgrastim only versus 2.5 x 10(6) (range, 1.7-7.0) in poor mobilizers. Patients who needed additional cytokine administration were those with a more extensive previous antineoplastic treatment and mobilizing regimens containing PBPC toxic agents.\n\n\nCONCLUSIONS\nThe results confirm the efficacy and feasibility of PBPC mobilization with chemotherapy and single-dose pegfilgrastim in patients with lymphoproliferative malignacies. In less heavily pretreated patients, 6 mg of pegfilgrastim after chemotherapy induced an adequate mobilization, whereas dose and schedule in patients after numerous cytotoxic regimens need further investigation.", "affiliations": "1st Medical Department, University Hospital Dresden, Dresden, Germany. [email protected]", "authors": "Kroschinsky\|Frank\|F\|;Hölig\|Kristina\|K\|;Platzbecker\|Uwe\|U\|;Poppe-Thiede\|Kirsten\|K\|;Ordemann\|Rainer\|R\|;Blechschmidt\|Matthias\|M\|;Oelschlaegel\|Uta\|U\|;Schaich\|Markus\|M\|;Hänel\|Mathias\|M\|;Bornhäuser\|Martin\|M\|;Ehninger\|Gerhard\|G\|", "chemical_list": "D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D005047:Etoposide; D003907:Dexamethasone; D000069585:Filgrastim; D008558:Melphalan; D002330:Carmustine", "country": "United States", "delete": false, "doi": "10.1111/j.1537-2995.2006.00911.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1132", "issue": "46(8)", "journal": "Transfusion", "keywords": null, "medline_ta": "Transfusion", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003561:Cytarabine; D003907:Dexamethasone; D005047:Etoposide; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008223:Lymphoma; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012074:Remission Induction; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "0417360", "other_id": null, "pages": "1417-23", "pmc": null, "pmid": "16934080", "pubdate": "2006-08", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Efficacy of single-dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma.", "title_normalized": "efficacy of single dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma" }	[ { "companynumb": "DE-AMGEN-DEUSP2020018797", "fulfillexpeditecriteria": "2", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUPOGEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "125031", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "6 MILLIGRAM, (48 HOURS AFTER CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEULASTA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Aplasia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone pain", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PLATZBECKER U. EFFICACY OF SINGLE-DOSE PEGFILGRASTIM AFTER CHEMOTHERAPY FOR THE MOBILIZATION OF AUTOLOGOUS PERIPHERAL BLOOD STEM CELLS IN PATIENTS WITH MALIGNANT LYMPHOMA OR MULTIPLE MYELOMA. TRANSFUSION. 2006?46:1417-1423", "literaturereference_normalized": "efficacy of single dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17394556, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "DE-AMGEN-DEUSP2020018810", "fulfillexpeditecriteria": "2", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUPOGEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "6 MILLIGRAM, AFTER CHEMO", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEULASTA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PLATZBECKER U. EFFICACY OF SINGLE-DOSE PEGFILGRASTIM AFTER CHEMOTHERAPY FOR THE MOBILIZATION OF AUTOLOGOUS PERIPHERAL BLOOD STEM CELLS IN PATIENTS WITH MALIGNANT LYMPHOMA OR MULTIPLE MYELOMA. TRANSFUSION. 2006?46:1417-1423", "literaturereference_normalized": "efficacy of single dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397411, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]
{ "abstract": "BACKGROUND\nDrug hypersensitivity is classically divided into IgE mediated and non-IgE mediated disease. We report a rare case of consequent IgE mediated and non-IgE mediated reactions within the beta lactam class of antibiotics.\n\n\nMETHODS\nAn 84-year-old man developed toxic epidermal necrolysis (TEN) due to ceftriaxone, a third generation cephalosporin, involving 72% of the body surface area. The patient recovered but within weeks subsequently developed an acute IgE mediated allergic reaction to piperacillin/tazobactam, an extended spectrum penicillin. Further IgE RAST revealed positive results to penicillin major determinant.\n\n\nCONCLUSIONS\nThis case demonstrates the complexity of drug hypersensitivity reactions. While it is accepted that IgE mediated penicillin allergy is a predisposition to cephalosporin allergy, this case displays an unusual correlation between drug hypersensitivity and drug class. There have been few studies that evaluate the cross reactivity with penicillin or other beta-lactams in subjects with primary hypersensitivity to cephalosporins. This clinical scenario emphasizes the need of more studies on cephalosporin allergy in particular as shown by this case of sequential non-IgE mediated cephalosporin induced TEN reaction pursuant by an IgE mediated penicillin allergy.", "affiliations": "UCLA West Los Angeles VA Medical Center 90073, USA. [email protected]", "authors": "Lam\|Amanda\|A\|;Randhawa\|Inderpal\|I\|;Klaustermeyer\|William\|W\|", "chemical_list": "D002511:Cephalosporins; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin", "country": "England", "delete": false, "doi": "10.2332/allergolint.C-07-55", "fulltext": null, "fulltext_license": null, "issn_linking": "1323-8930", "issue": "57(3)", "journal": "Allergology international : official journal of the Japanese Society of Allergology", "keywords": null, "medline_ta": "Allergol Int", "mesh_terms": "D000369:Aged, 80 and over; D002511:Cephalosporins; D004342:Drug Hypersensitivity; D005076:Exanthema; D006801:Humans; D008297:Male; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "9616296", "other_id": null, "pages": "281-4", "pmc": null, "pmid": "18566552", "pubdate": "2008-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem.", "title_normalized": "cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem" }	[ { "companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-07120", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065125", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM (EVERY 4 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sepsis", "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": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065125", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (WAS MISTAKENLY DOSED WITH CEFTRIAXONE AGAIN)", "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" } ], "patientagegroup": null, "patientonsetage": "84", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Lam A, Randhawa I, Klaustermeyer W. Cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem. Allergology International. 2008;57(3):281-287", "literaturereference_normalized": "cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220517", "receivedate": "20220517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20838094, "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": "BACKGROUND\nWe report a case of fungal endophthalmitis which developed after subtenon injections of triamcinolone acetonide (TA).\n\n\nMETHODS\nA 63-year-old man had Graves' ophthalmopathy. He had received subtenon injections of TA in his left eye. He was admitted to Kimura Eye & Internal Medicine Hospital because of a subconjunctival abscess with inflammatory cells in the anterior chamber. Although we treated it as a suspected bacterial infection at the first visit, it deteriorated rapidly. Because prolonged antibiotics and antifungal therapy seemed ineffective, we performed diagnostic surgery. The lower sclera around the subtenon injections of TA was hard and thick, and a white spotty lesion and retinal detachment were seen on the lower retina. A culture of the Tenon sac showed filamentous fungus. After the surgery the subconjunctival abscess recurred because intravenous antifungal therapy had been discontinued. A culture of the abscess identified Alternaria sp. The subconjunctival abscess, thickened sclera, and retinal exudate were limited to the region of the sub-Tenon injection of TA, We conclude that the sclera had been permeated by hyphae of Alternaria sp.\n\n\nCONCLUSIONS\nIn this case, critical infection was caused by the sub-Tenon injections of TA.", "affiliations": "Kimura Eye & Internal Medicine Hospital, Hiroshima, Japan. [email protected]", "authors": "Isshiki\|Yoshihiko\|Y\|;Kimura\|Tohru\|T\|;Yokoyama\|Mitsunobu\|M\|;Kimura\|Wataru\|W\|;Syoge\|Keisuke\|K\|;Ryu\|Momoyoshi\|M\|;Uchida\|Yoshiko\|Y\|;Yoshiki\|Hiroka\|H\|;Suzuki\|Takashi\|T\|", "chemical_list": "D014222:Triamcinolone Acetonide", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0029-0203", "issue": "111(9)", "journal": "Nippon Ganka Gakkai zasshi", "keywords": null, "medline_ta": "Nippon Ganka Gakkai Zasshi", "mesh_terms": "D000528:Alternaria; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D049970:Graves Ophthalmopathy; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D014222:Triamcinolone Acetonide", "nlm_unique_id": "7505716", "other_id": null, "pages": "741-4", "pmc": null, "pmid": "17907469", "pubdate": "2007-09", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Case of fungal endophthalmitis developed after subtenon injections of triamcinolone acetonide.", "title_normalized": "case of fungal endophthalmitis developed after subtenon injections of triamcinolone acetonide" }	[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-01056", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207651", "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": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alternaria infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Infective scleritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ISSHIKI Y, KIMURA T, YOKOYAMA M, KIMURA W AND ET AL.. CASE OF FUNGAL ENDOPHTHALMITIS DEVELOPED AFTER SUBTENON INJECTIONS OF TRIAMCINOLONE ACETONIDE. NIPPON GANKA GAKKAI ZASSHI.. 2007?111:741?4", "literaturereference_normalized": "case of fungal endophthalmitis developed after subtenon injections of triamcinolone acetonide", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180306", "receivedate": "20180306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14601969, "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": "Clinically available targeted agents to treat advanced renal cell carcinoma (RCC) include sunitinib, sorafenib and temsirolimus. Sorafenib and sunitinib have been associated with bleeding in selected trials, but clinical and endoscopic characteristics of gastrointestinal bleeding are not well described. Herein, we report four cases of advanced RCC in which endoscopic hemostasis effectively resolved high-grade, life-threatening gastrointestinal bleeding that occurred during targeted therapy. Although stomatitis and mucositis have occurred during targeted therapies, life-threatening gastrointestinal bleeding is less common. In these four patients, the origins of gastrointestinal bleeding were identified, and complete endoscopic hemostasis was achieved. Endoscopies revealed variable characteristics including angiodysplasia, multiple gastric ulcers and oozing bleeding of the normal mucosa. Although the most effective diagnostic and treatment strategies are disputed, endoscopic examinations are best performed before starting targeted therapies. Additionally, these patients should be monitored even for rare life-threatening events.", "affiliations": "Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Urology, Tottori Red Cross Hospital, Tottori 680-8517, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.", "authors": "Fujihara\|Shintaro\|S\|;Mori\|Hirohito\|H\|;Kobara\|Hideki\|H\|;Nishiyama\|Noriko\|N\|;Ayaki\|Maki\|M\|;Ohata\|Ryo\|R\|;Ueda\|Nobufumi\|N\|;Sugimoto\|Mikio\|M\|;Kakehi\|Yoshiyuki\|Y\|;Masaki\|Tsutomu\|T\|", "chemical_list": null, "country": "Greece", "delete": false, "doi": "10.3892/ol.2015.3671", "fulltext": null, "fulltext_license": null, "issn_linking": "1792-1074", "issue": "10(5)", "journal": "Oncology letters", "keywords": "argon plasma coagulation; gastrointestinal bleeding; sorafenib; sunitinib; targeted therapy; temsirolimus", "medline_ta": "Oncol Lett", "mesh_terms": null, "nlm_unique_id": "101531236", "other_id": null, "pages": "2895-2898", "pmc": null, "pmid": "26722259", "pubdate": "2015-11", "publication_types": "D016428:Journal Article", "references": "8778606;21251188;23841849;22235142;14673156;17538086;22056247;22206873;19615940;11057898;17519900;19767240;19470934", "title": "Uncommon gastrointestinal bleeding during targeted therapy for advanced renal cell carcinoma: A report of four cases.", "title_normalized": "uncommon gastrointestinal bleeding during targeted therapy for advanced renal cell carcinoma a report of four cases" }	[ { "companynumb": "JP-MYLANLABS-2016M1000702", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201275", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AXITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AXITINIB" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200MG/DAY", "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": "SORAFENIB" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLY 800MG/DAY, LATER DOSE REDUCED TO 200MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Interstitial lung disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FUJIHARA S, MORI H, KOBARA H, NISHIYAMA N, AYAKI M, OHATA R, ET AL. UNCOMMON GASTROINTESTINAL BLEEDING DURING TARGETED THERAPY FOR ADVANCED RENAL CELL CARCINOMA: A REPORT OF FOUR CASES. ONCOL-LETT 2015?10(5):2895-2898.", "literaturereference_normalized": "uncommon gastrointestinal bleeding during targeted therapy for advanced renal cell carcinoma a report of four cases", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160111", "receivedate": "20160111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11908570, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160526" } ]
{ "abstract": "BACKGROUND\nBeyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation.\n\n\nMETHODS\nWe retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated.\n\n\nRESULTS\nMedian age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG.\n\n\nCONCLUSIONS\nOur single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.", "affiliations": "Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA.;Department of Radiation Oncology, University of Washington, Seattle, WA, USA.;Department of Laboratories, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Department of Laboratory Medicine, Genetics and Solid Tumor Diagnostics Laboratory, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.;Department of Laboratory Medicine, Genetics and Solid Tumor Diagnostics Laboratory, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA. [email protected].", "authors": "Crotty\|Erin E\|EE\|;Leary\|Sarah E S\|SES\|;Geyer\|J Russell\|JR\|;Olson\|James M\|JM\|;Millard\|Nathan E\|NE\|;Sato\|Aimee A\|AA\|;Ermoian\|Ralph P\|RP\|;Cole\|Bonnie L\|BL\|;Lockwood\|Christina M\|CM\|;Paulson\|Vera A\|VA\|;Browd\|Samuel R\|SR\|;Ellenbogen\|Richard G\|RG\|;Hauptman\|Jason S\|JS\|;Lee\|Amy\|A\|;Ojemann\|Jeffrey G\|JG\|;Vitanza\|Nicholas A\|NA\|http://orcid.org/0000-0002-3966-4985", "chemical_list": "D000068258:Bevacizumab; D000077146:Irinotecan; D000077204:Temozolomide", "country": "United States", "delete": false, "doi": "10.1007/s11060-020-03558-w", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-594X", "issue": "148(3)", "journal": "Journal of neuro-oncology", "keywords": "Bevacizumab; Diffuse intrinsic pontine glioma; Irinotecan; Pediatric high-grade glioma; Temozolomide", "medline_ta": "J Neurooncol", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D020295:Brain Stem Neoplasms; D002648:Child; D002675:Child, Preschool; D000080443:Diffuse Intrinsic Pontine Glioma; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D060787:Neoplasm Grading; D012189:Retrospective Studies; D015996:Survival Rate; D000077204:Temozolomide", "nlm_unique_id": "8309335", "other_id": null, "pages": "607-617", "pmc": null, "pmid": "32556862", "pubdate": "2020-07", "publication_types": "D016428:Journal Article", "references": "28966033;28821206;27157931;30445539;28161497;29280457;31207154;16265674;19147777;21858607;17932894;23592571;17278121;17293590;17031553;26092413;21345842;21339192;19897538;21038110;11051264;24189654;32123717;30833574;30766509;26626490;24050762;29412784;23017588;29763623;25433556;22735884;21666852;27020328;25757751", "title": "Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.", "title_normalized": "children with dipg and high grade glioma treated with temozolomide irinotecan and bevacizumab the seattle children s hospital experience" }	[ { "companynumb": "US-009507513-1905USA009060", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "90 MG/M2/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MILLIGRAM/SQ. METER, EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG TMP/KG/DAY BIW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE (+) TRIMETHOPRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "200 MG/M2/DAY FOR THE FIRST 5 DAYS OF 28 CDAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "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": "DIPHENHYDRAMINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10 MG/KG/DOSE EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HYDROCHLORIDE." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product administered to patient of inappropriate age", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CROTTY EE, LEARY SES, GEYER JR, OLSON JM, MILLARD NE, SATO AA, ET AL.. CHILDREN WITH DIPG AND HIGH?GRADE GLIOMA TREATED WITH TEMOZOLOMIDE, IRINOTECAN, AND BEVACIZUMAB: THE SEATTLE CHILDREN^S HOSPITAL EXPERIENCE. JOURNAL OF NEURO?ONCOLOGY. 2020", "literaturereference_normalized": "children with dipg and high grade glioma treated with temozolomide irinotecan and bevacizumab the seattle children s hospital experience", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200703", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16335516, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" }, { "companynumb": "US-009507513-1905USA006318", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "125 MILLIGRAM/SQ. 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CHILDREN WITH DIPG AND HIGH?GRADE GLIOMA TREATED WITH TEMOZOLOMIDE, IRINOTECAN, AND BEVACIZUMAB: THE SEATTLE CHILDREN^S HOSPITAL EXPERIENCE. JOURNAL OF NEURO?ONCOLOGY. 2020", "literaturereference_normalized": "children with dipg and high grade glioma treated with temozolomide irinotecan and bevacizumab the seattle children s hospital experience", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200704", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16335532, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" } ]
{ "abstract": "Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.", "affiliations": "Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.;Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens' Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy.;Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens' Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy.;Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.;Dialysis and Transplantation Unit, Pediatric Nephrology, Department of Woman's and Child's Health, University Hospital of Padua, 35128 Padua, Italy.;Medical Genetics Unit, Department of Medical and Surgical Science, S. Orsola-Malpighi Hospital_Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Medical Genetics Unit, DIMEC, University of Bologna, 40138 Bologna, Italy.;\"Lalla Seràgnoli\", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.;Pediatric Radiology Unit, Department of Diagnostic and Preventive Medicine, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy.;Immunology Research Area-Unit of Diagnostic Immunology, Unit of B-cell Pathophysiology, Department of Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy.;Pediatric Unit, Department of Woman, Child and Urologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.;\"Lalla Seràgnoli\", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.", "authors": "Bertulli\|Cristina\|C\|;Marzollo\|Antonio\|A\|0000-0003-2177-8500;Doria\|Margherita\|M\|0000-0001-5533-0304;Di Cesare\|Silvia\|S\|0000-0002-9912-7997;La Scola\|Claudio\|C\|0000-0002-2644-7447;Mencarelli\|Francesca\|F\|;Pasini\|Andrea\|A\|;Affinita\|Maria Carmen\|MC\|;Vidal\|Enrico\|E\|0000-0003-3963-0803;Magini\|Pamela\|P\|;Dimartino\|Paola\|P\|;Masetti\|Riccardo\|R\|0000-0002-1264-057X;Greco\|Laura\|L\|0000-0002-3914-8614;Palomba\|Patrizia\|P\|;Conti\|Francesca\|F\|0000-0002-3665-8926;Pession\|Andra\|A\|", "chemical_list": "C000620371:IL7R protein, human; D053699:Interleukin-7 Receptor alpha Subunit; C412482:SMARCAL1 protein, human; D004265:DNA Helicases", "country": "Switzerland", "delete": false, "doi": "10.3390/ijms21228604", "fulltext": "\n==== Front\nInt J Mol Sci\nInt J Mol Sci\nijms\nInternational Journal of Molecular Sciences\n1422-0067 MDPI \n\n33203071\n10.3390/ijms21228604\nijms-21-08604\nArticle\nExpanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells\nBertulli Cristina 1† https://orcid.org/0000-0003-2177-8500Marzollo Antonio 2† https://orcid.org/0000-0001-5533-0304Doria Margherita 3 https://orcid.org/0000-0002-9912-7997Di Cesare Silvia 3 https://orcid.org/0000-0002-2644-7447La Scola Claudio 1 Mencarelli Francesca 1 Pasini Andrea 1 Affinita Maria Carmen 2 https://orcid.org/0000-0003-3963-0803Vidal Enrico 4 Magini Pamela 5 Dimartino Paola 6 https://orcid.org/0000-0002-1264-057XMasetti Riccardo 7 https://orcid.org/0000-0002-3914-8614Greco Laura 8 Palomba Patrizia 9 https://orcid.org/0000-0002-3665-8926Conti Francesca 10‡ Pession Andrea 710‡ 1 Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy; [email protected] (C.B.); [email protected] (C.L.S.); [email protected] (F.M.); [email protected] (A.P.)\n2 Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy; [email protected] (A.M.); [email protected] (M.C.A.)\n3 Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens’ Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy; [email protected] (M.D.); [email protected] (S.D.C.)\n4 Dialysis and Transplantation Unit, Pediatric Nephrology, Department of Woman’s and Child’s Health, University Hospital of Padua, 35128 Padua, Italy; [email protected]\n5 Medical Genetics Unit, Department of Medical and Surgical Science, S. Orsola-Malpighi Hospital_Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy; [email protected]\n6 Medical Genetics Unit, DIMEC, University of Bologna, 40138 Bologna, Italy; [email protected]\n7 “Lalla Seràgnoli”, Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy; [email protected] (R.M.); [email protected] (A.P.)\n8 Pediatric Radiology Unit, Department of Diagnostic and Preventive Medicine, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy; [email protected]\n9 Immunology Research Area—Unit of Diagnostic Immunology, Unit of B-cell Pathophysiology, Department of Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy; [email protected]\n10 Pediatric Unit, Department of Woman, Child and Urologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy\n Correspondence: [email protected] or [email protected]; Tel.: +39-(51)-2144666† These authors contributed equally to the manuscript.\n\n‡ These authors contributed equally to the manuscript.\n\n\n15 11 2020 \n11 2020 \n21 22 860423 9 2020 11 11 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype–genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD—both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.\n\ncongenitalhereditaryneonatal diseases and abnormalitiesconsanguinityDNA methylationimmune system diseases\n==== Body\n1. Introduction\nSchimke immuno-osseous dysplasia (SIOD) (OMIM 242900) is a rare autosomal recessive multisystemic disorder characterized by spondyloepiphyseal dysplasia, growth retardation, renal impairment, and T-cell dysfunction [1,2,3]. Cerebrovascular events, premature atherosclerosis, hypothyroidism, ectodermal abnormalities such as altered tooth development have been described. Patients with SIOD are at increased risk of developing cancer, mainly osteosarcoma, undifferentiated carcinoma, and non-Hodgkin lymphoma [4,5,6,7,8,9]. Early death is common and is mainly related to opportunistic infection or end-stage renal disease.\n\nSchimke immuno-osseous dysplasia is caused by biallelic variants in SMARCAL1, encoding the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A-like protein-1 (SMARCAL-1) from the SWI2/SNF2 family of ATP-dependent chromatin remodeling proteins [10,11,12]. Disease severity inversely correlates with residual SMARCAL1 activity—mild and severe forms of SIOD are associated with missense and predicted loss-of-function (LOF) variants (nonsense, frameshift, or splicing), respectively [13]. SMARCAL1 plays an important role in DNA stabilization and its deficiency leads to the impairment of cellular function due to the accumulation of DNA damage, resulting in a progressive systemic disease. It is still not clear how functional impairment of SMARCAL1 causes such a specific SIOD phenotype represented by alterations in the bones, kidney, and immune system, however it has been shown that proteins encoded by SMARCAL1 orthologs buffer fluctuations in gene expression and that alterations in gene expression contribute to SIOD manifestations [14,15,16]. Cell-mediated immune defects have been partially explained by the lack of IL7Rα expression and IL-7 responsiveness due to hypermethylation of the IL7R promoter in SIOD T cells thus representing a hallmark of T-cell immunodeficiency in SIOD [17].\n\nWe describe two brothers born from consanguineous Moroccan parents, with different clinical courses of SIOD, due to the same homozygous c.1682G>A (p.Arg561His) variant in SMARCAL1.\n\n2. Results\n2.1. Clinical Report\n2.1.1. Patient 1 (P1)\nThe index case was born from consanguineous Moroccan parents (first cousins) at 32 weeks of gestation with a weight and length below the 3rd centile and with a prenatal diagnosis of multiple malformations, including a single umbilical artery, duplication of the choroid plexuses with mild lateral ventriculomegaly, a hypoplastic corpus callosum and cerebellar vermis, cardiovascular anomalies, abdominal calcifications, hyperechogenic bowel, and rocker-bottom feet. After birth liver calcifications, a right ectopic kidney, an atrial septal defect type II, and asymmetric ventriculomegaly were found. Persistent leukopenia and lymphopenia led to the diagnosis of combined immunodeficiency (CID) and the introduction of cotrimoxazole prophylaxis. After birth a right-sided hemiparesis was noted. Cerebral MRI performed at 4 months showed a malacic area located at the lentiform nucleus and external left capsule, with dilatation of the subarachnoid spaces of the insula and left lateral ventricle, consistent with a previous cerebral ischemic event. The exam was repeated 2 years later showing the same alterations (Figure 1).\n\nDuring infancy he suffered from several upper respiratory tract infections and one episode of intestinal amebiasis caused by Entamoeba histolytica. Severe episodes of migraine-like headaches were reported and psychomotor and growth retardation was observed. At the age of four, he attended kindergarten with school support, he had not attained sphincter control and language skills were almost absent; on clinical examination, he presented growth retardation (weight and height below the 3rd centile) and some dysmorphic features—microcephaly, sparse eyebrows, epicanthus, telecanthus, wide nasal root, blue sclerae, prominent metopic, and protruding ears with a thin helix. At the age of five, he presented with steroid-resistant nephrotic syndrome which progressed to chronic kidney disease and was managed with conservative treatment. Detection of hypogammaglobulinemia led to the initiation of intravenous immunoglobulin (IVIg) replacement therapy. The clinical features of the patient associated with the typical skeletal abnormalities (left convex thoracic scoliosis, abnormal femoral heads, and dismorphic vertebrae), led to the suspicion of Schimke immuno-osseous dysplasia (SIOD) (Table 1).\n\n2.1.2. Patient 2 (P2)\nThe younger brother, carrying the same homozygous variant in SMARCAL1, was born at 31 weeks of gestation, with a prenatal diagnosis of intrauterine growth restriction, multicystic left kidney, and a neoformation on the right kidney. Furthermore, hyperpigmented macules on the right arm were reported at birth and oral levothyroxine was started for congenital hypothyroidism. Leukopenia and persistent lymphopenia were detected with an immunological phenotype consistent with a diagnosis of combined immunodeficiency (CID). Moreover, ecochardiography revealed an interatrial defect with pulmonary stenosis. An abdominal MRI scan confirmed the presence of a multicystic left kidney (MCDK) and a mass on the right kidney which was hard to distinguish from the overall kidney parenchyma (Figure 2).\n\nOpen surgical biopsy of the lesion was consistent with classical-type congenital mesoblastic nephroma (CMN). Molecular detection of the ETV6-NTRK3 gene fusion was negative, thus excluding a possible congenital cause of the tumors. The right renal mass associated with the left MCDK caused progressive chronic kidney disease (maximum sCr 2.09 mg/dL) with the presence of residual diuresis. Given the patient’s low body weight, the residual renal function maintained only on a small portion of functional right kidney (not infiltrated by the tumor) and the benign nature of the CMN, warranted a ‘wait-and-see’ approach. Five months later, the nephroma had increased in size to 11 cm causing respiratory distress and reduced oral tolerance with failure to thrive. Chemotherapy with vincristine was started (0.05 mg/kg/dose weekly for 6 weeks), with the aim of reducing the CMN in order to perform nephron-sparing surgery. The treatment successfully reduced the tumor volume to 4.5 cm, but unacceptable toxicity (prolonged grade 4 neutropenia and repeated sepsis), associated with severe psychomotor delay and growth retardation, led to treatment interruption. Therefore, an attempt of surgical removal of the mass was attempted which resulted in a partial debulking only and the patient developed end-stage kidney disease requiring kidney replacement therapy. Unfortunately, the tumor progressed a month later. Thus, vincristine treatment was resumed and 9 weekly doses were administered during the period in which the patient was being treated with IVIg, antifungal mold-active and antiviral prophylaxis. The treatment was well-tolerated, however the tumor continued to expand and infiltrate contiguous structures. Palliative treatment was administered until death at 15 months of age.\n\n2.2. WES Findings\nWES analysis was performed on P1. A mean coverage of 145X was obtained and 98.3% of bases were covered >20X. Two homozygous variants survived the prioritization process (Table 2), but only the p.Arg561His in SMARCAL1 emerged as the most prominent candidate, with a CADD score of 32 and affecting a disease gene causing a clinical condition similar to that presented by the two siblings, Schimke immunoosseous dysplasia (MIM 242900). The homozygous SMARCAL1 variant was also present in P2 and both parents were heterozygous carriers (Figure 3).\n\nThis missense change, mapping in a run of homozygosity (ROH) of about 5 Mb, involved a highly-conserved residue; it was classified as likely pathogenic by Varsome (https://varsome.com/), according to the American College of Medical Genetics (ACMG) guidelines [18], and it had been previously reported in two patients with clinically-diagnosed Schimke immuno-osseous dysplasia (SIOD), in a compound heterozygous state with another variant (c.3G>A, p.Met1Ile) in one case [19] and in a homozygous state in the other one [20,21] (Table 1).\n\n2.3. P1 and P2 Showed a Combined Immunodeficiency Phenotype\nImmunophenotyping of the peripheral blood mononuclear cells (PBMCs) revealed that both patients had significant T-cell lymphopenia characterized by low naïve CD4+ T-cell (CD4+CD45RA+) and CD8+ T-cell (CD8+CD45RA+) counts (Table 3). The frequencies of B cells (CD19+) and NK cells (CD3-CD56+CD16+) were close to those of age-matched controls. P1 and P2 B phenotype showed normal subset distribution compared to age-matched values except for an increased percentage of transitional B cells (CD38++IgM++). After stimulation with CpG oligonucleotide in vitro, B cell proliferation was reduced (Figure 4A) and differentiation into plasmablasts was abolished (Figure 4B). Accordingly, no immunoglobulin production was found in the supernatant (Figure 4C).\n\nThe immunoglobulin levels in both patients’ sera showed a reduction of IgG with normal levels of IgA and IgM. IL-7Rα (CD127) expression on P1 T lymphocytes was severely reduced on total CD3+ and CD4+ cells and almost absent on CD8+ T cells, while the mother’s CD4+ and CD8+ T lymphocytes showed only a slightly decreased CD127 expression (Figure 5).\n\nThe NK-cell compartment was further analyzed in P1 showing a strong expansion of the CD56bright NK-cell subset [45.2% vs. 13.6% (12.9, 15.6), median % (interquartile range, IQR) of Healthy Donors (HDs)], at the expense of CD56dim cells (46.0% vs. median 65.8% (60.0, 69.2) of HDs) (Figure 6A,B). The majority of CD56bright cells in the SIOD patient did not express CD16 and had an immature phenotype, with an overall expansion of CD56brightCD16−NKG2A+NKG2C−CD57− cells (29.7% vs. 13.7% (12.8, 16.2) of HDs; Figure 6C), which has been previously described in children with X-linked severe combined immunodeficiency (X-SCID) [25]. A further analysis of the NK-cell phenotype showed that the patient presented a normal pattern of expression of the NKG2A and KIR inhibitory receptors and DNAM-1 and NKG2D activating receptors (Figure 6D shows comparison with a representative HD). On the other hand, the intracellular levels of perforin, which is highly expressed by virtually all CD56dim cells in HDs, were reduced by 3-fold in the patient’s CD56dim cells (Figure 6E). Moreover, we found that IL-7Rα (CD127) expression, which is typically restricted to the CD56bright subset within NK cells, was present on the patient’s CD56bright cells albeit reduced by 4-fold (Figure 6E). Next, we analyzed the cytotoxicity of the patient’s NK cells against K562 cell targets by measuring the expression of the CD107a degranulation marker. Figure 6F shows that the cytotoxic activity of the patient’s NK cells was strongly reduced when compared with cells of HDs.\n\n3. Discussion\nWe describe two brothers with SIOD carrying the same missense homozygous variant in SMARCAL1, with different clinical manifestations and degrees of severity. P1 presented with growth retardation, stroke, skeletal anomalies, developmental delay (especially language), cardiac and renal malformation and immunodeficiency since birth and he developed severe nephrotic syndrome at 5 years of age. Despite the presence of a combined immunodeficiency, he did not experience any severe infections. P2 presented with MCDK, a clinically-aggressive classical type CMN, growth retardation, hypothyroidism, and combined immunodeficiency. Even though an unclear genotype–phenotype correlation was previously supposed, suggesting milder effects for missense variants and severe consequences for LOF molecular events, the observation of intra- and inter-familial clinical variability revealed that disease severity or outcome cannot be predicted by SMARCAL1 genotype [2,26,27]. Nonetheless, the available literature suggests that missense variants seem to allow for some residual SMARCAL1 function, causing a mild SIOD phenotype, while nonsense, frameshift or splicing variants consistent with a loss-of-function (LOF) mechanism cause the more severe form [2,26]. Both siblings developed a severe SIOD phenotype (onset of disease symptoms in the first year of life, growth failure, nephropathy, abnormal thyroid function, severe infections, and cerebrovascular symptoms). In addition to the well-known SIOD signs and symptoms, they had atypical clinical features, including congenital right ectopic kidney in P1 and MCDK affecting the left kidney associated with nephroma in P2 as well as an atrial septal defect and cerebral anomalies (ventriculomegaly and hypoplasia of the corpus callosum) in P1 and interatrial defect and pulmonary stenosis in P2. Within the spectrum of congenital anomalies of the kidneys and of the urinary tract (CAKUT), ectopic kidney and MCDK have never been reported as a manifestation of SIOD to date. The homozygous p.Arg561His variant has already been described in a patient with early-onset SIOD, who developed non-Hodgkin lymphoma [28]. In this previous study, the SIOD patient, despite immunodeficiency, did not experience recurrent infections or ischemic events, supporting a milder phenotype compared to the siblings presented herein. Moreover, no congenital kidney, heart, or brain anomalies were observed in that patient. A similar mild form of SIOD was described in a patient with a different homozygous change at the same residue (p.Arg561Cys). Severe clinical manifestations were reported in a boy carrying the p.Arg561His variant in the compound heterozygous state with the c.3G>A (p.Met1Ile) change, causing a start loss and generating a predicted truncated protein missing the nuclear location signal [20]. Clinical features of SIOD patients with variants involving the Arg561 residue are summarized in Table 1. The Arg561 residue lies within the helicase ATP-binding domain (amino acids 445–600, Uniprot database, https://www.uniprot.org/) and its substitution with a histidine could interfere with DNA binding and/or ATP hydrolyzation, potentially leading to a LOF effect. All these findings indicate that variants of Arg561 residue are likely responsible for SIOD with variable severity, depending on the resulting amino acid, on the type of alteration on the other allele, and on the individual genomic background. We searched for additional WES pathogenic variants contributing to the complex phenotype of P1, especially to extra-SIOD features. No homozygous variants in disease genes, except the SMARCAL1 variant, were known or predicted to be pathogenic or were previously associated with congenital kidney and heart defects. The evaluation of heterozygous variants excluded the co-occurrence of dominant or recessive (through compound heterozygosity) genetic diseases modifying the typical SIOD phenotype. Unfortunately, the impossibility of extending WES analysis to P2 due to technical issues, prevented us from investigating additional genetic variants underlying his atypical manifestations, especially the congenital mesoblastic nephroma. CMN is a rare tumor in children representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically–classical, cellular, and mixed. Treatment consists of nephrectomy or nephron-sparing surgery at birth. Preoperative chemotherapy with actinomycin and vincristin can be administered [29]. Biological target therapy can be considered in the presence of ETV6-NTRK3 gene fusions [30]. Even though malignancies are reported in SIOD patients, nephroma has never been observed. In a review of 71 patients, two developed Epstein–Barr virus (EBV)-positive, non-Hodgkin lymphoma, one EBV-negative non-Hodgkin lymphoma, and one osteosarcoma [14]; a case of undifferentiated carcinoma has also been reported [5]. Literature regarding the relationship between SMARCAL1 and neoplasia is poor. EBV-driven lymphomas can be attributed to immunodeficiency, but other malignancies reported in SIOD patients are less clearly associated with immune system disorders. SIOD is not currently considered a cancer predisposition syndrome and the incidence of malignancy in these patients is not well described, due to the limited number of cases and short life expectancy. However, members of the SWI/SNF2 family of ATPases are frequently mutated in human cancer, behaving as tumor suppressors, and the function of SMARCAL1 in DNA transcription, replication, and repair could play a role in the development of malignancy if the gene is mutated [31].\n\nRegardless of a possible pathogenetic link, in the study, we describe the first classical-type mesoblastic nephroma in a patient with SIOD (P2) with implications for cancer treatment. In our patient, the tumor showed an unusually aggressive course with transient response to chemotherapy and failure of surgical treatment. It is well known that patients with SIOD are hypersensitive to DNA-damaging agents, so chemotherapy should be administered with caution, and even in the case of a transplant (kidney or bone marrow) a reduced-intensity conditioning must be adopted [14]. Both patients showed a combined immunodeficiency as proven by a profound lymphopenia, a lack of thymic output, and defective IL7Rα expression on lymphocytes. These results are consistent with data already reported in the literature [17]. We also show that B cells have a reduced ability to proliferate and differentiate into plasmablasts in vitro resulting in a lack of immunoglobulin in the supernatant (Figure 4). As IL7 is not necessary for the development of B cells and their response to CpG [32] impaired epigenetic remodeling may explain the altered B cell function [33]. Furthermore, we have characterized the NK-cell compartment of a SIOD patient for the first time, highlighting phenotypic and functional abnormalities. In particular, P1 presented a relative increment of the CD56bright cell subset at the expense of CD56dim cells. In addition, the patient’s NK cells displayed a normal phenotype with the exception of a strong down-modulation of IL-7Rα on CD56bright cells and intracellular perforin in CD56dim cells. In a healthy condition, the highly cytotoxic CD56dim cells represent the vast majority of peripheral NK cells, whereas CD56bright consist in a small percentage of NK cells that are considered to be immature precursors of CD56dim cells, but yet can release large amounts of cytokines and exert immunoregulatory functions (e.g., killing of activated immune cells) [34]. The significance of the increased CD56bright cell frequency that is found in various pathologic settings such as chronic viral infection, cancer, and autoimmunity, is not clear, as yet, and a potential immunosuppressive role has been suggested [26,35]. One possible leading mechanism for accumulation of CD56bright cells is a decreased rate differentiation towards mature CD56dim cells, hence it is possible that the SMARCAL-1 mutation in P1 had a negative impact on NK cell development, although not as dramatic as for T cells. Of note, IL-7Rα expression in our patient was nearly absent on T cells, a previously-reported hallmark of SIOD patients that may restrict T-cell development [17], while it was present, albeit reduced, on CD56bright NK cells. This suggests that the mechanisms controlling IL-7Rα expression are distinct in T and NK cells and that residual IL-7 signalling in the patient’s CD56bright cells is sufficient for their homeostasis. Importantly, IL-7Rα down-modulation on CD56bright NK cells occurring in chronic Hepatitis C Virus (HCV) and HIV infection has been shown to impair IL-7-dependent NK-cell activation and effector functions [36], a phenomenon that deserves to be investigated in SIOD patients as well. Finally, we found an overall impairment of NK cell cytotoxicity, possibly due to the reduced frequency and low perforin content of CD56dim cells, which contribute to the immunological dysfunction and increased risk of developing tumors or severe infections in the SIOD patient.\n\nTaken together these results led us to consider these patients as leaky-SCID and thus evaluable for hematopoietic stem cell transplantation as a therapeutic option to treat the immunodeficiency. In the literature few cases have been reported with poor outcomes for this procedure. Only one affected individual has been successfully treated with bone marrow transplantation (BMT) [14,37] thus this procedure should be considered for the severe phenotype only. Factors described as a possible cause for a poor outcome were a debilitated state of the patient and the potential role of SMARCAL1 in cell hypersensitivity to genotoxic agents. However, the low number of bone marrow transplants and the heterogeneity of the patients’ genotypes and phenotype as well as the diversity of the procedures do not shed light on any specific predictors of outcome. Our knowledge about SIOD is still limited and, considering the rarity of the disease, multicentric studies are necessary in order to identify the best management of these patients.\n\n4. Materials and Methods\n4.1. Subjects and Families/Collection of Samples and Informed Consent \nThe parents of the two siblings with SIOD gave written informed consent for the clinical evaluations and genetic analyses, in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The clinical data for the patients were obtained from questionnaires completed by the attending physician as well as from medical records. Ethics Committee approval was obtained along with written informed consent for data collection (protocol n. 138/2017/U/Tess approved date: 12 December 2017).\n\n4.2. Whole Exome Sequencing/Sanger Sequencing\nGenomic DNA purified from whole peripheral blood samples of P1 was enriched for whole exome sequences through the Roche SeqCap EZ MedExome Kit and sequenced as 100 bp paired-end reads on the Illumina NextSeq 500 system. Quality check for the generated reads was performed with FastQC (http://www.bioinformatics.babraham.ac.uk/ publications.html). Reads were aligned with Burrows-Wheeler Aligner (BWA) to the University of California Santa Cruz (UCSC) reference genome, hg19. Local realignment and base quality score recalibration was performed with Genome Analysis ToolKit (GATK) and duplicate removal with PicardTools (http://picartools.sourceforge.net). SAMtools and GATK were used to collect alignment statistics. Variants passing quality filters were annotated against Ensembl (http://www.ensembl.org/). Since the pedigree suggested a likely recessive disease (two affected siblings born from consanguineous healthy parents), we focused on biallelic, especially homozygous variants. Runs of homozygosity (ROHs) were detected from WES data through the H3M2 algorithm [38].\n\nNovel or very rare homozygous variants (MAF < 0.001) within ROHs > 1.5 Mb were considered for further analyses when they caused predicted loss-of-function alterations or when PhyloP and pathogenicity prediction scores indicated conserved nucleotides and probably damaging affected amino acids for missense changes. The same filtering parameters (frequency, conservation, and functional-prediction scores) were used to identify candidate heterozygous variants potentially contributing to atypical clinical manifestations through a dominant or a recessive (compound heterozygosity) mechanism.\n\nThe quality and amount of the available DNA sample of P2 were not adequate for WES analysis.\n\nSanger sequencing was performed to validate filtered variants and to verify segregation in the healthy parents and affected brother (P2).\n\n4.3. Flow Cytometry Analysis\n4.3.1. Immunophenotype and IL7Ra Membrane Expression\nAfter red blood cell lysis with ammonium chloride of peripheral blood samples, lymphocytes were surface stained for T and B cell analysis. The following previously-titrated monoclonal antibodies were employed to surface stain the lymphocytes: CD3 PerCP (clone BW264/56, Miltenyi Biotec, Bergisch Gladbach, Germany), CD4 APC (clone OKT4, Becton Dickinson, Franklin Lakes, NJ, USA), CD8 PE-Cy7 (clone RPA-T8, Becton Dickinson, USA), TCR alpha-beta APC (clone T10B9, Becton Dickinson), TCR gamma-delta FITC (11F3, Miltenyi Biotec, DE), CD45RA APC-H7 (clone T6D11, Miltenyi Biotec, DE), CCR7 PE (clone 3D12, Ebioscience, San Diego, CA, USA), CD127 PE-CY7 (clone eBioRDR5, eBiosciences), CD16 PE (clone 3G8), CD56 PE (clone NCAM16.2), CD19 PE-CY7 (clone SJ25C1, Becton Dickinson), CD27 FITC (clone M-T271, Becton Dickinson). \n\nNK cell studies were performed on cryopreserved lymphocytes previously isolated through Ficoll density gradient and stained with NKG2A(CD159a) FITC (clone REA110, Miltenyi Biotec), NKG2C (CD159c) PE (clone REA205, Miltenyi Biotec); NKG2D(CD314) PE (clone 1D11, eBioscience), CD3 APC (clone UCHT1, eBioscience), CD16/APC-eFluor780 (clone CB16, eBioscience), CD57/PECy7 (clone TB01, eBioscience); CD3/AlexaFluor700 (clone UCHT1, Becton Dickinson), CD56/PerCpCy5.5 (clone B159, Becton Dickinson), CD16/BV510 (clone 3G8, Becton Dickinson), Perforin/BV421 (clone delta g9, Becton Dickinson), conjugated mouse IgG for isotype control staining (BD Pharmingen); CD56/PerCp (MEM-188) from Thermo Fisher Scientific (Waltham, MA, USA); CD107a/FITC (H4A3), DNAM-1(CD226)/FITC (11A8), NKp46/PE-Cy7 (9E2), KIR2DL1/S1/S3/S5/APC (HP-MA4), and KIR2DL2/L3/S2/APC (DX27) from Biolegend (San Diego, CA, USA). Cells were incubated with the appropriate antibody cocktail for 30 min at 4 °C, washed with PBS and suspended in PBS. For intracellular perforin staining, cells were reacted with FOXP3 Fix/Perm Buffer Set (Biolegend, USA) as recommended by the manufacturer. At least 50,000 events in the lymphocyte live gate were acquired on a FACSCANTO II (BD Biosciences, San Diego, CA, USA) or Cytoflex (Beckman Coulter, Brea, CA, USA) and analyzed with FlowJo (Tree Star Inc, version 9.3.2, Ashland, OR, USA) or Kaluza (Beckman Coulter, Brea, CA, USA) software.\n\n4.3.2. NK-cell Degranulation Assay\nA flow cytometry-based cytotoxicity assay was performed using the patient’s PBMCs as effectors (E) and K562 cells as targets (T) at an E:T ratio of 10:1 and measuring the frequency of CD107a+ cells within gated NK cells, as previously described [19].\n\n4.4. Cell Preparation and B Cell Proliferation Assay\nPBMCs were isolated by Ficoll PaqueTM Plus (Amersham Pharmacia Biotech) density-gradient centrifugation. Lymphocytes were washed in PBS (1×) and before stimulation, peripheral blood mononuclear cells were labelled with Carboxyfluorescein succinimidyl ester (CFSE, Invitrogen) at a final concentration of 0.1 µg/mL (ThermoFisher Scientific) and cultured at 5 × 105 cells per well in 96-well plates in complete Roswell Park Memorial Institute medium (RPMI) 1640 (Euroclone) supplemented with 10% FBS (Hyclone Laboratories, Logan, UT, USA) in the presence or absence of 2.5 µg/mL of CpG oligodeoxynucleotide (ODN 2006, Hycult Biotechnology, Uden, The Netherlands). Cell proliferation was measured on day 7 by flow cytometry.\n\n4.4.1. Flow Cytometric Analysis\nTo evaluate the proliferation and differentiation of B cells after stimulation with CpG, cells were stained with the appropriate combination of fluorochrome-conjugated Abs to identify B cell subsets: CD19 BB700 (clone SJ25C1 Becton Dickinson), CD27 PE (clone M-T271 Becton Dickinson), CD38 BV421 (clone HIT2, Becton Dickinson), and IgM Alexafluor647 (conjugated Affinipure F(ab’)2, Jackson ImmunoResearch Laboratories, West Grove, PA, USA). Dead cells were excluded from analysis by side/forward scatter gating. All analyses were performed on a LSRFortessaX-20 (Becton Dickinson, San Jose, CA, USA) interfaced to a FACSDiva software (BD Biosciences, San Jose, CA, USA). Fifty thousand gated events on living cells were analyzed, whenever possible, for each sample.\n\n4.4.2. ELISA Immunoassay for IgM, IgA, and IgG\nELISA immunoassay was employed to quantify plasma Igs and secreted Igs after stimulation with CpG. 96-well plates (Corning) were coated overnight with purified anti-human IgA, IgG, and IgM (Jackson ImmunoResearch Laboratories, PA, USA). Plates were washed with PBS/0.1% Tween and blocked with PBS/1% gelatin. Subsequently, two incubation steps for 1 h at 37 °C, first with culture supernatants and second with peroxidase-conjugated goat anti-human IgA, IgG, or IgM Abs (Jackons ImmunoResearch Laboratories, PA, USA) were performed. The chromogene substrate employed to developed the assay was o-phenylen-diamine solution (Sigma-Aldrich, St. Louis, MO, USA). Measurement of the absorbance at 450 nm and calculation of Ig concentrations by interpolation from the standard curve were performed lastly.\n\nAcknowledgments\nWe thank for their valuable contribution to this work Simona Ferrari, Giovanni Innella, Fraia Melchionda, Arcangelo Prete, Caterina Cancrini, Simona Cascioli, Rita Carsetti and Alexandra Teff.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nC.B. and A.M. conceptualized the article, participated in the visualization and prepared the original draft. M.D., S.D.C., P.P. participated in the investigation, performed the immunological experiments and the formal analysis of the article. C.L.S., F.M., M.C.A., E.V., R.M., F.M., and L.G. participated in data curation and resources. A.P. (Andrea Pasini) and A.P. (Andra Pession) participated in the validation of the article. P.M., and P.D. participated in the investigation and performed the genetic analysis and the formal analysis of the article. F.C. and A.P. (Andra Pession) participated in the project administration, supervised the work, and reviewed and edited the article. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research was funded by Fondazione Città della Speranza ONLUS (http://cittadellasperanza.org/, to AM), “Fondazione del Monte”, grant for the identification of genetic causes of congenital malformations and intrauterine fetal demise through whole exome sequencing (ID ROL: FDM/6360, to MS), and by the Italian Ministry of Health, Ricerca Corrente from Bambino Gesù Childrens’ Hospital, Rome, Italy to MD.\n\nConflicts of Interest\nThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Cerebral MRI of Patient 1 (P1, index case). (A) Malacic area located at the lentiform nucleus and external left capsule and dilatation of the subaracnoid spaces of the insula and (B) Dilatation of the left lateral ventricle and T2-weighted hypointense lesion compatible with hemoglobin degradation.\n\nFigure 2 Computerized tomography (CT) urogramof Patient 2 (P2) (performed after vincristine therapy and before surgery). (A) Mesoblastic nephroma located in the right kidney (arrow), (B) contrast-enhanced portion of the functioning right kidney located in the superior pole of the nephroma (arrow) without a cleavage plane, and (C) multicystic left kidney (arrow).\n\nFigure 3 Pedigree and family segregation of SMARCAL1 variant (c.1682G>A; p.Arg561His).\n\nFigure 4 Stimulation with CpG. (A) The histograms represent B cell proliferation in a healthy control and P1. B cells were loaded with CFSE dye. The intensity of fluorescence decreased with cell division. The numbers indicate the percentage of B cells that had proliferated. (B) CD27 and IgM expression is determined in P1 and in a healthy donor with or without the addition of CpG (untreated, UNT). Different B cell populations can be recognized—CD27- mature/naive B cells, IgM+CD27+ memory B cells, IgM-CD27+ switched-memory B cells, and CD27bright plasmablasts (either IgM+ or IgM−, arrows). Percentages of these subpopulations in the CD19+ B cells gate are indicated. Black arrows indicate plasmablasts. (C) IgM (white columns), IgA (grey columns), and IgG (black) concentration (µg/mL) in the supernatants after 7 days of stimulation with CpG in a healthy control and in P1.\n\nFigure 5 IL7Rα (CD127) surface expression on T-cell subsets from a healthy donor, P1, and the patient’s mother. (A) Grey histogram plots represent signals from isotype control staining. Note that total CD3+, total CD4+, and total CD8+ uniformly express reduced IL7Rα in P1 and are slightly reduced in the mother. (B,C) IL7Rα (CD127) surface expression of T-cell subsets of a healthy donor, the mother, and P1. Grey histogram plots represent signals from isotype control staining. Note that total CD4+, naive CD4+ cells (CD4+CD27+CD45RA+), central memory CD4+ cells (CD4+CD27+CD45RA and effector memory (CD4+CD45RA-CD27-) uniformly express reduced IL7Rα in P1 and are slightly reduced in the mother. (C) Note that total CD8+, naive CD8+ cells (CD8+CCR7+CD45RA+), central memory CD8+ cells (CD8+-CCR7+CD45RA−), effector memory (CD8+-CCR7-CD45RA−) and terminal effector memory CD45RA+ (CD8+-CCR7-CD45RA+) uniformly express severely-reduced IL7Rα in P1 and are slightly reduced in the mother. Grey numbers represent mean fluorescence intensities (MFI) of the isotype control staining and black numbers represent mean fluorescence intensities of the specific CD127 staining on the different T cell subsets.\n\nFigure 6 Phenotypic and functional alterations of NK cells in the P1 SIOD patient. (A–C) peripheral blood mononuclear cells (PBMCs) of P1 and of age-matched healthy donors (HDs) were analyzed by flow cytometry to measure the frequency of NK-cell subsets, the phenotype of gated CD56bright and CD56dim NK cells (D,E), and the NK-cell cytotoxicity (F). (A) The gating strategy used to identify CD56bright, CD56dim, and CD56neg NK cell subsets is shown for a representative HD and the SIOD patient, (B) Median and range of CD56bright and CD56dim cell frequencies among NK cells of the patient and four HDs is shown; (C) Median and range of CD56bright cell percentage with a CD16-NKG2A+ NKG2C- CD57- immature phenotype among NK cells of P1 and three HDs is depicted, (D) Filled black histograms show the cell surface expression of NKG2A, KIR (KIRmix: KIR2DL1/S1/S3/S5 and KIR2DL2/L3/S2), DNAM-1, NKG2D, and CD127 as well as intracellular perforin expression of gated CD56bright and CD56dim NK cells of P1 and a representative HD. Filled gray histograms represents staining with isotype control IgG. The mean fluorescence intensity (MFI) values for both NK marker labeling (black) and control IgG (gray), as well as the percentage of positive cells are indicated, (E) The values of perforin MFI (left) and CD127 MFI (right) divided by their control IgG MFI values (ratio) measured on CD56bright and CD56dim cells as shown in (D) are reported, (F) Bar plots represent pattern of CD107a expression measured by flow cytometry on gated NK cells of the patient and age-matched (n = 2, circles) and adult (n = 7, triangles) HDs following 6-h culture of PBMCs with and without (not stimulated, ns) K562 cell targets. The mean ± SD is reported.\n\nijms-21-08604-t001_Table 1Table 1 Comparison of clinical features among the two siblings and previously-published cases with at least one mutation involving the same SMARCAL1 residue (p.Arg561).\n\nClinical and Genetic Features\tP1\n(6 Years)\tP2\n(18 Months)\tBasiratnia 2011 \n(8 Years)\tYue 2010 (8 Years)\tBökenkamp 2005 \n(12 Years)\t\n\n\tSMARCAL1 genotype\t\np.Arg561His/\n\n\np.Arg561His\n\t\np.Arg561His/\n\n\np.Arg561His\n\t\np.Arg561His/\n\n\np.Arg561His\n\t\np.Arg561His/\n\n\np.Met1Ile\n\t\np.Arg561Cys/\n\n\np.Arg561Cys\n\t\nClinical features\t\n\t\nGrowth\tIUGR\t+\t+\tNR\t+\t−\t\nShort stature \t+\t+\t+\t+\t+\t\nSkeletal features\tShort neck\t+\t+\t+\t+\t+\t\nShort trunk\t+\t+\tNR\t+\t+\t\nThoracic scoliosis\t+\tNR\tNR\t\n\t+ (kyphosis)\t\nLumbar lordosis\t−\t−\tNR\tNR\t+\t\nDysmorphic vertebrae\t+\t−\t+\t+\t+\t\nHypoplastic pelvis\t−\t−\tNR\tNR\tNR\t\nAbnormal femoral heads\t+\t−\t+\tNR\t+\t\nMicrocephaly\t+\t+\tNR\tNR\tNR\t\nOsteopenia\t−\t−\t+\t+\tNR\t\nRenal disease and malformations\tProteinuria or nephropathy\t+\t+\t+\t+\t+\t\nFSGS\t−\t−\tNR\t+\t+\t\nEctopic kidney\t+\t−\tNR\tNR\tNR\t\nMulticystic kidney\t−\t+\tNR\tNR\tNR\t\nHeart defects\tAtrial septal defects\t+\t+\tNR\tNR\tNR\t\nPulmonary valve stenosis\t−\t+\tNR\tNR\tNR\t\nCerebral anomalies\tVentriculomegaly\t+\t−\tNR\tNR\tNR\t\nHypoplasia corpus callosum\t+\t−\tNR\tNR\tNR\t\nPhysical features \tBroad nasal tip\t−\t−\tNR\t+\tNR\t\nWide and depressed nasal bridge\t−\t−\tNR\t+\t+\t\nProtruding abdomen\t−\t+\t+\t+\t+\t\nPigmented macules\t−\t+\tNR\t+\tNR\t\nUnusual hair\t−\t−\tNR\tNR\tNR\t\nMicrodontia\t−\t−\tNR\tNR\tNR\t\nCorneal opacities\t+\t−\tNR\tNR\tNR\t\nDevelopment\tNeuro-developmental delay\t+\t+\tNR\t−\t−\t\nLanguage development delay\t+\t−\tNR\t−\t−\t\nVasculature\tHeadaches\t+\t−\tNR\tNR\t−\t\nTIAs\t−\t−\tNR\tNR\t−\t\nStrokes\t+\t−\tNR\tNR\t−\t\nOther \tHypothyroidism\t−\t+\t+\t−\t−\t\nNon−Hodgkin lymphoma\n\t−\t−\t+\tNR\tNR\t\nRecurrent infections\t+\t+\t−\t+\t−\t\nMesoblastic nephroma\t−\t+\t−\tNR\tNR\t\nExtremity edema\t−\t−\t+\t+\t+ (minimal)\t\nHypertension\t−\t−\t+\tNR\tNR\t\nNR: Not Reported. +: feature present; −: feature absent.\n\nijms-21-08604-t002_Table 2Table 2 Analysis of WES: potentially interesting variants associated with clinical phenotype.\n\nGenomic Position (hg19)\tcDNA/\nProtein Position\tGene\tROH Size (Mb)\tGnomAD Frequency\tPhyloP100way\nVertebrate\tCADD\tDisease\t\nchr2:\tNM_001127207.2:c.1682G>A/ p.Arg561His\t\nSMARCAL1\n\t5.081\t0.00001593\t7.994\t32\tSIOD\t\n217303180\t\nchr11:\tNM_001198810.2:c.1471G>A/\np.Ala491Thr\t\nSLC43A1\n\t14.523\t0.00003184\t7.537\t23.2\t/\t\n57254630\t\nijms-21-08604-t003_Table 3Table 3 Immunological features of patients P1 and P2.\n\n\n\tP1\tP2\t\n\nSex\n\tMale\tMale\t\n\nAge\n\t7 years\tDied (15 months of age)\t\n\nAge at diagnosis\n\t5 years 6 month\t1 year\t\n\nWhite blood cells, 103/μL\n\t3.04\t4.1\t\n\nHemoglobin, g/L\n\t10.5\t7.4\t\n\nPlatelets, 103/μL\n\t305\t49\t\n\nNeutrophils, 103/μL\n\t2.06\t2.92\t\n\nLymphocytes, 103/μL\n\t0.57\t0.55\t\n(1.2–4.7)\t(3.2–12.3)\t\n\nCD3+ (PAN T), % (cells/µL)\n\t64.2% (0.36)\t30% (0.16)\t\n(0.77–4.0)\t(2.4–8.3)\t\n\nCD3+/α+β\n\t86.60%\t75.40%\t\n\nCD3+/γ+σ+\n\t12.70%\t24.6% \t\n\nCD3+CD4-CD8-, %\n\t1.70%\t27%\t\n\nCD4, % (cells/µL)\n\t24.6% (0.14)\t14% (0.16)\t\n(0.4–2.5) \t(1.3–7.1)\t\n\nCD4+CD45 RA+ (naïve), %\n\t2.40%\t17%\t\n(46–99)\t(77–96)\t\n\nCD4+CD45 RA-CCR7+ (central memory), %\n\t55.60%\tND\t\n(0.35–100)\t\n\nCD4+CD45 RA-CCR7- (effector memory), %\n\t39.40%\tND\t\n(0.27–18)\t\n\nCD4+CD45 RA+CCR7- (terminal effector memory), %\n\t2.37%\tND\t\n(0.0031–1.8)\t\n\nCD3+CD4+CD31+CD45 RA+ (recent thymic emigrant) %\n\t2%\tND\t\n(41–81)\t\n\nCD8, % (cells/µL)\n\t26.6% (0.15)\t10% (0.05)\t\n(0.2–1.7)\t(0.4–4.1)\t\n\nCD8+CD45 RA+ (naïve), %\n\t2%\tND\t\n(16–100)\t\n\nCD8+CD45 RA-CCR7+ (central memory), %\n\t1.57%\tND\t\n(1–6)\t\n\nCD8+CD45 RA-CCR7- (effector memory), %\n\t80%\tND\t\n(5–100)\t\n\nCD8+CD45 RA+CCR7- (terminal effector memory), %\n\t16.50%\tND\t\n(15–41)\t\n\nCD56+16+CD3- (NK), % (cells/µL)\n\t15% (0.08)\t26% (0.14)\t\n(0.012–0.34)\t(0.0075–0.33)\t\n\nCD19 (PAN B), % (cells/µL)\n\t18.4% (0.1)\t42% (0.23)\t\n(0.10–0.80)\t(0.11–7.7)\t\n\nCD19+IgD+CD27- (B naïve)\n\t85%\t94%\t\n(47.3–77.0)\t(76.5–94.7)\t\n\nCD19+IgD+CD27+ (B memory)\n\t8.80%\t1%\t\n(5.2–20.4)\t(3.0–10.7)\t\n\nCD19+IgD-CD27+ (switched B memory)\n\t6.16%\t1.8%\t\n(4.7–21.2)\t(1.4–11.9)\t\n\nCD19+CD21+CD38- (B CD21+low)\n\t0.80%\tND\t\n(5.9–25.8)\t\n\nCD19+IgM++CD38++ (B transitional)\n\t18.40%\t30%\t\n(4.6–8.3)\t(3.6–12.7)\t\n\nCD19+IgM-+CD38++ (B plasmablast)\n\t0.10%\t1%\t\n(0.6–5.3)\t(0.4–5.5)\t\n\nIgM\n\t0.10 g/L\t0.56 g/L\t\n(0.03-0.20) \t(0.02–0.18)\t\n\nIgA\n\t0.10 g/L\t0.10 g/L\t\n(0.02–0.20)\t(0.02–0.15)\t\n\nIgG\n\t0.64 g/L \t1.16 g/L \t\n(0.52–1.49)\t(0.42-1-1)\t\nFISH, fluorescence in situ hybridization; ND, not done; PHA, phyto hemagglutinin; TCR, T-cell receptor; WBC, white blood cell. 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Successful renal transplantation following prior bone marrow transplantation in pediatric patients Pediatr. Transplant. 2004 8 507 512 10.1111/j.1399-3046.2004.00208.x 15367289 \n38. Magi A. Tattini L. Palombo F. Benelli M. Gialluisi A. Giusti B. Abbate R. Seri M. Gensini G.F. Romeo G. H3M2: Detection of runs of homozygosity from whole-exome sequencing data Bioinformatics 2014 30 2852 2859 10.1093/bioinformatics/btu401 24966365\n\n", "fulltext_license": "CC BY", "issn_linking": "1422-0067", "issue": "21(22)", "journal": "International journal of molecular sciences", "keywords": "DNA methylation; congenital; consanguinity; hereditary; immune system diseases; neonatal diseases and abnormalities", "medline_ta": "Int J Mol Sci", "mesh_terms": "D019943:Amino Acid Substitution; D001161:Arteriosclerosis; D004265:DNA Helicases; D005260:Female; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit; D007668:Kidney; D007694:Killer Cells, Natural; D008297:Male; D020125:Mutation, Missense; D018201:Nephroma, Mesoblastic; D009404:Nephrotic Syndrome; D010009:Osteochondrodysplasias; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism; D014551:Urinary Tract; D000073336:Whole Genome Sequencing", "nlm_unique_id": "101092791", "other_id": null, "pages": null, "pmc": null, "pmid": "33203071", "pubdate": "2020-11-15", "publication_types": "D002363:Case Reports; D016430:Clinical Trial; D016428:Journal Article", "references": "29286563;28400540;11113849;19793861;20179009;28769923;15367289;16419127;23630135;23644491;10857751;23359635;16562781;28124468;21815909;28826739;10653321;18805831;15880370;19796992;22699664;16237566;21914180;28796785;11799392;24966365;25741868;29703886;20533385;22888040;2066860;27859047;26499378;17676601;19278419;4282260;18356746", "title": "Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.", "title_normalized": "expanding phenotype of schimke immuno osseous dysplasia congenital anomalies of the kidneys and of the urinary tract and alteration of nk cells" }	[ { "companynumb": "IT-PFIZER INC-2021544556", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "CONGENITAL HYPOTHYROIDISM", "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": "1", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": "UNKNOWN", "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." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.05 MG/KG, QW", "drugenddate": null, "drugenddateformat": null, "drugindication": "MESOBLASTIC NEPHROMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".05", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE SULFATE." } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Growth retardation", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Psychomotor skills impaired", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sepsis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BERTULLI, C.. EXPANDING PHENOTYPE OF SCHIMKE IMMUNO?OSSEOUS DYSPLASIA: CONGENITAL ANOMALIES OF THE KIDNEYS AND OF THE URINARY TRACT AND ALTERATION OF NK CELLS. 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{ "abstract": "We describe a case of acquired monosomy 7 myelodysplastic syndrome (MDS) in a boy with congenital adrenocortical insufficiency, genital anomalies, growth delay, skin hyperpigmentation, and chronic lung disease. Some of his clinical manifestations were suggestive of dyskeratosis congenita (DC), while other features resembled IMAGe association. DC has been linked to mutations in telomere maintenance genes. The genetic basis of IMAGe association is unknown, although mice harboring a mutation in a telomere maintenance gene, Tpp1, have adrenal hypoplasia congenita. We considered the possibility that this patient has a defect in telomere function resulting in features of both DC and IMAGe association.", "affiliations": "Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. [email protected]", "authors": "McDonald\|Sharon\|S\|;Wilson\|David B\|DB\|;Pumbo\|Elena\|E\|;Kulkarni\|Shashikant\|S\|;Mason\|Philip J\|PJ\|;Else\|Tobias\|T\|;Bessler\|Monica\|M\|;Ferkol\|Thomas\|T\|;Shenoy\|Shalini\|S\|", "chemical_list": "C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; C509186:TERT protein, human; D019098:Telomerase; C000717267:TPP1 protein, human", "country": "United States", "delete": false, "doi": "10.1002/pbc.22283", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "54(1)", "journal": "Pediatric blood & cancer", "keywords": null, "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D019871:Dyskeratosis Congenita; D006801:Humans; D008297:Male; D009006:Monosomy; D009154:Mutation; D009190:Myelodysplastic Syndromes; D012880:Skin Pigmentation; D019098:Telomerase; D000091346:Tripeptidyl-Peptidase 1", "nlm_unique_id": "101186624", "other_id": null, "pages": "154-7", "pmc": null, "pmid": "19760774", "pubdate": "2010-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and IMAGe association.", "title_normalized": "acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and image association" }	[ { "companynumb": "US-FRESENIUS KABI-FK201805657", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078393", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE (MANUFACTURER UNKNOWN)" }, { "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": "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": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory tract infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MCDONALD S,WILSON D,PUMBO E,KULKARNI S,MASON P,ELSE T. ACQUIRED MONOSOMY 7 MYELODYSPLASTIC SYNDROME IN A CHILD WITH CLINICAL FEATURES SUGGESTIVE OF DYSKERATOSIS CONGENITA AND IMAGE ASSOCIATION.. PEDIATR-BLOOD-CANCER 2010?54 (1):154-157.", "literaturereference_normalized": "acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and image association", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180514", "receivedate": "20180514", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14891722, "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": "US-MYLANLABS-2018M1030112", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "120 MG/M2", "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": "FLUDARABINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": "3", "drugadministrationroute": "061", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower respiratory tract infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MCDONALD S, WILSON DB, PUMBO E, KULKARNI S, MASON PJ, ELSE T, ET AL. ACQUIRED MONOSOMY 7 MYELODYSPLASTIC SYNDROME IN A CHILD WITH CLINICAL FEATURES SUGGESTIVE OF DYSKERATOSIS CONGENITA AND IMAGE ASSOCIATION. PEDIATR-BLOOD-CANCER 2010?54(1):154-157.", "literaturereference_normalized": "acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and image association", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180509", "receivedate": "20180509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14870691, "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": "We present a case report of a 31-year-old female patient who presented to us with a 1 day history of acute bilateral eye pain, blurred vision and headache. She was found to have a myopic shift, raised intraocular pressure (IOP) and shallow anterior chambers in both eyes. She had been commenced on oral topiramate 1 week previously. A number of investigations, including anterior segment optical coherence tomography (AS-OCT) were done and a diagnosis of topiramate induced bilateral acute angle closure (TiAAC) was made. Topiramate was discontinued and she was managed with topical and oral antiglaucoma medications, topical steroids and cyclopegics. Her symptoms subsided dramatically at the next follow-up. The AS-OCT documentation revealed lucidly the improvement in her anterior chamber depth and anterior chamber angle parameters. Her IOP decreased, her myopic shift showed reversal and her AS-OCT findings revealed gross improvement in all the parameters angle opening distance, trabecular iris space area and scleral spur angle. This case report clearly shows with AS OCT documentation the changes which occur in the anterior segment in a case of TiAAC.", "affiliations": "Department of Glaucoma, Aravind-Ziess Centre for Excellence in Glaucoma, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu, India.", "authors": "Mitra\|Arijit\|A\|;Ramakrishnan\|R\|R\|;Kader\|Mohideen Abdul\|MA\|", "chemical_list": "D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose", "country": "India", "delete": false, "doi": "10.4103/0301-4738.129784", "fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 24881612IJO-62-61910.4103/0301-4738.129784Brief CommunicationsAnterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure Mitra Arijit Ramakrishnan R Kader Mohideen Abdul Department of Glaucoma, Aravind-Ziess Centre for Excellence in Glaucoma, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu, IndiaCorrespondence to: Dr. Arijit Mitra, Aravind-Ziess Centre for Excellence in Glaucoma, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli - 627 001, Tamil Nadu, India. E-mail: [email protected] 2014 62 5 619 622 19 4 2013 25 12 2013 Copyright: © Indian Journal of Ophthalmology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case report of a 31-year-old female patient who presented to us with a 1 day history of acute bilateral eye pain, blurred vision and headache. She was found to have a myopic shift, raised intraocular pressure (IOP) and shallow anterior chambers in both eyes. She had been commenced on oral topiramate 1 week previously. A number of investigations, including anterior segment optical coherence tomography (AS-OCT) were done and a diagnosis of topiramate induced bilateral acute angle closure (TiAAC) was made. Topiramate was discontinued and she was managed with topical and oral antiglaucoma medications, topical steroids and cyclopegics. Her symptoms subsided dramatically at the next follow-up. The AS-OCT documentation revealed lucidly the improvement in her anterior chamber depth and anterior chamber angle parameters. Her IOP decreased, her myopic shift showed reversal and her AS-OCT findings revealed gross improvement in all the parameters angle opening distance, trabecular iris space area and scleral spur angle. This case report clearly shows with AS OCT documentation the changes which occur in the anterior segment in a case of TiAAC.\n\nAnterior segment optical coherence tomographyangle opening distanceangle recess areamyopic shiftshallow anterior chambertopiramate induced bilateral acute angle closuretrabecular iris space area\n==== Body\nAcute bilateral angle-closure glaucoma and myopia has been reported widely after the use of topiramate and the condition is usually reversible when the drug is discontinued. However, even though there have been case reports of topiramate induced bilateral acute angle closure (TiAAC) in the past, to the best of our knowledge no published Indian case report shows documented anterior segment optical coherence tomography (OCT) evidence of the change in the anterior segment parameters pre- and post-treatment.\n\nCase Report\nThis was a case of a 31-year-old female patient who presented to us with a 1 day history of acute bilateral eye pain, blurred vision and headache. Her headache was similar in nature to her chronic daily headaches for which she and been commenced on tablet epimate (25 mg) (topiramate) OD orally by her neurologist 1 week prior to presentation.\n\nAt presentation, she was found to have blurred vision with an unaided visual acuity of 4/60 in both eyes. On refraction, a myopic shift in a previously emmetropic individual was established. Her vision was improving to 6/6 (P) with a correction of-3.25 D Spherical and-1.0 D Cylinder at 180° in both eyes. Keratometry was within normal limits. Circumciliary congestion was present along with mild corneal edema [Fig. 1a, b and 2a–d] and shallow anterior chambers in both eyes [Fig. 3a and b]. Gonioscopy showed closed angles in both eyes [Fig. 4a and b]. There was 360° of iridocorneal apposition but no peripheral anterior synechiae on indentation. A raised intraocular pressure (IOP) of 28 and 32 mm of Hg in right and left eye respectively was noted. Anterior segment OCT was done and it corroborated the Gonioscopic findings showing 360° iridocorneal apposition with grossly reduced anterior segment parameters [Fig. 5a and b]. The AS-OCT pictures confirmed shallow anterior chamber depth, narrow angles and forward movement of the lens iris diaphragm with increased convexity of the iris profile. The AS-OCT parameters seen at presentation are shown in Table 1.\n\nFigure 1 (a) Slit lamp photo of right eye showing marked shallowing of the anterior chamber. (b) Slit lamp photo of left eye showing marked shallowing of the anterior chamber\n\nFigure 2 (a) and (c) Clinical photographs showing congestion in the right eye along with shallow anterior chamber, (b) and (d) Clinical photographs showing congestion in the left eye along with shallow anterior chamber\n\nFigure 3 (a) Slit lamp photograph showing the marked shallowing of the anterior chamber in right eye, (b) Slit lamp photograph showing the marked shallowing of the anterior chamber in left eye\n\nFigure 4 (a) Gonioscopy of right eye showing closed angles. There was 360° of iridocorneal apposition but no peripheral anterior synechia on indentation, (b) Gonioscopy of left eye showing closed angles. There was 360° of iridocorneal apposition but no peripheral anterior synechia on indentation\n\nFigure 5 (a) Anterior segment optical coherence tomography of right eye at presentation showing reduced anterior chamber depth, occludable angles with reduced anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle), (b) Anterior segment optical coherence tomography of left eye at presentation showing reduced anterior chamber depth, occludable angles with reduced anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle)\n\nTable 1 AS-OCT parameters of the right and left eye at presentation\n\nTiAAC was diagnosed and she was started treatment with Dexamethasone eye drops 0.1% 6 times per day, Atropine 1% eye drops BD, Timolol Maleate eye drops (0.5% BD) and tablet Acetazolamide (250 mg) 1 tablet TDS. The following day her IOP had dropped to 14 mm of Hg in the right eye and 12 mm of Hg in the left eye. Slit-lamp examination revealed bilateral mild conjunctival congestion, clear corneas, mild anterior chamber reaction with occasional cells and Grade I flare and markedly shallow anterior chambers both centrally and peripherally. Both optic discs had a cup: disc ratio of 0.5 with healthy neuroretinal rims. Since the IOP had come down, only Timolol was continued along with dexamethasone and atropine eye-drops. Tablet acetazolamide was deliberately withheld.\n\nBy the 4th day, her IOP was 12 mmHg in both eyes. There was no evidence of congestion and the anterior chambers of both eyes were deep and quiet. Gonioscopy showed 360° open angles with grade 4 (Shaffer's) in all quadrants of both eyes with no evidence of PAS. All topical medications were discontinued and the patient was reassured.\n\nThe AS-OCT done on this follow-up visit showed that all the anterior chamber angle parameters had increased [Fig. 6a and b] and that the angles were wide open in both eyes [Table 2].\n\nFigure 6 (a) Anterior segment optical coherence tomography of right eye showing improvement in the anterior chamber depth and anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle) post-treatment, (b) Anterior segment optical coherence tomography of left eye showing improvement in the anterior chamber depth and anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle) post-treatment\n\nTable 2 AS-OCT parameters of the right and left eye post-treatment\n\nThus this case report shows very clearly with AS-OCT documentation the changes which occur in the anterior segment in a case of TiAAC.\n\nDiscussion\nTopiramate, a sulfamate-substituted monosaccharide, is used to treat epilepsy in children and adults. It was however originally used as an anticonvulsant. Psychiatrists have used topiramate to treat bipolar disorder, to augment psychotropics, or to counteract the weight gain associated with numerous antidepressants.\n\nIt is FDA approved for and most frequently prescribed for the prevention of migraine due to the effect it has on the blood vessels in the brain.[1] It is used as a preventative for atypical migraine sufferers. It widens the blood vessels in the brain which become restricted by increased serotonin levels.\n\nBanta et al. first reported a case of uveal effusion and secondary angle-closure glaucoma associated with topiramate use in July 2001.[2] In September 2001, Ortho-McNeil Pharmaceuticals sent out a “Dear Healthcare Professional” letter, indicating 21 cases of acute angle-closure glaucoma had been reported to their safety division and physicians should be aware of this adverse drug reaction. The FDA released a case series with an overview of the package insert[3] and a case report from Rhee et al. described a 43-year-old patient with topiramate associated glaucoma that included high-frequency ultrasound evidence of ciliary process swelling and forward displacement of the lens iris diaphragm.[4] Since, then many case reports have appeared in the literature.[56]\n\nThe largest series reported by Fraunfelder et al. in 2004 described the ocular side-effects of topiramate in 115 patients.[6] There were seven cases of permanent vision loss reported indicating that if unrecognized as a drug related event there was the potential for a serious adverse outcome. Other reported side-effects included retinal vascular occlusions, visual field defects, peri-orbital edema, scleritis, blepharospasm, oculogyric crisis, nystagmus and diplopia. In contrast to primary AAC, which is rare under 40 years of age, secondary AAC associated with topiramate has been reported in pediatric patients as well as adults,[7] with an age range from 3 years to 70 years and a mean of 34 years. The condition has predominantly been reported in females (80%).\n\nThe presentation of TiAAC is usually within the first 2 weeks (range 1-49 days) of commencing this drug for the 1st time or within hours of doubling the dose, although there appears to be no relationship with the dose of topiramate taken. Absorption of topiramate is rapid, reaching peak plasma concentrations1-4 h following an oral dose. Typically the presenting symptoms include blurred vision, ocular pain, headache, nausea and vomiting. The clinical signs associated with this syndrome are shallowing of the anterior chamber, occluded angles, papillary changes, significantly elevated IOP, suprachoroidal effusion, ciliary body edema, forward displacement of the crystalline lens and acute myopia.\n\nAcute myopia up to -9.0 diopters can occur in a matter of hours after starting topiramate, but might take weeks to fully resolve. There are several cases in the literature of topiramate-associated transient myopia without secondary angle closure.[8] Transient myopia is a well-known complication of other oral sulfa medications and their derivatives like acetazolamide.[9]\n\nMyopia in TiAAC may be due to a disturbance of the osmotic state of the lens and concomitant alteration of the refractive index.\n\nThe first published TiAAC using AS-OCT for documentation was by van Issum et al. in 2011.[10] To the best of our knowledge, no Indian case report on TiAAC using AS-OCT has yet been published. Thus, this case report is unique and it suggests AS-OCT documentation of all cases of TiAAC for proper quantification and understanding of the disease process.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Silberstein SD Lipton RB Dodick DW Freitag FG Ramadan N Mathew N Efficacy and safety of topiramate for the treatment of chronic migraine: A randomized, double-blind, placebo-controlled trial Headache 2007 47 170 80 17300356 \n2 Banta JT Hoffman K Budenz DL Ceballos E Greenfield DS Presumed topiramate-induced bilateral acute angle-closure glaucoma Am J Ophthalmol 2001 132 112 4 11438067 \n3 Thambi L Kapcala LP Chambers W Nourjah P Beitz J Chen M Topiramate-associated secondary angle-closure glaucoma: A case series Arch Ophthalmol 2002 120 1108 12149075 \n4 Rhee DJ Goldberg MJ Parrish RK Bilateral angle-closure glaucoma and ciliary body swelling from topiramate Arch Ophthalmol 2001 119 1721 3 11709030 \n5 Chen TC Chao CW Sorkin JA Topiramate induced myopic shift and angle closure glaucoma Br J Ophthalmol 2003 87 648 9 12714417 \n6 Fraunfelder FW Fraunfelder FT Keates EU Topiramate-associated acute, bilateral, secondary angle-closure glaucoma Ophthalmology 2004 111 109 11 14711721 \n7 Lin J Fosnot J Edmond J Bilateral angle closure glaucoma in a child receiving oral topiramate J AAPOS 2003 7 66 8 12690373 \n8 Sen HA O’Halloran HS Lee WB Case reports and small case series: Topiramate-induced acute myopia and retinal striae Arch Ophthalmol 2001 119 775 7 11346412 \n9 Bovino JA Marcus DF The mechanism of transient myopia induced by sulfonamide therapy Am J Ophthalmol 1982 94 99 102 6979937 \n10 van Issum C Mavrakanas N Schutz JS Shaarawy T Topiramate-induced acute bilateral angle closure and myopia: Pathophysiology and treatment controversies Eur J Ophthalmol 2011 21 404 9 21058272\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0301-4738", "issue": "62(5)", "journal": "Indian journal of ophthalmology", "keywords": null, "medline_ta": "Indian J Ophthalmol", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000869:Anterior Eye Segment; D004282:Documentation; D005260:Female; D005632:Fructose; D015812:Glaucoma, Angle-Closure; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D018696:Neuroprotective Agents; D041623:Tomography, Optical Coherence; D000077236:Topiramate", "nlm_unique_id": "0405376", "other_id": null, "pages": "619-22", "pmc": null, "pmid": "24881612", "pubdate": "2014-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "6979937;12690373;12714417;14711721;17300356;11346412;21058272;11438067;11709030;12149075", "title": "Anterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure.", "title_normalized": "anterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure" }	[ { "companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2015-03327", "fulfillexpeditecriteria": "2", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TOPIRAMATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078410", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TOPIRAMATE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Angle closure glaucoma", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MITRA A, RAMAKRISHNAN R, KADER M. ANTERIOR SEGMENT OPTICAL COHERENCE TOMOGRAPHY DOCUMENTATION OF A CASE OF TOPIRAMATE INDUCED ACUTE ANGLE CLOSURE. INDIAN JOURNAL OF OPTHALMOLOGY. 2014 MAY?62(5):619-622.", "literaturereference_normalized": "anterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure", "qualification": "1", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20151228", "receivedate": "20151228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11869724, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160305" } ]
{ "abstract": "BACKGROUND\nWe describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).\n\n\nMETHODS\nWe identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.\n\n\nRESULTS\nTwo percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.\n\n\nCONCLUSIONS\nTwo percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.", "affiliations": "*Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; †Department of Medicine, Weill Cornell Medical College; ‡Department of Pathology; and §Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.", "authors": "Varghese\|Anna M\|AM\|;Zakowski\|Maureen F\|MF\|;Yu\|Helena A\|HA\|;Won\|Helen H\|HH\|;Riely\|Gregory J\|GJ\|;Krug\|Lee M\|LM\|;Kris\|Mark G\|MG\|;Rekhtman\|Natasha\|N\|;Ladanyi\|Marc\|M\|;Wang\|Lu\|L\|;Berger\|Michael F\|MF\|;Pietanza\|M Catherine\|MC\|", "chemical_list": "D000970:Antineoplastic Agents; D002864:Chromogranins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C509186:TERT protein, human; D019098:Telomerase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C067419:CBL protein, human", "country": "United States", "delete": false, "doi": "10.1097/JTO.0000000000000142", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-0864", "issue": "9(6)", "journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", "keywords": null, "medline_ta": "J Thorac Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D002864:Chromogranins; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs; D005784:Gene Amplification; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D016160:Retinoblastoma Protein; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma; D012907:Smoking; D015996:Survival Rate; D019098:Telomerase; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins", "nlm_unique_id": "101274235", "other_id": null, "pages": "892-6", "pmc": null, "pmid": "24828667", "pubdate": "2014-06", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "19652623;22941189;21361067;22941188;19096304;21430269;22228640;16049312;23470965;18403609;11030152;17601631;16837691;15737014;23407558", "title": "Small-cell lung cancers in patients who never smoked cigarettes.", "title_normalized": "small cell lung cancers in patients who never smoked cigarettes" }	[ { "companynumb": "US-MYLANLABS-2015M1008031", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915967, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "US-MYLANLABS-2015M1008032", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "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": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915968, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "US-MYLANLABS-2015M1008029", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915970, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "US-MYLANLABS-2015M1008030", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]
{ "abstract": "BACKGROUND\nPrevious randomized controlled trials evaluating the efficacy of mycophenolate mofetil (MMF) in patients with immunoglobulin A nephropathy (IgAN) have produced varying results.\n\n\nMETHODS\nDouble-blind placebo-controlled randomized controlled trial.\n\n\nMETHODS\n52 children, adolescents, and adults with biopsy-proven IgAN in 30 centers in the United States and Canada. Entry criteria: age older than 7 to younger than 70 years; urine protein-creatinine ratio (UPCR), ≥0.6g/g (males) or ≥0.8g/g (females); and estimated glomerular filtration rate ≥ 50mL/min/1.73m(2) (≥40mL/min/1.73m(2) if receiving angiotensin-converting enzyme inhibitor). Mean age, 32±12 (SD) years; 62% men; and 73% white.\n\n\nMETHODS\nLisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor [Pronova Biocare]) was given to 94 patients for 3 months; 52 of the patients with persistent UPCR≥0.6g/g (males) and ≥0.8g/g (females) were randomly assigned to MMF or placebo (target dose, 25-36mg/kg/d) in addition to lisinopril/losartan plus Omacor.\n\n\nRESULTS\nChange in UPCR after 6 and 12 months treatment with MMF/placebo and 12 months after the end of treatment.\n\n\nMETHODS\nUPCR measured on 24-hour urine samples. Glomerular filtration rate estimated with the Schwartz (age < 18 years) or Cockcroft-Gault (age ≥ 18 years) formula.\n\n\nRESULTS\n44 patients completed 6 months of treatment with MMF (n=22) or placebo (n=22). The trial was terminated early at the recommendation of the Data Monitoring Committee because of the lack of benefit. No patient achieved a complete remission (UPCR<0.2g/g). Mean UPCRs at randomization and after 6 months were 1.45 (95% CI, 1.16-1.75) and 1.40 (95% CI, 1.09-1.70) for MMF and 1.41 (95% CI, 1.17-1.65) and 1.58 (95% CI, 1.13-2.04) for placebo, respectively. The mean difference in UPCR change between these groups (MMF minus placebo) was -0.22 (95% CI, -0.75 to 0.31; P=0.4). Adverse events were rare apart from nausea (MMF, 8.7%; placebo, 3.7%); one of these MMF patients withdrew.\n\n\nCONCLUSIONS\nLow patient enrollment and short follow-up.\n\n\nCONCLUSIONS\nMMF did not reduce proteinuria significantly in patients with IgAN who had persistent proteinuria after lisinopril/losartan plus Omacor.", "affiliations": "Baylor Scott and White Healthcare, Temple, TX. Electronic address: [email protected].;A.T. Still University, Mesa, AZ.;University of North Carolina at Chapel Hill, NC.;Stanford University, Stanford, CA.;Dallas Nephrology Associates, Dallas, TX.;Mayo Clinic, Rochester, MN.;Columbia University, New York, NY.;Toronto General Hospital, Toronto, Ontario, Canada.;Kidney and Hypertension, Cincinnati, OH.;BC Children's Hospital, Vancouver, British Columbia, Canada.;Capital Dist Renal Physicians, Albany, NY.;Kidney Specialists of Central Oklahoma, Oklahoma City, OK.;St. Paul's Hospital, Vancouver, British Columbia, Canada.;Texas Tech University Health Science Center, El Paso, TX.;University of Michigan, Ann Arbor, MI.;University of Tennessee Health Science Center, Memphis, TN.", "authors": "Hogg\|Ronald J\|RJ\|;Bay\|R Curtis\|RC\|;Jennette\|J Charles\|JC\|;Sibley\|Richard\|R\|;Kumar\|Sumit\|S\|;Fervenza\|Fernando C\|FC\|;Appel\|Gerald\|G\|;Cattran\|Daniel\|D\|;Fischer\|Danny\|D\|;Hurley\|R Morrison\|RM\|;Cerda\|Jorge\|J\|;Carter\|Brad\|B\|;Jung\|Beverly\|B\|;Hernandez\|German\|G\|;Gipson\|Debbie\|D\|;Wyatt\|Robert J\|RJ\|", "chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D003404:Creatinine; C405603:Omacor; D017706:Lisinopril; D009173:Mycophenolic Acid; D019808:Losartan", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0272-6386", "issue": "66(5)", "journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation", "keywords": "IgA nephropathy (IgAN); MEST scores; Mycophenolate mofetil (MMF); proteinuria; randomized controlled trial (RCT); remission; urinary protein-creatinine ratio (UPCR)", "medline_ta": "Am J Kidney Dis", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002648:Child; D003404:Creatinine; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D015118:Eicosapentaenoic Acid; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA; D006801:Humans; D007166:Immunosuppressive Agents; D017706:Lisinopril; D019808:Losartan; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011507:Proteinuria; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8110075", "other_id": null, "pages": "783-91", "pmc": null, "pmid": "26209543", "pubdate": "2015-11", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy.", "title_normalized": "randomized controlled trial of mycophenolate mofetil in children adolescents and adults with iga nephropathy" }	[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP005331", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "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": null, "activesubstance": { "activesubstancename": "OMEGA-3-ACID ETHYL ESTERS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G PER DAY, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMACOR" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HOGG RJ, BAY RC, JENNETTE JC, SIBLEY R, KUMAR S, FERVENZA FC, ET AL. RANDOMIZED CONTROLLED TRIAL OF MYCOPHENOLATE MOFETIL IN CHILDREN, ADOLESCENTS, AND ADULTS WITH IGA NEPHROPATHY. AM J KIDNEY DIS. 2015;66(5):783-91", "literaturereference_normalized": "randomized controlled trial of mycophenolate mofetil in children adolescents and adults with iga nephropathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170724", "receivedate": "20170724", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13781208, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]
{ "abstract": "OBJECTIVE\nTo estimate the prevalence of gestational trophoblastic disease (GTD) in the western region of Saudi Arabia, and to evaluate the success of treatment and the effect of age and risk group on survival.\n\n\nMETHODS\nBetween January 2001 and December 2010, all patients treated for GTD were identified from the King Abdulaziz University Hospital database. Patients with persistent disease were evaluated according to their clinical treatment outcomes.\n\n\nRESULTS\nIn total, 122 cases of GTD were identified in the database. Of these, 77 (63%) cases were diagnosed and received initial treatment at the study centre, resulting in an incidence of 1.26 cases per 1000 deliveries. The mean (±standard deviation) age of the study participants was 31.52 ± 10.8 years, mean gestational age at diagnosis was 12.42 ± 3.2 weeks, and mean follow-up for each patient was 24 months. There were 20 cases (26%) of persistent GTD after treatment. The majority of patients with low-risk disease were treated with single-agent methotrexate, with an overall success rate of 83%. The overall 5-year survival rate for all patients was 98%. Using the Wilcoxon (Gehan) test, risk group and age (cut-off 40 years) were not found to be significantly associated with survival (p=0.69).\n\n\nCONCLUSIONS\nThis single-institute study reports the first survival data for GTD for Saudi Arabia. However, the overall incidence of GTD in Saudi Arabia will be defined by establishment of a GTD registry.", "affiliations": "Scientific chair of prof. Abdullah Hussain Basalamah for Gynecological Cancer, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.;Scientific chair of prof. Abdullah Hussain Basalamah for Gynecological Cancer, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Electronic address: [email protected].;Scientific chair of prof. Abdullah Hussain Basalamah for Gynecological Cancer, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.", "authors": "Anfinan\|Nisrin\|N\|;Sait\|Khalid\|K\|;Sait\|Hesham\|H\|", "chemical_list": "D000970:Antineoplastic Agents; D003609:Dactinomycin; D008727:Methotrexate", "country": "Ireland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0301-2115", "issue": "180()", "journal": "European journal of obstetrics, gynecology, and reproductive biology", "keywords": "Incidence; Survival rate; Trophoblastic disease", "medline_ta": "Eur J Obstet Gynecol Reprod Biol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000970:Antineoplastic Agents; D002822:Choriocarcinoma; D003609:Dactinomycin; D005260:Female; D031901:Gestational Trophoblastic Disease; D006801:Humans; D006828:Hydatidiform Mole; D008175:Lung Neoplasms; D008727:Methotrexate; D008875:Middle Aged; D011247:Pregnancy; D015995:Prevalence; D011379:Prognosis; D012529:Saudi Arabia; D014594:Uterine Neoplasms; D055815:Young Adult", "nlm_unique_id": "0375672", "other_id": null, "pages": "8-11", "pmc": null, "pmid": "24972119", "pubdate": "2014-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Gestational trophoblastic disease in the western region of Saudi Arabia (single-institute experience).", "title_normalized": "gestational trophoblastic disease in the western region of saudi arabia single institute experience" }	[ { "companynumb": "SA-MYLANLABS-2015M1007950", "fulfillexpeditecriteria": "1", "occurcountry": "SA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201529", "drugbatchnumb": null, "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": "METHOTREXATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "DACTINOMYCIN" }, { "actiondrug": "5", "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": "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": "CYCLOPHOSPHAMIDE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "ANFINAN N, SAIT K, SAIT H. GESTATIONAL TROPHOBLASTIC DISEASE IN THE WESTERN REGION OF SAUDI ARABIA (SINGLE-INSTITUTE EXPERIENCE). 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{ "abstract": "Hoyeraal-Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after successful HSCT. We present an HHS patient with an X-linked recessive DKC1 c.1058C > T; Ala353Val mutation who successfully underwent unrelated HSCT at 5 years of age. After months of early infections and organ toxicities immediately post-transplant, he had more than two years of excellent quality of life with correction of bone marrow failure and immunodeficiency. However, episodic massive variceal bleeding and progressive respiratory insufficiency, which were secondary to non-cirrhotic portal hypertension and pulmonary arteriovenous shunts, respectively, developed over 2 years after HSCT and resulted in his death from respiratory failure 4 years after HSCT. This outcome suggests that while HSCT can correct bone marrow failure and immunodeficiency, it may fail to prevent or even aggravate other fatal processes, such as portal hypertension and pulmonary arteriovenous shunting.", "affiliations": "Department of Pediatric Hematology and Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 11259, Taiwan. [email protected].;Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.;Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan. [email protected].", "authors": "Chen\|Rong-Long\|RL\|;Lin\|Kuanyin K\|KK\|;Chen\|Liuh-Yow\|LY\|0000-0002-9857-068X", "chemical_list": "D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins", "country": "Switzerland", "delete": false, "doi": "10.3390/ijms20133261", "fulltext": "\n==== Front\nInt J Mol SciInt J Mol SciijmsInternational Journal of Molecular Sciences1422-0067MDPI 10.3390/ijms20133261ijms-20-03261Case ReportComplications for a Hoyeraal–Hreidarsson Syndrome Patient with a Germline DKC1 A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation Chen Rong-Long 1Lin Kuanyin K 2https://orcid.org/0000-0002-9857-068XChen Liuh-Yow 21 Department of Pediatric Hematology and Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 11259, Taiwan2 Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan* Correspondence: [email protected] (R.-L.C.); [email protected] (L.-Y.C.); Tel.: +886-2-2897-0011 (R.-L.C. & L.-Y.C.)02 7 2019 7 2019 20 13 326105 6 2019 01 7 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Hoyeraal–Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after successful HSCT. We present an HHS patient with an X-linked recessive DKC1 c.1058C > T; Ala353Val mutation who successfully underwent unrelated HSCT at 5 years of age. After months of early infections and organ toxicities immediately post-transplant, he had more than two years of excellent quality of life with correction of bone marrow failure and immunodeficiency. However, episodic massive variceal bleeding and progressive respiratory insufficiency, which were secondary to non-cirrhotic portal hypertension and pulmonary arteriovenous shunts, respectively, developed over 2 years after HSCT and resulted in his death from respiratory failure 4 years after HSCT. This outcome suggests that while HSCT can correct bone marrow failure and immunodeficiency, it may fail to prevent or even aggravate other fatal processes, such as portal hypertension and pulmonary arteriovenous shunting.\n\ndyskeratosis congenitaHoyeraal–Hreidarsson syndromeportal hypertensionpulmonary arteriovenous shuntsreduced intensity conditioningtelomeropathyunrelated peripheral blood stem cell transplantationvascular aging\n==== Body\n1. Introduction\nHoyeraal–Hreidarsson syndrome (HHS, OMIM 500545)—a severe variant of dyskeratosis congenita (DC, OMIM 305000) involving very short leukocyte telomere length—is characterized by intrauterine growth retardation and cerebellar hypoplasia, in addition to the classical mucocutaneous DC triad (nail dystrophy, skin hyperpigmentation, oral leukoplakia), with early life-threatening presentations related to immunodeficiency and bone marrow failure (BMF) [1]. Germline variants resulting from different gene mutations—namely DKC1, TINF2, TERC, TERT, NOP10, NHP2, CTC1, WRAP53, ACD, RTEL1, and PARN—have been implicated in HHS and other DC variants. These variants have been documented as mainly perturbing telomeric functions, with the most severe disease forms presenting significantly shorter telomeres than milder forms [2]. Among affected gene variants, X-linked recessive male patients with the DKC1 c.1058C > T; Ala353Val missense mutation present with a diverse clinical phenotype, ranging from late-onset DC without BMF to lethal HHS [2]. Given the high rate of early mortality due to BMF and/or immunodeficiency in HHS patients, there are very few reports in the literature on HHS patients with variable genetic variants that have received hematopoietic stem cell transplantation (HSCT) [3,4,5,6,7]. Herein, we report our experience of treating an HHS patient with a characterized DKC1 mutation, who successfully recovered from early life-threatening complications after receiving a reduced intensity conditioning (RIC) preparation, followed by unrelated peripheral blood stem cell transplantation (PBSCT). However, regrettably, vascular aging events continued to evolve and resulted in mortality four years after HSCT.\n\n2. Case Reports\nThe patient, a boy, suffered oligohydramnios during pregnancy and was born prematurely in December 2009, with a gestational age of 33 weeks and a birth body weight of 1318 g. Growth and developmental delay requiring rehabilitation were noted from early infancy. In addition, progressive skin hyperpigmentation, nail dysplasia, and leukoplakia of the tongue were also noted. In January 2011, aged 1 year, he was first noted to have cytopenia (leukocytes 5.22 × 109/L, hemoglobin 8.1 mg/dL, platelet count 18 × 109/L). He was treated with intravenous immunoglobulins and prednisolone, but the pancytopenia worsened. He required increasingly frequent transfusions and treatment for infections and, by late 2014, he had a neutrophil count of around 0.5 × 109/L, hemoglobin ranging from 6 to 7 mg/dL, and a platelet count of less than 10 × 109/L.\n\nSevere aplastic anemia was confirmed by bone marrow studies in November 2014. In addition, he presented with severe immunodeficiency; very low CD16+56+ natural killer cell (0.013, reference 0.16–0.57 × 109/L) and CD19+ B cell (0.001, reference 0.43–1.27 × 109/L) counts were recorded. Moderate T-lymphopenia was also diagnosed; cell counts of CD3+ T cells = 0.415 (reference 1.58–3.71) × 109/L, CD4+ T cells = 0.253 (reference 0.87–2.14) × 109/L, and CD8+ T cells = 0.138 (reference 0.47–1.11) × 109/L. Levels of immunoglobulins G, A, and M were within normal ranges for his age (data not shown). HHS arising from recurrent X-linked recessive DKC1 c.1058C > T; Ala353Val mutation with extremely short telomeres was diagnosed (Figure 1). Phenotypes of this mutant variant include intrauterine growth retardation, severe lymphopenia, cerebellar hypoplasia (Figure 2), and the characteristic DC mucocutaneous triad of nail dystrophy, skin hyperpigmentation, and oral leukoplakia (Figure 3). He also had non-cirrhotic non-icteric hepatic biochemical abnormalities, but without evidence of pulmonary fibrosis or other lung pathologies.\n\nAs HLA-identical sibling donors were unavailable, a decision was made to pursue unrelated HSCT as salvage therapy. The conditioning consisted of alemtuzumab (a total of 1 mg/kg given from day −10 to day −6) and fludarabine (30 mg/m2 daily from day −8 to day −3), kindly provided by Boston Children’s Hospital [8]. For prophylaxis against graft-versus-host disease (GVHD), the patient received cyclosporine and mycophenolate mofetil. On 10 March 2015 (day 0), he received PBSCs from an unrelated donor comprising 45 × 108 total nucleated cells/kg and 23 × 106 CD34+ cells/kg. The patient and the donor were HLA-8/8 matched (A 1101/2402, B 4001/4601, Cw 0102/0702, DR 0809/0901) and ABO-matched (B to B). Neutrophil engraftment was documented on day +11. The patient did not require any transfusion after day +18. Chimerism analyses were performed from bone marrow (nine months post-transplantation) and from peripheral blood (repeatedly from day +27), all of which showed 100% donor chimerism.\n\nThe initial course was complicated by an episode of Hickman catheter-related Kocuria rosea sepsis and stage 2 skin acute GVHD. Concurrently with the development of skin GVHD, phimosis progressed with the appearance of an erythematous and bullous-like foreskin lesion. The lesion partially regressed following treatment with oral valacyclovir and prednisolone. In addition, diarrhea arose, with stool content changing from loose to watery then bloody, and was associated with cramping abdominal pain and intermittent fever. He required a long admission from day +51 to day +167, with complications including cytomegalovirus (CMV) reactivation, severe enterocolitis, buccal mucositis/cellulitis, and parotitis. He required parenteral nutritional support for nearly two months and developed Wernicke encephalopathy during this period that was responsive to thiamine treatment. Finally, these complications were alleviated and he was discharged under on-going prednisolone and cyclosporine treatment. \n\nHowever, he still experienced repeated CMV reactivation, episodes of diarrhea with or without fever, Escherichia coli urinary tract infection, Clostridium difficile-associated diarrhea, Salmonella group E enteric fever, and influenza during the first year post-transplantation. He also underwent circumcision because of a difficulty urinating, which was secondary to progressive obstructive phimosis at nine months post-transplantation. Steroid and cyclosporine treatments were discontinued 9 months and 1 year post-transplantation, respectively. Recovery of bone marrow hematopoiesis was documented (Figure 4). Moreover, the frequency of serious infections markedly decreased over the course of the second year post-transplantation, so the boy returned to school.\n\nAt the early post-transplantation stage, the patient’s hepatic abnormalities remained stationary, with mildly elevated transaminase levels, though hepatic ultrasonography revealed heterogeneous echotexture with multiple tiny hypoechoic nodules. He gradually gained body weight purely by oral intake from 12.4 kg before HSCT to 15.9 kg in November 2016. He had become transfusion-independent by 21 November 2016, with a neutrophil count of 2.69 × 109/L, hemoglobin of 10.6 mg/dL, and a platelet count of 128 × 109/L. A lymphocyte subset analysis in November 2016 revealed normal counts of CD16+56+ natural killer cells (0.184, reference 0.12–0.48 × 109/L) and CD19+ B cells (0.390, reference 0.28–0.64 × 109/L). The extent of T-lymphopenia had also decreased with CD3+ T, CD4+ T, and CD8+ T cell counts of 0.803 (reference 1.24–1.21), 0.272 (0.65–1.52), and 0.392 (0.37–0.95) × 109/L, respectively.\n\nHowever, massive upper gastrointestinal bleedings happened after respiratory tract infections in late April 2017 when portal hypertension complicated with esophago-gastric varices was diagnosed by emergency endoscopy and computerized tomography (Figure 5). In addition, he was noted to have persistent hypoxemia, with the arterial partial pressure of oxygen always less than 50 mmHg after treatment for a documented influenza episode in May 2017. The patient had very severe hepatopulmonary syndrome, with a calculated alveolar-arterial oxygen gradient of 70 mmHg at sitting and 75 mmHg at supine positions, respectively. Pulmonary arteriovenous shunting was documented by a lung perfusion scan in August 2017 (Figure 6). Only palliative management was considered thereafter. The patient was still able to enjoy school and home life under regular oxygen supplementation, although intermittent admissions were required to manage severe upper gastrointestinal bleeding or aggravated respiratory symptoms in his final days. Ultimately, he passed away in February 2019, primarily due to respiratory compromise.\n\n3. Discussion\nWe have characterized herein the lifelong events of an HHS patient with DKC1 A353V and extremely short telomeres. Despite the presence of perinatal intrauterine growth restriction and developmental delay, HHS was not diagnosed until the patient suffered from complications related to rapidly progressive BMF and immunodeficiency when the characteristic mucocutaneous DC triad and cerebral hypoplasia were noted.\n\nHSCT is the first consideration for treatment when DC-associated BMF develops and a matched-sibling donor is available [9,10]. Until recently, HSCT for DC has been associated with an inferior outcome, mainly owing to early and late post-transplantation complications including graft failure, GVHD, sepsis, and, in particular, the increased propensity to develop pulmonary failure [11]. The largest cohort (n = 94) of non-myeloablative HSCT for DC still showed the crude mortality rate of 41%, with about one-third of deaths resulting from late complications such as organ damage and secondary malignancies [12]. For unrelated donor HSCT in DC, the risks are even higher, though RIC preparative regimens have been suggested as being more successful [8,13].\n\nInstances of HSCT treatment for genotype-determined HHS are rarely reported. One of two sibling HHS with homozygous TERT mutation had early engraftment after HLA-9/10 unrelated bone marrow transplantations. However, another died one month after post-matched unrelated cord blood transplantation (CBT) [5]. Two HHS patients with the RTEL mutation were successfully rescued: one by haploidentical PBSCT and the other by unrelated CBT [6,7]. Another HHS patient with the DKC1 mutation had delayed marrow reconstitution after an unrelated bone marrow transplant [3]. In contrast, our HHS patient (with the DKC1 mutation) had prompt and complete donor engraftment, as well as steady immune recovery, after unrelated PBSCT following a novel radiation/alkylator-free RIC regimen [8]. Our patient gradually attained abilities to overcome mild and brief GVHD/infections.\n\nThe previously reported HHS patient with the DKC1 mutation developed severe gastrointestinal problems that required chronic steroid therapy, long-term total parenteral nutrition, and jejunostomy feeding following an unrelated bone marrow transplant [3]. Another HHS patient with the RTEL mutation also required total parenteral nutrition at home for 2 years after CBT [7]. Protracted enterocolitis was also the most troublesome early post-transplantation complication in our patient, which has caused significant morbidities elsewhere [14]. We emphasize that the increased propensity of HHS patients to develop telomere-mediated intestinal disease (as reviewed by Jonassaint et al. [14]) should be highlighted as an early and life-threatening post-transplantation complication, even after RIC preparation.\n\nThe early success of HSCT in our patient failed to prevent (and may have even aggravated) as yet uncharacterized vascular aging processes that particularly affected the liver and lungs, causing severe non-cirrhotic portal hypertension and pulmonary arteriovenous shunting that resulted in death four years after HSCT. This scenario contrasts with those of germline telomerase mutations that predispose cirrhosis formation and familial idiopathic pulmonary fibrosis but, in general, do not result in the expression of classical DC phenotypes [15,16,17]. The vascular changes in our patient are similar to the setting of chronic liver diseases leading to hepatopulmonary syndrome, in which dilatation of pulmonary pre-capillary and capillary vessels is the striking pathological feature, and with some patients exhibiting a few pleural/pulmonary shunts as well as portopulmonary venous anastomoses [18]. Recently, pulmonary arteriovenous malformations, with or without hepatopulmonary syndrome, have been characterized as a pulmonary phenotype of DC, with 77% of such patients undergoing HSCT [19]. Among the 13 such cases reported, germline mutations were documented in twelve including TINF2 (six), TERT (two), RTEL1 (two), PARN (one), and DKC1 T408I (one). We now add a case of a germline DKC1 A353V HHS patient having pulmonary arteriovenous malformations with hepatopulmonary syndrome 2 years after HSCT.\n\nIn conclusion, a boy with characteristics of HHS caused by an X-linked recessive DKC1 mutation developed life-threatening BMF and severe lymphopenia. These complications were successfully ameliorated over time through unrelated PBSCT using a novel radiation/alkylator-free RIC regimen with manageable early complications. He was subsequently able to return to school, but ultimately developed severe portal hypertension and fatal hepatopulmonary syndrome.\n\n4. Materials and Methods\n4.1. Whole Exome Sequencing (WES)\nTo identify genetic variants in the patient, genomic DNA from leukocytes of the subject was subjected to WES. The sequence data was aligned to a reference genome (hg19) to identify genetic variants. Analysis of the variants in genes associated with dyskeratosis congenita led to the identification of the DKC1 c.1058C>T mutation. Sanger sequencing was carried out to verify the DKC1 mutation. A fragment of DNA containing the DKC1 mutation site was amplified by PCR using oligonucleotide primers 5′-tgagctgcaagcctgttatg-3′ and 5′-caaatccccctctgtgagaa-3′, which were also used for direct sequencing. Our results confirmed the DKC1 mutation in the patient and revealed the mother to be a carrier with wild-type and mutant DKC1 alleles. Written informed consent was obtained from all the participants for public release of the survey results.\n\n4.2. Telomere Length Analysis\nLeukocyte telomere length was analyzed by telomere restriction fragment assay, as previously described [20]. Briefly, leukocyte genomic DNA was digested by Rsa I and Hinf I restriction enzymes and resolved by agarose gel electrophoresis. Telomeric DNA was detected by in gel hybridization using a [32P]-labeled telomeric probe.\n\n4.3. Tecnetium-99m MAA Lung and Brain Scanning\nA technetium-99m-labeled macroaggregated albumin lung perfusion scan was performed according to a previous report [21]. The extrapulmonary shunt fraction, assuming that 13% of the cardiac output is delivered to the brain, was calculated using the geometric mean of technetium (GMT) counts around the brain and lung according to the following formula: (GMTbrain/0.13)/ ((GMTbrain/0.13) + GMTlung).\n\nAcknowledgments\nWe would like to thank Suneet Agarwal for assistance in clinical management of the patient.\n\nAuthor Contributions\nR.-L.C. and L.-Y.C. designed the study. R.-L.C., K.K.L., and L.-Y.C. carried out the experiments and performed the data analysis. R.-L.C and L.-Y.C. wrote the manuscript.\n\nFunding\nThis study was supported by Career Development Award CDA-105-L01 from Academia Sinica and grants from the Ministry of Science and Technology (105-2311-B-001-055-MY3).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 (A) Pedigree of the affected family. Solid symbol represents the affected patient and open symbols represent unaffected relatives. Squares indicate males and circle indicates a female subject. (B) Sanger DNA sequencing of DKC1 exon 11 on chromosome X from peripheral blood cells taken from subjects of the studied pedigree. Wild-type (S1), patient (P1), carrier (M1). (C) Telomere length analysis (by terminal restriction fragment assay) of DNA from leukocytes of the patient (P1), an age-matched control (Ctrl), a carrier (M1), and from HT1080 fibrosarcoma cancer cells. The patient (P1) had exceedingly shortened and heterogeneous telomeres compared to the control (Ctrl).\n\nFigure 2 Brain magnetic resonance imaging of the patient in December 2014 showing characteristic cerebellar hypoplasia.\n\nFigure 3 Pre-transplant photographs of the patient showing nail dysplasia (A), abnormal skin pigmentation (B), and tongue leukoplakia (white arrowhead) (C).\n\nFigure 4 H&E-stained micrographs (40× A,C; 400× B,D) showing the severe hypocellularity with scanty hematopoiesis of bone marrow obtained pre-hematopoietic stem cell transplantation (HSCT) in February 2015 (A,B) compared to much more cellular material with abundant hematopoiesis obtained in December 2015 (i.e., nine months post-HSCT) (C,D).\n\nFigure 5 Enhanced computerized tomography scans showing esophageal (A) and gastric (B) varices.\n\nFigure 6 Technetium-99m-labeled macroaggregated albumin (Tc-99m MAA) dynamic perfusion imaging and total-body scans showing abnormal increased uptake in the brain immediately after Tc-99m MAA injection, with calculated intrapulmonary right-to-left shunts of 57.6%. LT, left; RT, right; R+L, right plus left; WB, whole body.\n==== Refs\nReferences\n1. Hreidarsson syndrome, a complex telomere biology disorder Br. J. Haematol. 2015 170 457 471 10.1111/bjh.13442 25940403 \n2. Vulliamy T.J. Marrone A. Knight S.W. Walne A. Mason P.J. Dokal I. Mutations in dyskeratosis congenita: Their impact on telomere length and the diversity of clinical presentation Blood 2006 107 2680 2685 10.1182/blood-2005-07-2622 16332973 \n3. Knight S.W. Heiss N.S. Vulliamy T.J. Aalfs C.M. McMahon C. Richmond P. Jones A. Hennekam R.C. Poustka A. Mason P.J. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1 Br. J. Haematol. 1999 107 335 339 10.1046/j.1365-2141.1999.01690.x 10583221 \n4. Coman D. Herbert A. McGill J. Lockwood L. Hallahan A. Unrelated cord blood transplantation in a girl with Hoyeraal-Hreidarsson syndrome Bone Marrow Transpl. 2008 42 293 294 10.1038/bmt.2008.163 18560411 \n5. Gramatges M.M. Qi X. Sasa G.S. Chen J.J. Bertuch A.A. A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal-Hreidarsson syndrome Blood 2013 121 3586 3593 10.1182/blood-2012-08-447755 23538340 \n6. Bhattacharyya R. Tan A.M. Chan M.Y. Jamuar S.S. Foo R. Iyer P. TCR-αβ and CD19-depleted haploidentical stem cell transplant with reduced intensity conditioning for Hoyeraal–Hreidarsson syndrome with RTEL1 mutation Bone Marrow Transpl. 2016 51 753 754 10.1038/bmt.2015.352 \n7. Moriya K. Niizuma H. Rikiishi T. Yamaguchi H. Sasahara Y. Kure S. Novel compound heterozygous RTEL1 gene mutations in a patient with Hoyeraal-Hreidarsson syndrome Pediatr. Blood Cancer 2016 63 1683 1684 10.1002/pbc.26030 27128385 \n8. Lehmann L.E. Williams D.A. London W.B. Agarwal S. Full donor myeloid engraftment with minimal toxicity in dyskeratosis congenita patients undergoing allogeneic bone marrow transplantation without radiation or alkylating agents Blood 2014 124 2941 \n9. Savage S.A. Dokal I. Armanios M. Aubert G. Cowen E.W. Domingo D.L. Giri N. Greene M.H. Orchard P.J. Tolar J. Dyskeratosis congenita: The first NIH clinical research workshop Pediatr. Blood Cancer 2009 53 520 523 10.1002/pbc.22061 19415736 \n10. Ayas M. Nassar A. Hamidieh A.A. Kharfan-Dabaja M. Othman T.B. Elhaddad A. Seraihy A. Hussain F. Alimoghaddam K. Ladeb S. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure Bone Marrow Transpl. 2013 48 1168 1172 10.1038/bmt.2013.35 \n11. Gadalla S.M. Sales-Bonfim C. Carreras J. Alter B.P. Antin J.H. Ayas M. Bodhi P. Davis J. Davies S.M. Deconinck E. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita Biol. Blood Marrow Transpl. 2013 19 1238 1243 10.1016/j.bbmt.2013.05.021 23751955 \n12. Fioredda F. Iacobelli S. Korthof E.T. Knol C. van Biezen A. Bresters D. Veys P. Yoshimi A. Fagioli F. Mats B. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita Br. J. Haematol. 2018 183 110 118 10.1111/bjh.15495 29984823 \n13. Dietz A.C. Orchard P.J. Baker K.S. Giller R.H. Savage S.A. Alter B.P. Tolar J. Disease-specific hematopoietic cell transplantation: Nonmyeloablative conditioning regimen for dyskeratosis congenita Bone Marrow Transpl. 2011 46 98 104 10.1038/bmt.2010.65 20383216 \n14. Jonassaint N.L. Guo N. Califano J.A. Montgomery E.A. Armanios M. The gastrointestinal manifestations of telomere-mediated disease Aging Cell 2013 12 319 323 10.1111/acel.12041 23279657 \n15. Calado R.T. Brudno J. Mehta P. Kovacs J.J. Wu C. Zago M.A. Chanock S.J. Boyer T.D. Young N.S. Constitutional telomerase mutations are genetic risk factors for cirrhosis Hepatology 2011 53 1600 1607 10.1002/hep.24173 21520173 \n16. Hartmann D. Srivastava U. Thaler M. Kleinhans K.N. N’kontchou G. Scheffold A. Bauer K. Kratzer R.F. Kloos N. Katz S.F. Telomerase gene mutations are associated with cirrhosis formation Hepatology 2011 53 1608 1617 10.1002/hep.24217 21520174 \n17. Armanios M.Y. Chen J.J. Cogan J.D. Alder J.K. Ingersoll R.G. Markin C. Lawson W.E. Xie M. Vulto I. Phillips J.A. III Telomerase mutations in families with idiopathic pulmonary fibrosis N. Engl. J. Med. 2007 356 1317 1326 10.1056/NEJMoa066157 17392301 \n18. Rodríguez-Roisin R. Krowka M.J. Hepatopulmonary syndrome—A liver-induced lung vascular disorder N. Engl. J. Med. 2008 358 2378 2387 10.1056/NEJMra0707185 18509123 \n19. Khincha P.P. Bertuch A.A. Agarwal S. Townsley D.M. Young N.S. Keel S. Shimamura A. Boulad F. Simoneau T. Justino H. Pulmonary arteriovenous malformations: An uncharacterized phenotype of Dyskeratosis Congenita and related Telomere Biology Disorders Eur. Respir. J. 2017 49 1601640 10.1183/13993003.01640-2016 27824607 \n20. Chen L.Y. Majerská J. Lingner J. Molecular basis of telomere syndrome caused by CTC1 mutations Genes Dev. 2013 27 2099 2108 10.1101/gad.222893.113 24115768 \n21. Krowka M.J. Wiseman G.A. Burnett O.L. Spivey J.R. Therneau T. Porayko M.K. Wiesner R.H. Hepatopulmonary syndrome: A prospective study of relationships between severity of liver disease, PaO2 response to 100% oxygen, and brain uptake after 99m Tc MAA lung scanning Chest 2000 118 615 624 10.1378/chest.118.3.615 10988181\n\n", "fulltext_license": "CC BY", "issn_linking": "1422-0067", "issue": "20(13)", "journal": "International journal of molecular sciences", "keywords": "Hoyeraal–Hreidarsson syndrome; dyskeratosis congenita; portal hypertension; pulmonary arteriovenous shunts; reduced intensity conditioning; telomeropathy; unrelated peripheral blood stem cell transplantation; vascular aging", "medline_ta": "Int J Mol Sci", "mesh_terms": "D018797:Cell Cycle Proteins; D002675:Child, Preschool; D019871:Dyskeratosis Congenita; D005317:Fetal Growth Retardation; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008831:Microcephaly; D009687:Nuclear Proteins; D036102:Peripheral Blood Stem Cell Transplantation; D017354:Point Mutation", "nlm_unique_id": "101092791", "other_id": null, "pages": null, "pmc": null, "pmid": "31269755", "pubdate": "2019-07-02", "publication_types": "D002363:Case Reports", "references": "10583221;10988181;16332973;17392301;18509123;18560411;19415736;20383216;21520173;21520174;23279657;23538340;23542225;23751955;24115768;25940403;26808564;27128385;27824607;29984823", "title": "Complications for a Hoyeraal-Hreidarsson Syndrome Patient with a Germline DKC1 A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation.", "title_normalized": "complications for a hoyeraal hreidarsson syndrome patient with a germline dkc1 a353v variant undergoing unrelated peripheral blood stem cell transplantation" }	[ { "companynumb": "PHHY2019TW184467", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "050715", "drugbatchnumb": null, 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{ "abstract": "The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM.", "affiliations": "Department of Neurosurgery, Ankara Ataturk Education and Research Hospital, Ankara, Turkey.;Department of Neurosurgery, Ankara Bayındır Hospital, Ankara, Turkey.", "authors": "Kazanci\|Atilla\|A\|;Tekkök\|İsmail Hakkı\|İH\|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.3340/jkns.2015.58.2.163", "fulltext": "\n==== Front\nJ Korean Neurosurg SocJ Korean Neurosurg SocJKNSJournal of Korean Neurosurgical Society2005-37111598-7876The Korean Neurosurgical Society 10.3340/jkns.2015.58.2.163Case ReportPhenytoin Induced Erythema Multiforme after Cranial Radiation Therapy Kazanci Atilla M.D.1Tekkök İsmail Hakkı M.D.21 Department of Neurosurgery, Ankara Ataturk Education and Research Hospital, Ankara, Turkey.2 Department of Neurosurgery, Ankara Bayındır Hospital, Ankara, Turkey.\nAddress for reprints: Atilla Kazanci, M.D. Department of Neurosurgery, Ankara Ataturk Education and Research Hospital, Ankara 06810, Turkey. Tel: +00905057793149, Fax: +90 312 291 27 26, [email protected] 2015 28 8 2015 58 2 163 166 25 8 2014 11 1 2015 14 1 2015 Copyright © 2015 The Korean Neurosurgical Society2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM.\n\nCranial RadiotherapyErythema MultiformePhenytoin\n==== Body\nINTRODUCTION\nTreatment of intracranial malignancies includes prophylactic anti-convulsant and steroid medication in addition to a combination of surgery, radiation therapy and chemotherapy. Phenytoin as a anti-convulsant therapy has been known for variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis for a long time246101113). Erythema multiforme (EM) is a skin reaction that ranges from self-limited cutaneous eruption to a progressive mucocutaneous disease145891315). EM typically presents with self-limited targetoid lesions on the extensor surfaces of extremities and is often associated with underlying infection (commonly herpes simplex) or a hypersensitivity reaction to a variety of medications like sulfonamides, penicillines, quinolones and anti-convulsants124611).\n\nHypersensitivity reaction mechanism caused by anti-convulsant drugs is not clear however, it has been proposed that toxic metabolite of aromatic anti-convulsants could bind the cellular macromolecules causing a secondary immunological response3). In patients receiving phenytoin as a prophylactic anti-convulsant who have also treated with radiotherapy, anti-eppileptics must be administered with caution, and all cutaneous reactions developing subsequently within the radiation site must be promptly evaluated with a high index of suspicion for erythema multiforme.\n\nHerein we report the case of a patient who developed EM after administration of cranial irradiation and phenytoin treatment.\n\nCASE REPORT\nA 41-year-old female patient with left temporal lobe WHO grade IV glioblastome multiforme underwent surgery on the first day after admitting to our hospital (Fig. 1). The patient was given 300 mg/day of phenytoin and 16 mg/day dexamethasone before the surgery. Upon initial diagnosis of glioblastoma multiforme (GBM) after maximal surgical resection the patient underwent radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. She continued taking phenythoin and tapering dosage of dexamethasone. She subsequently underwent whole brain radiation therapy and was given a total dose of 6000 cGy over 5 days per week in doses of 2.0 Gy fractions spaced over 6 weeks. The patient underwent chemotherapy with temozolomide 130 mg/day for 42 days. After 1 month without chemotherapy she was given 6 cycles of 300 mg/day temozolomide for 5 days.\n\nAfter completing radiation therapy and tapering of dexamethasone on the 24th day of continous prophylactic phenytoin therapy the patient developed minor skin reactions on the scalp within the radiation field especially on left temporal side. The maculopappular eruption generalized within a few days to involve the neck, face, trunk and extremities (Fig. 2). Edema on the lips, mucosal lesions consisting of oral erosions, conjunctival suffusion and periorbital edema also evolved. Laboratory serology included a normal blood cell differential with 12% monocytes, 1.9% eosinophils. Transaminase levels were midly elevated-aspartate aminotransferase 49 U/L and alanine aminotransferase 57 U/L. Anti-nuclear antibody (ANA), anti-double stranded DNA (Anti-dsDNA), anti-extractable nuclear antigen (Anti-ENA), anti-neutrophil cytoplasmic antibody (ANCA) were negative and serum immunoglobulin levels were normal. The was no clinical and/or laboratory evidence of a infection or an autoimmune disease.\n\nDermatological consultation was sought and a diagnosis of phenytoin induced EM was considered. Phenytoin was discontinued and patient received intravenous corticosteroid that was tapered over 4 days. The patient was also given topical corticosteroid for oral ulcerations. On the 6th day of discontinuation of phenytoin patient had temporal lobe seizure and levetiracetam 2000 mg/day and carbamezapine 400 mg/day was initiated for seizure prophylaxis. Over the following 1 week resolution of the mucocutaneous lesions occured and the patient completely recovered within 3 weeks after stopping phenytoin.\n\nDISCUSSION\nEM is a mucocutaneous reaction associated with several precipitating factors that include infections and various drugs such as sulfonamides, penicilinle, anti-convulsants, allopurinol and anti-inflammotory drugs1347810). EM typically presents with self-limited targetoid lesions on the extensor surfaces of extremities but skin lesions range from skin rashes to a progressive mucocutaneous disease145891315).\n\nPhenytoin is commonly prescribed as a prophylactic anti-convulsant in patients with intracranial malignancies. Phenytoin induced skin reactions ranging from urticaria to toxic epidermal necrolysis has been reported several times12346891112131415). Skin reactions associated with anti-convulsant therapy mainly occur during the first few days to 8 weeks of anti-convulsant drug administration81011). As in our case skin lesions occured 24 days after continous prophylactic phenytoin therapy.\n\nA generalized hypersensitivity has also been described in approximately 10% of patients receiving phenytoin that consists of fever, arthralgias, peripheral eosinophilia, generalized lymphadenopathy and hepatosplenomegaly1378). This hypersensitivity reaction frequently associated with aromatic anti-convulsants such as phenytoin, phenobarbital and carbamezapine. Anti-convulsants are converted to reactive metabolites and induce cytochrome P450 3A and produce oxidative reactive intermediates that may be implicated in hypersensitivity reactions and then these metabolites excreted from kidney via another hepatic enzyme epoxide hydrolase23589101113). Imbalance between the formation of metabolites and enzymatic detoxification leads to accumulation of metabolites causes them to bind with celluler macromoleculles resulting in a toxic role in type 4 hypersensitivity reactions135810). Baba et al.3) suggested that hypersensitivity reactions developed after craniotomy and surgical trauma could have been involved in decreasing activity of hepatic enzymes due to exposure to anaesthetic agents3). Thus this is a clinical phenomenon that occurs with unusual frequency in patients with brain tumor who undergo radiation therapy while taking phenytoin or other anticonvulsants such as phenobarbital and carbamazepine8). Both carbamazepine and barbiturates have shown cross-sensitivity with phenytoin\n\nRecently management of glioblastoma multiforme progressively changed to maximal surgical resection with postoperative radiotherapy and concurrent chemotherapy. In our case after maximal surgical resection the patient underwent radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. Several reports in literature suggest the existance of a phenomenon in which EM, Stevens-Johnson syndrome or toxic epidermal necrolysis may ocur in patients with brain tumors treated with radiation therapy and anti-convulsant drugs and it was concluded that radiation therapy was responsible because reinstitution of the drugs did not result in recurrence of the reaction. As in our case the clinical picture differed from the classic form of EM in that the erythema began on the scalp and spread to the extremities, progressing to extensive bullous formation16810). As a well recognized phenomenon cutaneous reactions with radiation therapy is usually dose dependent and consists of erythema limited to the radiation field14610). Irradiation can enhance a primary antibody response and impairs T suppressor cells and radiation therapy might promote the development of a hypersensitivity reaction to phenytoin that may be more evident patients receive a tapering dosage of steroids8).\n\nAhmed et al.1) recently used definition EMPACT (E : erythema M : multiforme associated with P : phenytoin and C : cranial radiation T : therapy) to best describe this disorder. Ahmed et al. reviewed 24 patients which had taken phenytoin for variable time periods (mean 40 days) the lesions developed within the port site during the radiation treatments or soon after its completion. In literature many cases, as in our case, the skin rashes and eruptions first ocur in the irradiation area which may resulted in misdiagnosis as a normal radiation reaction and this may cause delaying the diagnosis of EM lesions and more severe syndromes246810). In literature as in our case not only skin eruptions but EM lesions on the irradiation area with pheytoin treatment was described as diagnostic criteria for EMPACT1). It is also reported that the incidence of this syndrome is much more frquent in cases where phenytoin was administered less than 2 months prior to start of radiotherapy, compared to cases where treatment commenced more then 2 months before irradiation1013).\n\nThe optimal treatment for EM is not well defined. Phenytoin should be discontinued immediatelly and high dose intravenous steroid application resolves dermal lesions. For the oral mucosal lesions topical steroid is necessarry8101113). If the lesions are more severe like Stevens-Johnson syndrome or toxic epidermal necrolysis sympthomatic treatment should be applied similiar to that used for burns. Metabolic and electrolyte imbalance should be corrected by replacement of intravenous fluids.\n\nCONCLUSION\nThe prophylactic use of anti-convulsants after brain surgery or during cranial irradiation is very common. In patients receiving phenytoin as a prophylactic anti-convulsant who have also treated with radiotherapy EM is a relatively rare adverse situation. The physician must be aware of the anti-convulsant hypersensitivity syndrome when combined with radiotherapy and all cutaneous reactions developing subsequently within the radiation field must be evaluated with the suspicion of EM. In patients with disseminated rashes phenytoin administration should be discontinued immediately and intravenous steroid treatment should be given and if necessary sympthomatic and supportive treatment should be started similiar to that given to patients with burns.\n\nFig. 1 Preoperative sagital MRI scan showing left temporal lobe glioblastome multiforme.\nFig. 2 A : The maculo-pappular eruptions (smooth skin rash or redness covered by elevated bumps) on the neck, face, trunk and extremities. B : The maculo-pappular rashes on the extremities.\n==== Refs\n1 Ahmed I Reichenberg J Lucas A Shehan JM Erythema multiforme associated with phenytoin and cranial radiation therapy : a report of three patients and review of the literature Int J Dermatol 2004 43 67 73 14693027 \n2 Arif H Buchsbaum R Weintraub D Koyfman S Salas-Humara C Bazil CW Comparison and predictors of rash associated with 15 antiepileptic drugs Neurology 2007 68 1701 1709 \n3 Baba M Karakaş M Aksungur VL Homan S Yücel A Acar MA The anticonvulsant hypersensitivity syndrome J Eur Acad Dermatol Venereol 2003 17 399 401 12834448 \n4 Barbosa LA Teixeira CR Erythema multiforme associated with prophylactic use of phenytoin during cranial radiation therapy Am J Health Syst Pharm 2008 65 1048 1050 18499877 \n5 Lin MS Dai YS Pwu RF Chen YH Chang NC Risk estimates for drugs suspected of being associated with Stevens-Johnson syndrome and toxic epidermal necrolysis : a case-control study Intern Med J 2005 35 188 190 15737140 \n6 Mamon HJ Wen PY Burns AC Loeffler JS Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy Epilepsia 1999 40 341 344 \n7 Man CB Kwan P Baum L Yu E Lau KM Cheng AS Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese Epilepsia 2007 48 1015 1018 17509004 \n8 Micali G Linthicum K Han N West DP Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies Pharmacotherapy 1999 19 223 227 10030773 \n9 Mockenhaupt M Messenheimer J Tennis P Schlingmann J Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics Neurology 2005 64 1134 1138 15824335 \n10 Oner Dincbas F Yörük S Demirkesen C Uzel O Koca S Toxic epidermal necrolysis after cranial radiotherapy and phenytoin treatment Onkologie 2004 27 389 392 15347896 \n11 Pelekanos J Camfield P Camfield C Gordon K Allergic rash due to antiepileptic drugs : clinical features and management Epilepsia 1991 32 554 559 1831121 \n12 Roujeau JC Kelly JP Naldi L Rzany B Stern RS Anderson T Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis N Engl J Med 1995 333 1600 1607 7477195 \n13 Rzany B Correia O Kelly JP Naldi L Auquier A Stern R Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy : a case-control study Lancet 1999 353 2190 2194 10392983 \n14 Welykyj S Gradini R Nakao J Massa M Carbamazepine-induced eruption histologically mimicking mycosis fungoides J Cutan Pathol 1990 17 111 116 2140116 \n15 Wöhrl S Loewe R Pickl WF Stingl G Wagner SN EMPACT syndrome J Dtsch Dermatol Ges 2005 3 39 43 16353748\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1225-8245", "issue": "58(2)", "journal": "Journal of Korean Neurosurgical Society", "keywords": "Cranial Radiotherapy; Erythema Multiforme; Phenytoin", "medline_ta": "J Korean Neurosurg Soc", "mesh_terms": null, "nlm_unique_id": "101467054", "other_id": null, "pages": "163-6", "pmc": null, "pmid": "26361537", "pubdate": "2015-08", "publication_types": "D002363:Case Reports", "references": "17502552;10030773;18499877;10080516;10392983;15737140;15347896;2140116;16353748;7477195;17509004;12834448;14693027;15824335;1831121", "title": "Phenytoin Induced Erythema Multiforme after Cranial Radiation Therapy.", "title_normalized": "phenytoin induced erythema multiforme after cranial radiation therapy" }	[ { "companynumb": "TR-VISTAPHARM, INC.-VER201711-001256", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHENYTOIN" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "040342", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": 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{ "abstract": "Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab.\n\n\n\nThis is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805.\n\n\n\nBetween July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related.\n\n\n\nPyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy.\n\n\n\nJiangsu Hengrui Medicine and National Key R&D Program of China.\n\n\n\nFor the Chinese translation of the abstract see Supplementary Materials section.", "affiliations": "National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].;The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Fudan University Cancer Hospital, Shanghai, China.;Jiangsu Cancer Hospital, Nanjing, China.;Hunan Cancer Hospital, Changsha, China.;Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.;Beijing Cancer Hospital, Beijing, China.;Harbin Medical University Cancer Hospital, Harbin, China.;Liaoning Cancer Hospital & Institute, Shenyang, China.;Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China.;The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Jilin Cancer Hospital, Changchun, China.;The First Bethune Hospital of Jilin University, Changchun, China.;The First Bethune Hospital of Jilin University, Changchun, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.;Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.;Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, China.;Wuhan Union Hospital, Wuhan, China.;The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.;Cancer Centre of Jinling Hospital, Nanjing, China.;Sun Yat-Sen University Cancer Center, Guangzhou, China.;Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China.;Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China.;Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.;Zhejiang Cancer Hospital, Hangzhou, China.;The Third Hospital of Nanchang, Nanchang, China.;West China Hospital, Sichuan University, Chengdu, China.;The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Jiangxi Cancer Hospital, Nanchang, China.;Shandong Tumor Hospital, Jinan, China.;Jiangsu Hengrui Medicine, Shanghai, China.;Jiangsu Hengrui Medicine, Shanghai, China.;Jiangsu Hengrui Medicine, Shanghai, China.", "authors": "Xu\|Binghe\|B\|;Yan\|Min\|M\|;Ma\|Fei\|F\|;Hu\|Xichun\|X\|;Feng\|Jifeng\|J\|;Ouyang\|Quchang\|Q\|;Tong\|Zhongsheng\|Z\|;Li\|Huiping\|H\|;Zhang\|Qingyuan\|Q\|;Sun\|Tao\|T\|;Wang\|Xian\|X\|;Yin\|Yongmei\|Y\|;Cheng\|Ying\|Y\|;Li\|Wei\|W\|;Gu\|Yuanting\|Y\|;Chen\|Qianjun\|Q\|;Liu\|Jinping\|J\|;Cheng\|Jing\|J\|;Geng\|Cuizhi\|C\|;Qin\|Shukui\|S\|;Wang\|Shusen\|S\|;Lu\|Jinsong\|J\|;Shen\|Kunwei\|K\|;Liu\|Qiang\|Q\|;Wang\|Xiaojia\|X\|;Wang\|Hong\|H\|;Luo\|Ting\|T\|;Yang\|Jin\|J\|;Wu\|Yudong\|Y\|;Yu\|Zhiyong\|Z\|;Zhu\|Xiaoyu\|X\|;Chen\|Chunxia\|C\|;Zou\|Jianjun\|J\|;\|\|\|", "chemical_list": "D000178:Acrylamides; D000634:Aminoquinolines; C000622954:pyrotinib; D000077341:Lapatinib; D000069287:Capecitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2", "country": "England", "delete": false, "doi": "10.1016/S1470-2045(20)30702-6", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2045", "issue": "22(3)", "journal": "The Lancet. Oncology", "keywords": null, "medline_ta": "Lancet Oncol", "mesh_terms": "D000178:Acrylamides; D000328:Adult; D000634:Aminoquinolines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011379:Prognosis; D018719:Receptor, ErbB-2; D015996:Survival Rate", "nlm_unique_id": "100957246", "other_id": null, "pages": "351-360", "pmc": null, "pmid": "33581774", "pubdate": "2021-03", "publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.", "title_normalized": "pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of her2 positive metastatic breast cancer phoebe a multicentre open label randomised controlled phase 3 trial" }	[ { "companynumb": "NVSC2021CN036209", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LAPATINIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022059", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1250 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAPATINIB" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CAPECITABINE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1000 MG/M2, BID (ON DAYS 1?14 OF EACH 21?DAY CYCLE)", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1000", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CAPECITABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sudden death", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "XU B, VAN M, MA F, XU X, FENG J, OUYANG Q ET AL.. 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{ "abstract": "Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for the active phase of moderate to severe Graves' orbitopathy (GO). However, acute and severe liver damage has been reported during and after IVMP therapy. In this retrospective study, we investigated risk factors for liver dysfunction during and after IVMP therapy based on 175 Japanese patients with moderate to severe GO and treated at our center between 2003 and 2011. The results showed that seven patients developed severe liver dysfunction with elevated serum alanine aminotransferase (ALT > 300 U/L). Mild (40-100 U/L) and moderate (100-300 U/L) increases of ALT occurred in 62 patients (35%) and 10 patients (6%), respectively. Liver dysfunction was more frequently observed in males, in patients receiving high-dose methylprednisolone, and patients aged over 50 years. Preexistent viral hepatitis was significantly associated with liver dysfunction (65% in patients positive for hepatitis B core antibody and patients positive for hepatitis C virus antibodies). Our study confirmed the association of liver dysfunction with IVMP during and after treatment. It suggests that, in patients with GO, evaluation of preexisting risk factors-including viral hepatitis-and careful weekly monitoring of liver function during IVMP therapy and monthly thereafter for 12 months are warranted.", "affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Department of Ophthalmology, Kurume University School of Medicine, Kurume 830-0011, Japan.;Department of Ophthalmology, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Biostatistics Center, Kurume University, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.", "authors": "Eguchi\|Hiroyuki\|H\|;Tani\|Junichi\|J\|;Hirao\|Saori\|S\|;Tsuruta\|Munehisa\|M\|;Tokubuchi\|Ichiro\|I\|;Yamada\|Kentaro\|K\|;Kasaoka\|Masataka\|M\|;Teshima\|Yasuo\|Y\|;Kakuma\|Tatsuyuki\|T\|;Hiromatsu\|Yuji\|Y\|", "chemical_list": null, "country": "Egypt", "delete": false, "doi": "10.1155/2015/835979", "fulltext": "\n==== Front\nInt J EndocrinolInt J EndocrinolIJEInternational Journal of Endocrinology1687-83371687-8345Hindawi Publishing Corporation 10.1155/2015/835979Clinical StudyLiver Dysfunction Associated with Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy Eguchi Hiroyuki \n1\nTani Junichi \n1\nHirao Saori \n1\nTsuruta Munehisa \n1\nTokubuchi Ichiro \n1\nYamada Kentaro \n1\nKasaoka Masataka \n2\nTeshima Yasuo \n2\nKakuma Tatsuyuki \n3\nhttp://orcid.org/0000-0002-0415-5005Hiromatsu Yuji \n1\n\n\n1Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan2Department of Ophthalmology, Kurume University School of Medicine, Kurume 830-0011, Japan3Division of Biostatistics Center, Kurume University, Kurume 830-0011, JapanYuji Hiromatsu: [email protected] Editor: Carlo Cappelli\n\n2015 28 6 2015 2015 83597931 12 2014 5 5 2015 7 5 2015 Copyright © 2015 Hiroyuki Eguchi et al.2015This 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.Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for the active phase of moderate to severe Graves' orbitopathy (GO). However, acute and severe liver damage has been reported during and after IVMP therapy. In this retrospective study, we investigated risk factors for liver dysfunction during and after IVMP therapy based on 175 Japanese patients with moderate to severe GO and treated at our center between 2003 and 2011. The results showed that seven patients developed severe liver dysfunction with elevated serum alanine aminotransferase (ALT > 300 U/L). Mild (40–100 U/L) and moderate (100–300 U/L) increases of ALT occurred in 62 patients (35%) and 10 patients (6%), respectively. Liver dysfunction was more frequently observed in males, in patients receiving high-dose methylprednisolone, and patients aged over 50 years. Preexistent viral hepatitis was significantly associated with liver dysfunction (65% in patients positive for hepatitis B core antibody and patients positive for hepatitis C virus antibodies). Our study confirmed the association of liver dysfunction with IVMP during and after treatment. It suggests that, in patients with GO, evaluation of preexisting risk factors—including viral hepatitis—and careful weekly monitoring of liver function during IVMP therapy and monthly thereafter for 12 months are warranted.\n==== Body\n1. Introduction\nIntravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for patients with active-phase moderate to severe Graves' orbitopathy (GO) [1]. IVMP is widely used because it is more effective and better tolerated than oral steroids [2, 3]. However, acute and severe liver damage has been reported after pulse therapy, with a roughly estimated morbidity and mortality of 0.8% and 0.3%, respectively [4]. The cumulative dose of IVMP in four patients with fatal liver failure was 8.3–15 g [4, 5] but slightly higher in three patients who died (10.8 ± 3.6 g) than in four patients who recovered (7.9 ± 2.9 g) [4]. Therefore, the European Group of Graves' Orbitopathy (EUGOGO) now recommends that the cumulative dose of MP should be less than 8 g [1, 6].\n\nThe causes of IVMP-associated liver damage are incompletely understood. Thus, the aim of the present study was to investigate the risk factors for liver dysfunction during and after IVMP pulse therapy for GO.\n\n2. Materials and Methods\n2.1. Study Population\nThis was a retrospective study of 175 Japanese patients with moderate to severe GO who were treated in one center from 2003 to 2013. The mean age of the 118 females and 57 males was 51.7 ± 15.5 years. They had been admitted to our university hospital for GO and were treated with an intravenous injection of 1 g of MP daily for 3 consecutive days per week, repeated for three to six cycles, and followed by a tapering dose of oral prednisolone (20 mg/day for 4 weeks, 15 mg/day for 2 weeks, 10 mg/day for 2 weeks, 5 mg/day for 2 weeks, and 5 mg/2 days for 2 weeks). The daily dose of MP was reduced to 0.5 g except in cases with optic neuropathy after the recommendation by EUGOGO in 2008 [1]. Heart rate and ECG were monitored during the intravenous infusion of MP, administered every 2-3 h. In addition, 100 of the 175 patients were treated with orbital irradiation therapy (2 Gy/day, 10 times; total dose = 20 Gy) either during or after IVMP pulse therapy. All patients were given artificial tear drops to protect the cornea. Histamine receptor 2 antagonists or proton pump inhibitors were administered for all the cases. Bisphosphonates were administered in 82 patients to protect steroid-induced osteoporosis.\n\n2.2. Biochemical Examination and Diagnosis of Thyroid Diseases\nThyroid diseases were diagnosed by measuring serum-free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroglobulin, anti-thyroglobulin antibody, anti-thyroid peroxidase antibody, and anti-thyrotropin receptor antibodies (TRAbs). TRAbs were measured using three commercial kits: TRAb 1st generation (TRAb Cosmic III, Cosmic, Tokyo, Japan), TRAb 2nd generation, human TRAb (Yamasa, Tokyo, Japan) and TSAb (Yamasa TSAb kit), and thyroid 123I uptake on 123I scintigraphy. Orbitopathy was estimated by ophthalmologists using a modified NOSPECS classification [7] and the clinical activity score (CAS) [1]. Magnetic resonance imaging was also performed before and after pulse therapy, as previously reported [8]. Graves' disease was detected in 139 patients, 29 patients were euthyroid without a history of Graves' disease, and 7 patients had hypothyroidism without a history of Graves' disease. Orbitopathy with NOSPECS class VI was determined in 8 patients, class V in 3 patients, class IV in 139 patients, class III in 23 patients, and class II in 2 patients.\n\nLiver function tests were performed once a week during pulse therapy and repeated at every visit thereafter for 1 year. Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and hepatitis C virus antibody (HCVAb) were measured before pulse therapy. The one patient who was HBsAg-positive consulted with a hepatologist, who prescribed 0.5 mg of entecavir, during and after pulse therapy. In addition, 43 patients were HBcAb-positive and 17 were HCVAb-positive. They likewise consulted with hepatologists before pulse therapy. Serum HBV-DNA was not detected in any patient. HBV-DNA and HCV-RNA were also monitored. Liver dysfunction was classified based on serum alanine aminotransferase (ALT) and total bilirubin levels as mild (ALT: 40–100 U/L), moderate (ALT: 100–300 U/L), or severe (ALT > 300 U/L or total bilirubin: >3 mg/dL).\n\n2.3. Clinical Characteristics of Patients with GO\nFemale and male GO patients significantly differed with respect to age, body mass index (BMI), smoking habits, alcohol habits, and HBcAb positivity before pulse therapy (Table 1). Human TRAb and TSAb levels were significantly higher in female than in male patients before IVMP pulse therapy.\n\n2.4. Statistical Analysis\nStatistical analysis was performed using JMP Pro software (version 11.0.0, SAS Institute, USA). Data are expressed as the mean ± standard deviation. Statistical comparisons were performed using Student's t-test, one-way ANOVA, or Mann-Whitney U test for the analysis of continuous variables. The χ\n2 test or Fisher's exact probability test was used to analyze 2 × 2 or 2 × 4 tables. Multivariate logistic regression analyses were carried out to evaluate the risk factors for liver dysfunction, using exact method (LogXact, Cytel Inc., USA). In all tests, a P value < 0.05 was considered to indicate significance.\n\n3. Results\n3.1. Liver Dysfunction\nIncreases of ALT during and/or after pulse therapy were detected in 79 patients (45%) (Table 2). Mild (ALT 40–100 U/L), moderate (ALT 100–300 U/L), and severe (ALT > 300 U/L) increases of serum ALT were measured in 62 patients (35%), 10 patients (6%), and 7 patients (4%), respectively. All patients with severe liver dysfunction were female and most of them were female. Two were HBcAb positive and one of them developed jaundice with ALT 945 U/L, one day after the cessation of IVMP. Her total bilirubin 8 weeks after the cessation of IVMP was 18.45 mg/dL. Single and cumulative doses of IVMP were 0.5 g and 3.5 g, respectively. HBV-DNA was not detected in patients with severe liver dysfunction. Anti-nuclear and anti-single-stranded DNA antibodies were also negative, as were anti-smooth muscle antibody, and anti-double-stranded DNA antibody in those patients. The HBV carrier taking entecavir prescribed by the hepatologist did not show the elevation of ALT.\n\n3.2. Factors Associated with Liver Dysfunction during or after Pulse Therapy for GO\nLiver dysfunction occurred more frequently in male patients (P < 0.0012) and in patients over the age of 50 years (P < 0.0009). BMI was significantly higher in patients with mild liver dysfunction than in those without liver dysfunction (23.3 ± 4.33 kg/m2 versus 22.0 ± 3.39 kg/m2, Student's t-test, P = 0.043, data not shown). Liver dysfunction was not associated with smoking or alcohol habit but it was associated with a high dose of MP (cumulative dose >8 g versus <8 g, 2 × 2 table, χ\n2 = 6.280, P = 0.0122). Preexistent viral hepatitis was significantly associated with liver dysfunction during and after pulse therapy (P = 0.0035). HBcAb was positive in 43 GO patients (25%) before pulse therapy. In 28 of them (65%), ALT was significantly increased (P = 0.01125), although in most the increase was mild. HCVAb was positive in 17 GO patients (10%) before pulse therapy. In this group, 11 patients (65%) had increased ALT levels (P = 0.01132).\n\n3.3. Multivariate Logistic Regression Analysis\nMultivariate logistic regression analysis showed that age, gender, and cumulative MP dose (>8 g) were associated with liver dysfunction (Table 2).\n\n4. Discussion\nAlthough IVMP pulse therapy is widely used as the first-line treatment for active moderate-to-severe orbitopathy, severe related side effects have been reported, the most common of which is hepatotoxicity. In the recent review by Zang et al. [9], the morbidity and mortality of GO patients treated with IVMP pulse therapy were 6.5% and 0.6%, respectively. Fatal hepatotoxicity was reported to be associated with a cumulative dose of IVMP > 8 g. In two studies, the cumulative doses were 8.3–15 g [4, 5]. EUGOGO now recommends that the cumulative dose of IVMP does not exceed 8 g [1].\n\nIn our series of 175 patients, seven patients (4.0%) developed severe liver dysfunction. The rate of morbidity was similar to the previous report [9]. The cumulative doses of MP were more than 8 g in 5 out of seven patients. However, single and cumulative doses of IVMP in a patient with jaundice were 0.5 g and 3.5 g, respectively.\n\nKoga et al. [10] reported two fatal cases of HBV carriers after corticosteroid therapy, and the frequent reactivation of HBV after immune suppressive therapy, such as with rituximab, was noted [11]. Therefore, in GO patients during IVMP therapy, the reactivation of HBV leading to acute liver failure remains a concern, although its occurrence is rare [4, 9, 12, 13]. Indeed, in the series of Le Moli et al. [12], none of the 27 patients with GO suffered serious liver damage. Wichary and Gasińska [13] concluded that the risk of HBV reactivation is low, based on their experience with 30 patients treated with IVMP. Those studies suggest that it is difficult to predict who will develop severe liver failure, such that it is important to carefully monitor patients during and after IVMP therapy.\n\nOur study identified risk factors for mild to moderate liver dysfunction during and after IVMP therapy for GO. Among male patients, a mild elevation of ALT was associated with a cumulative dose of IVMP > 8 g; in female patients, a moderate elevation of ALT was associated with age over 50 years. A history of HBV and HCV infection also contributed to a high prevalence of hepatotoxicity, as approximately 25% of our GO patients were HBcAb-positive and 10% were HCVAb-positive before pulse therapy. Within this group, 65% had increased ALT levels during and/or after pulse therapy. Multivariate logistic regression analysis showed that gender, age, and cumulative dose of MP were associated with liver dysfunction. Our study in Japanese patients suggests that viral hepatitis, gender, age, and cumulative dose are predisposing risk factors for hepatotoxicity during and after IVMP therapy. The current study also supports recommendations of a cumulative dose of MP < 8 g. However, as even this dose may not be completely safe, careful monitoring of GO patients receiving IVMP is recommended both during and 12 months after therapy.\n\nAlthough the mechanisms of mild to severe hepatotoxicity remain unclear, reactivation of viral hepatitis [4, 10, 11], a direct toxicity of MP [12–14], and exacerbation of autoimmune hepatitis have been suggested [15, 16]. Le Moli et al. [12] reported that mild elevations in liver enzymes following IVMP were dose dependent. The toxic effect of glucocorticoids on hepatocytes, leading to drug-induced steatohepatitis, is thought to involve mitochondrial injury because of the impaired β-oxidation of fatty acids, with subsequent generation of reactive oxygen species and ATP depletion [17].\n\nSalvi et al. [15] and Marinò et al. [16] reported the exacerbation of autoimmune hepatitis with severe liver dysfunction during IVMP therapy. In our series, two patients were positive for antinuclear and anti-smooth muscle antibodies but in both cases liver dysfunction was mild.\n\nThe drug-drug interaction may be another possible mechanism of liver dysfunction [18]. None of patients received aspirin in combination of Ramipril or clopidogrel.\n\nThere were several limitations to this study. First, it was retrospective in design. However, it allowed us to assess the effect of single and cumulative doses of IVMP, because in line with the EUGOGO's recommendation we reduced the single dose of IVMP from 1 g to 0.5 g. Another limitation of the study was the small number of patients, which prevented definite conclusions because of the low incidence of severe liver dysfunction. Additionally, no histopathological examinations were done and the effectiveness of IVMP for GO was not evaluated. Therefore, further prospective studies are indicated to assess the hepatotoxicity of IVMP during and after pulse therapy for GO.\n\nIn conclusion, liver dysfunction is frequently associated with pulse therapy for GO, both during and after treatment. Our study supports the careful evaluation of preexisting risk factors (especially viral hepatitis, age, gender, body mass index, and smoking history) before initiating IVMP therapy in GO patients. In these patients, strict monitoring of liver function once a week during pulse therapy and every month thereafter for the next 12 months is warranted.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nTable 1 Clinical characteristic of patients with Graves' orbitopathy.\n\n\tTotal\tMale\tFemale\tMale versus female\t\n\t\nN = 175\t\nN = 57\t\nN = 118\t\nP value\t\n\n\n\t\nAge (yr)\t51.7 ± 15.5\t55.9 ± 16.3\t49.6 ± 11.9\t0.012\t\n\n\n\t\nBMI (kg/m2)\t22.5 ± 3.7\t23.4 ± 3.8\t22.1 ± 2.7\t0.021\t\n\n\n\t\nHBcAb (+)\t43 (25%)\t21 (37%)\t22 (19%)\t0.0102\t\n\n\n\t\nHCVAb (+)\t17 (10%)\t9 (16%)\t8 (7%)\t0.0677\t\n\n\n\t\nHBcAb (−) HCVAb (−)\t122 (70%)\t31 (54%)\t91 (77%)\t—\t\n\n\n\t\nIVMP > 8 g \t118 (67%)\t40 (70%)\t78 (66%)\t0.5884\t\n\n\n\t\nSmoking (+)\t57 (33%)\t27 (47%)\t30 (25%)\t0.0041\t\n\n\n\t\nAlcohol (+)\t48 (27%)\t28 (49%)\t20 (17%)\t0.0001\t\n\n\n\t\nCAS\t3.1 ± 1.7\t3.2 ± 1.8\t3.0 ± 1.7\t0.8263\t\n\n\n\t\nTRAb (%)\t29.3 ± 27.3\t25.8 ± 26.1\t30.8 ± 27.8\t0.2987\t\n\n\n\t\nhTRAb (IU/L)\t17.7 ± 44.4\t8.10 ± 11.4\t21.9 ± 52.2\t0.0407\t\n\n\n\t\nTSAb (%)\t1262 ± 1480\t931 ± 1229\t1404 ± 1559\t0.0346\t\n\n\n\t\n \t \t \t \t\nMean ± SD\t\nBMI, body mass index; HBcAb, anti-hepatitis B core antibody; HCVAb, anti-hepatitis C virus antibody; IVMP, intravenous injection of methylprednisolone; CAS, clinical activity score; TRAb, anti-thyrotrophin antibody; hTRAb, human TRAb; TSAb, thyroid stimulating antibody.\n\nTable 2 Risk factors associated with liver dysfunction during and/or after intravenous methylprednisolone pulse therapy for Graves' orbitopathy.\n\n\tNumber of patients\t Liver dysfunction\tUnivariate\tMultivariate analysis \t\nALT (IU/L) \t\nFisher's exact probability test\t\nMultinomial logit model for\nan unordered response\t\n<40\t40–100\t100–300\t>300\t95% CI\t2 sided\t\n2 × 4\tLower\tUpper\t\nP value \t\nTotal\t175\t96 (55%)\t62 (35%)\t10 (6%)\t7 (4%)\t \t \t \t \t\n\n\n\t\nMale\t57\t21 (37%)\t31 (54%)\t5 (9%)\t0 (0%)\t\nχ\n2 = 18.34\t \t \t \t\nFemale\t118\t75 (64%)\t31 (26%)\t5 (4%)\t7 (6%)\t\nP = 0.000278\t0.1348\t1.646\t0.01895\t\n\n\n\t\nHBcA b (+)\t43\t15 (35%)\t24 (56%)\t2 (5%)\t2 (5%)\t\nχ\n2 = 11.01\t \t \t \t\n\nP = 0.01125\t \t \t \t\nHCVAb (+)\t17\t6 (35%)\t6 (35%)\t4 (24%)\t1 (6%)\t\nχ\n2 = 11.94\t \t \t \t\n\nP = 0.01132\t \t \t \t\nHBcAb (+) and/or HCVAb (+)\t53\t19 (36%)\t26 (49%)\t5 (9%)\t3 (6%)\t\nχ\n2 = 11.36\n\nP = 0.008867∗\n\t \n\n−0.245\t \n\n1.417\t \n\n0.1846\t\nHBcAb (−) HCVAb (−)\t122\t77 (63%)\t36 (30%)\t5 (4%)\t4 (3%)\t—\t \t \t \t\n\n\n\t\nAge\t \t \t \t \t \t \t \t \t \t\n >50 yr\t95\t41 (43%)\t45 (47%)\t8 (8%)\t1 (1%)\t\nχ\n2 = 20.72\t0.03396\t1.553\t0.03972\t\n ≦50 yr\t80\t55 (69%)\t17 (21%)\t2 (3%)\t6 (8%)\t\nP = 0.00004\t \t \t \t\n\n\n\t\nIVMP\t \t \t \t \t \t \t \t \t \t\n >8 g\t118\t57 (48%)\t47 (40%)\t9 (8%)\t5 (4%)\t\nχ\n2 = 7.187\t0.1012\t1.640\t0.02426\t\n <8 g\t57\t39 (89%)\t15 (26%)\t1 (2%)\t2 (4%)\t\nP = 0.06052\t \t \t \t\n\n\n\t\nSmoking\t \t \t \t \t \t \t \t \t \t\n (+)\t57\t26 (46%)\t24 (42%)\t4 (7%)\t3 (5%)\t\nχ\n2 = 2.969\t \t \t \t\n (−)\t118\t70 (59%)\t38 (32%)\t6 (5%)\t4 (3%)\t\nP = 0.3887\t \t \t \t\n\n\n\t\nAlcohol\t \t \t \t \t \t \t \t \t \t\n (+)\t48\t24 (50%)\t19 (40%)\t3 (6%)\t2 (4%)\t\nχ\n2 = 0.6445\t \t \t \t\n (−)\t127\t72 (57%)\t43 (34%)\t7 (6%)\t5 (4%)\t\nP = 0.9176\t \t \t \t\n\n∗Compared to patients without HBcAb or HCVAb.\n\nALT, alanine aminotransferase; HBcAb, anti-hepatitis B core antibody; HCVAb, anti-hepatitis C virus antibody; IVMP, intravenous injection of methylprednisolone.\n==== Refs\n1 Bartalena L. Baldeschi L. Dickinson A. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO European Journal of Endocrinology 2008 158 3 273 285 10.1530/eje-07-0666 2-s2.0-40949140917 18299459 \n2 Marcocci C. Bartalena L. Tanda M. L. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study Journal of Clinical Endocrinology and Metabolism 2001 86 8 3562 3567 10.1210/jc.86.8.3562 2-s2.0-17944370142 11502779 \n3 Kahaly G. J. Pitz S. Hommel G. Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in graves' orbitopathy Journal of Clinical Endocrinology and Metabolism 2005 90 9 5234 5240 10.1210/jc.2005-0148 2-s2.0-24344492353 15998777 \n4 Marinól M. Morabito E. Brunetto M. R. Bartalena L. Pinchera A. Marocci C. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves' ophthalmopathy Thyroid 2004 14 5 403 406 10.1089/105072504774193276 2-s2.0-2942614927 15186621 \n5 Weissel M. Hauff W. Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease Thyroid 2000 10 6 p. 521 2-s2.0-0033933033 \n6 Marcocci C. Watt T. Altea M. A. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy: a questionnaire survey among members of the European Thyroid Association European Journal of Endocrinology 2012 166 2 247 253 10.1530/eje-11-0779 2-s2.0-84856100099 22058081 \n7 Classification of eye changes of Graves' disease Thyroid 1992 2 3 235 236 10.1089/thy.1992.2.235 1422237 \n8 Hiromatsu Y. Kojima K. Ishisaka N. Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy Thyroid 1992 2 4 299 305 10.1089/thy.1992.2.299 2-s2.0-0027048376 1493371 \n9 Zang S. Ponto K. A. Kahaly G. J. Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity The Journal of Clinical Endocrinology and Metabolism 2011 96 2 320 332 10.1210/jc.2010-1962 2-s2.0-79951716568 21239515 \n10 Koga Y. Kumashiro R. Yasumoto K. Two fatal cases of hepatitis B virus carriers after corticosteroid therapy for bronchial asthma Internal Medicine 1992 31 2 208 213 10.2169/internalmedicine.31.208 2-s2.0-0026722143 1600269 \n11 Seto W. K. Chan T. S. Hwang Y. Y. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study Journal of Clinical Oncology 2014 32 3736 3743 25287829 \n12 Le Moli R. Baldeschi L. Saeed P. Regensburg N. Mourits M. P. Wiersinga W. M. Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy Thyroid 2007 17 4 357 362 10.1089/thy.2006.0267 2-s2.0-34248657570 17465867 \n13 Wichary H. Gasińska T. Methylprednisolone and hepatotoxicity in Graves' ophthalmopathy Thyroid 2012 22 1 64 69 10.1089/thy.2010.0158 2-s2.0-84855427170 22029719 \n14 Kaplowitz N. Drug-induced liver injury Clinical Infectious Diseases 2004 38 supplement 2 S44 S48 10.1086/381446 2-s2.0-1542327565 14986274 \n15 Salvi M. Vannucchi G. Sbrozzi F. Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto's thyroiditis: case report Thyroid 2004 14 8 631 634 10.1089/1050725041692927 2-s2.0-4143065899 15320978 \n16 Marinò M. Morabito E. Altea M. A. Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves Journal of Endocrinological Investigation 2005 28 3 280 284 10.1007/bf03345386 2-s2.0-21444443356 15952415 \n17 Farrell G. C. Drugs and steatohepatitis Seminars in Liver Disease 2002 22 2 185 194 10.1055/s-2002-30106 2-s2.0-0036247430 12016549 \n18 Goyal R. K. Srivastava D. Lessnau K.-D. Clopidogrel-induced hepatocellular injury and cholestatic jaundice in an elderly patient: case report and review of the literature Pharmacotherapy 2009 29 5 608 612 10.1592/phco.29.5.608 2-s2.0-66249124628 19397467\n\n", "fulltext_license": "CC BY", "issn_linking": "1687-8337", "issue": "2015()", "journal": "International journal of endocrinology", "keywords": null, "medline_ta": "Int J Endocrinol", "mesh_terms": null, "nlm_unique_id": "101516376", "other_id": null, "pages": "835979", "pmc": null, "pmid": "26221141", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "1600269;14986274;11502779;25287829;15952415;12016549;18299459;17465867;10907999;22058081;1422237;15998777;15186621;21239515;1493371;15320978;22029719;19397467", "title": "Liver Dysfunction Associated with Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy.", "title_normalized": "liver dysfunction associated with intravenous methylprednisolone pulse therapy in 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LIVER DYSFUNCTION ASSOCIATED WITH INTRAVENOUS METHYLPREDNISOLONE PULSE THERAPY IN PATIENTS WITH GRAVES^ ORBITOPATHY. 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LIVER DYSFUNCTION ASSOCIATED WITH INTRAVENOUS METHYLPREDNISOLONE PULSE THERAPY IN PATIENTS WITH GRAVES^ ORBITOPATHY.. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY. 2015;2015:835979 (5 PAGES)", "literaturereference_normalized": "liver dysfunction associated with intravenous methylprednisolone pulse therapy in patients with graves orbitopathy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150818", "receivedate": "20150818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11389951, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]
{ "abstract": "This paper describes the association of two unusual side effects of treatment with isotretinoin for severe acne: paronychia and excess granulation tissue in the nails furrows. We report a case of male patient aged 19 years, who in the course of the 36th week of treatment with isotretinoin for acne grade III showed erythema, edema, excess granulation tissue and onychocryptosis in various nail beds of hands and feet, with no history of trauma associated. A literature review revealed few reports of these adverse events, and two clinical patterns of exuberant granulation tissue has been described: one in periungual location and other in lesions of previous acne. The rarity and lack of knowledge on the best treatment for granuloma-like reactions make this theme a considerable challenge.", "affiliations": "Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.", "authors": "Figueiras\|Daniela de Almeida\|Dde A\|;Ramos\|Ticiana Batista\|TB\|;Marinho\|Ayana Karla de Oliveira Ferreira\|AK\|;Bezerra\|Milena Soneley Mendonça\|MS\|;Cauas\|Renata Cavalcanti\|RC\|", "chemical_list": "D015474:Isotretinoin", "country": "Spain", "delete": false, "doi": null, "fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolabdAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20163817Case ReportParonychia and granulation tissue formation during treatment with\nisotretinoin\n Figueiras Daniela de Almeida 1Ramos Ticiana Batista 1Marinho Ayana Karla de Oliveira Ferreira 1Bezerra Milena Soneley Mendonça 1Cauas Renata Cavalcanti 11 Instituto Materno Infantil Professor Fernando\nFigueira (IMIP) – Recife (PE), Brazil.Mailing address: Daniela de Almeida Figueiras, Rua dos Coelhos,\n300, Boa Vista, 50070-902 - Recife -PE. Brazil Email:\[email protected] 2016 Mar-Apr 2016 91 2 223 225 05 7 2014 04 11 2014 © 2016 by Anais Brasileiros de\nDermatologia2016This is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium provided the original work is properly cited.This paper describes the association of two unusual side effects of treatment\nwith isotretinoin for severe acne: paronychia and excess granulation tissue in\nthe nails furrows. We report a case of male patient aged 19 years, who in the\ncourse of the 36th week of treatment with isotretinoin for acne grade III showed\nerythema, edema, excess granulation tissue and onychocryptosis in various nail\nbeds of hands and feet, with no history of trauma associated. A literature\nreview revealed few reports of these adverse events, and two clinical patterns\nof exuberant granulation tissue has been described: one in periungual location\nand other in lesions of previous acne. The rarity and lack of knowledge on the\nbest treatment for granuloma-like reactions make this theme a considerable\nchallenge.\n\nParonychiaGranulation tissueRetinoids\n==== Body\nINTRODUCTION\nIsotretinoin is effective and widely used in the treatment of nodulocystic acne, acne\nconglobata, acne with risk of permanent scarring and those resistant to the use of\nsystemic antibiotics and topical agents, as indicated in the letter from Kanigsberg\n& Des Groseilliers.1\n\nAdverse events of isotretinoin are well known as teratogenicity, myalgias and\narthralgias, hypertriglyceridemia, hypercholesterolemia and elevated\ntransaminases.\n\nIt is also associated with numerous adverse events including skin cheilitis, facial\ndermatitis, xerosis, rash, conjunctivitis, epistaxis, photosensitivity and dryness\nof mucous membranes. These are commonly observed and generally do not limit its\nuse.\n\nRarely patients may have stimulation of granulation tissue, leading to pyogenic\ngranuloma eruptions of acne lesions in areas of trauma and in nail folds; paronychia\nmay also occur.2,3 Knowing these unusual adverse events is important for the\nclinical management of patients, but its exact pathogenesis remains unclear.\n\nCASE REPORT\nMan, aged 19 years, with acne grade III, without comorbidities, pre-existing nail\nproblems or prior use of medication. He started treatment with isotretinoin at a\ndose of 40 mg/day (0.54 mg/kg/day).\n\nIn the sixth month of treatment, the patient presented edema, erosion and periungual\nerythema with serous discharge in 20 nails and onychocryptosis with excessive\ngranulation tissue on toes. He reported to have undergone treatment with “topic\ncreams” and compresses with boric acid solution prescribed in the emergency\ndepartment, with improvement of the lesions on the hands. Upon returning to our\nservice, the patient showed lesions in the first and second toes bilaterally and on\nthe right toe (Figures 1, 2 and 3).\n\nFigure 1 Paronychia and granulation tissue in feet, secondary to the use of\nisotretinoin\n\n\n\nFigure 2 Pyogenic-like granuloma and paronychia in lateral edge of the first and\nsecond right toes\n\n\n\nFigure 3 Excess of periungueal granulation tissue and paronychia, located in the\nfirst left toe\n\n\n\nTreatment with oral antibiotics was performed, with course of prednisone 40 mg/day,\ncompress with boric acid solution and guidance on the use of appropriate footwear.\nThe isotretinoin was maintained until obtaining a cumulative dose of 120 mg/kg,\ntotaling 7 months.\n\nAfter the end of treatment with isotretinoin, the patient evolved with improvement of\nparonychia and granulation tissue on toes, but with persistence of onychocryptosis\nin hallux valgus. Subsequently, the patient was submitted to matricectomy with\ncomplete resolution of the disease (Figure\n4).\n\nFigure 4 Two months after the completion of matricectomy: patient presented\nresolution of onicocriptosis without recurrence of the lesions on\ntoes\n\n\n\nDISCUSSION\nIsotretinoin was first introduced in the United States in 1982 for the treatment of\nnodulocystic acne, being the only medication that affects all of the major\netiological factors involved in acne. Although isotretinoin is a highly effective\ndrug, its clinical use has always been associated with reports of adverse events\nwith several implications for the patient. It is therefore essential that physicians\nbe aware of the adverse events that may occur during therapy with isotretinoin.\n4\n\nExuberant granulation tissue is described in the literature in patients using\nisotretinoin for acne treatment, but its occurrence is rare with few reports\ndescribed.\n\nThe largest series conducted in 1988 reported 4 cases of paronychia caused by\nexcessive growth of the lateral and distal nail folds, with an excess of granulation\ntissue associated. 5 Multiple\nfingers were involved in all patients and the attempt to restart isotretinoin in one\npatient led to the resurgence of previous lesions, suggesting causality.\n\nThe exact mechanism by which retinoids may lead to the development of granulation\ntissue in skin is not well known. Baran et al suggest that, in susceptible patients,\nexcess retinoids would lead to exacerbation of their functions in epithelial level\nof the nail matrix, generating local exfoliative dermatitis, with accumulation of\nscales in the nail folds. 6 The\nscales would act as foreign bodies, causing inflammation and formation of\ngranulation tissue. The nail fragility may also lead to the formation of nail\nspicules that, when introduced in the periungual tissue, would stimulate the\nappearance of granulation tissue and the ingrown toenail. Finally, the skin\nfragility of the periungual tissue under high doses of retinoids, associated with\ntrauma and/or local bacterial infection, may stimulate the formation of granulation\ntissue.\n\nIsotretinoin is also known to cause exuberant granulation tissue or pyogenic-like\ngranuloma lesions in acne sites between the 3rd and 12th week\nof treatment. 7 Reuben et al.\nsuggest that, according to the characteristics of the treatment group, such event\nmay not be as rare as previously thought. They observed the occurrence of exuberant\ngranulation tissue in 3 patients out of a total of 16 who used the drug.8 Therefore, it is reasonable to\nsuggest that it would cause such changes in other parts of the body.\n\nIn addition, periungual exuberant granulation tissue of both fingers and toes is a\ndocumented adverse event of other retinoids therapies. Campbell et al reported 6\npatients who develop this complication during therapy with etretinate for\npsoriasis.9 These lesions\nappear to be idiosyncratic and unrelated to the daily dose or total cumulative dose.\nSimilar comment can be made regarding our patient who developed the first lesions\nwith 6 months of treatment without having any change in the dosages used.\n\nThus, the knowledge of this unusual adverse event is important for the clinical\nmanagement of patients treated with isotretinoin, and it seems that it is not\nnecessary to discontinue it for the resolution of the lesion. Thus, advantages and\ndisadvantages of discontinuing therapy for this problem should be carefully weighed.\nAccording to the literature, a course of 2-3 weeks of topical steroid and antibiotic\non the occlusion is the first line of treatment for periungual pyogenic granuloma.\n10 In cases where the\nlocal treatment is insufficient, surgical removal becomes necessary.\n\nConflict of Interest: None.\n\nFinancial Support: None.\n\n Study performed at Instituto Materno Infantil Professor Fernando Figueira (IMIP)\n– Recife (PE), Brazil.\n==== Refs\nREFERENCES\n1 Kanigsberg N DesGroseilliers JP Use of 13-cis-retinoic acid in cystic acne Can Med Assoc J 1983 129 224 224 228 228 6222787 \n2 Exner JH Dahod S Pochi PE Pyogenic granuloma-like acne lesions during isotretinoin\ntherapy Arch Dermatol 1983 119 808 811 6225396 \n3 Brelsford M Beute TC Preventing and managing the side effects of\nisotretinoin Semin Cutan Med Surg 2008 27 197 206 18786498 \n4 Charakida A Mouser PE Chu AC Safety and side effects of the acne drug, oral\nisotretinoin Expert Opin Drug Saf 2004 3 119 129 15006718 \n5 Bigby M Stern RS Adverse reactions to isotretinoin. A report from the Adverse Drug\nReaction Reporting System J Am Acad Dermatol 1988 18 543 552 3280622 \n6 Baran R Etretinate and the nails (study of 130 cases) possible mechanisms\nof some side-effects Clin Exp Dermatol 1986 11 148 152 3720014 \n7 Hagler J Hodak E David M Sandbank M Facial pyogenic granuloma-like lesions under isotretinoin\ntherapy Int J Dermatol 1992 31 199 200 1533205 \n8 Azulay RD Abulafia LA Costa JAN Sodré CT Tecido de granulação exuberante: efeito\ncolateral da terapêutica com\nisotretinoína An Bras Dermatol 1985 60 179 182 \n9 Campbell JP Grekin RC Ellis CN Matsuda-John SS Swanson NA Voorhees JJ Retinoid therapy is associated with excess granulation tissue\nresponses J Am Acad Dermatol 1983 9 708 713 6227639 \n10 Piraccini BM Bellavista S Misciali C Tosti A de Berker D Richert B Periungual and subungual pyogenic granuloma Br J Dermatol 2010 163 941 953 20545691\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0365-0596", "issue": "91(2)", "journal": "Anais brasileiros de dermatologia", "keywords": null, "medline_ta": "An Bras Dermatol", "mesh_terms": "D000152:Acne Vulgaris; D006097:Granulation Tissue; D017789:Granuloma, Pyogenic; D006801:Humans; D015474:Isotretinoin; D008297:Male; D009260:Nail Diseases; D010304:Paronychia; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "0067662", "other_id": null, "pages": "223-5", "pmc": null, "pmid": "27192525", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15006718;6222787;6225396;6227639;20545691;3280622;1533205;18786498;3720014", "title": "Paronychia and granulation tissue formation during treatment with isotretinoin.", "title_normalized": "paronychia and granulation tissue formation during treatment with isotretinoin" }	[ { "companynumb": "BR-MYLANLABS-2016M1023995", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "ISOTRETINOIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "075945", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG/DAY (0.54 MG/KG/DAY); A CUMULATIVE DOSE OF 120 MG/KG, TOTALLING 7 MONTHS", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISOTRETINOIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Excessive granulation tissue", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Ingrowing nail", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paronychia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "FIGUEIRAS DA, RAMOS TB, MARINHO AKOF, BEZERRA MSM, CAUAS RC. PARONYCHIA AND GRANULATION TISSUE FORMATION DURING TREATMENT WITH ISOTRETINOIN. ANAIS-BRASIL-DERMATOL 2016;91(2):223-225.", "literaturereference_normalized": "paronychia and granulation tissue formation during treatment with isotretinoin", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20160610", "receivedate": "20160610", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12455796, "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" }, { "companynumb": "BR-AKORN PHARMACEUTICALS-2016AKN00406", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ISOTRETINOIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "076485", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "40 MG, 1X/DAY (0.54 MG/KG/DAY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACNE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISOTRETINOIN" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Excessive granulation tissue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Ingrowing nail", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Paronychia", "reactionmeddraversionpt": "19.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "FIGUEIRAS DA, RAMOS TB, MARINHO AKOF, BEZERRA MSM, CAUAS RC. PARONYCHIA AND GRANULATION TISSUE FORMATION DURING TREATMENT WITH ISOTRETINOIN. AN BRAS DERMATOL (DOI: 10.1590/ABD1806-4841.20163817). 2016;91(2):223-225", "literaturereference_normalized": "paronychia and granulation tissue formation during treatment with isotretinoin", "qualification": "3", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20160705", "receivedate": "20160705", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12527599, "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": "Immunoglobulin G4 (IgG4)-related disease is a systemic autoimmune disease that can affect various organs. Corticosteroid therapy is generally an effective treatment; however, IgG4-related aortic lesions pose a risk of aortic rupture related to corticosteroid use. Here, we report a case of IgG4-related periaortitis complicated with a false aneurysm during corticosteroid therapy. Although endovascular repair was successfully performed, autoimmune pancreatitis and sclerosing cholangitis emerged after surgery. The multiple lesions associated with IgG4-related disease were resolved through continuous corticosteroid therapy. Our case suggests that both appropriate surgical intervention and continuous corticosteroid therapy are essential for the treatment of IgG4-related periaortitis.", "affiliations": "Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan. Electronic address: [email protected].;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba, Japan.", "authors": "Ikeda\|Akihiko\|A\|;Mitomi\|Kisato\|K\|;Konishi\|Taisuke\|T\|;Matsuzaki\|Kanji\|K\|;Jikuya\|Tomoaki\|T\|;Hiramatsu\|Yuji\|Y\|", "chemical_list": "D000305:Adrenal Cortex Hormones; D007074:Immunoglobulin G", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0890-5096", "issue": "29(7)", "journal": "Annals of vascular surgery", "keywords": null, "medline_ta": "Ann Vasc Surg", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D017541:Aneurysm, False; D001014:Aortic Aneurysm; D001027:Aortography; D001327:Autoimmune Diseases; D019917:Blood Vessel Prosthesis Implantation; D015209:Cholangitis, Sclerosing; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D010195:Pancreatitis; D012185:Retroperitoneal Fibrosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "8703941", "other_id": null, "pages": "1452.e5-9", "pmc": null, "pmid": "26122411", "pubdate": "2015-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Endovascular Repair of a False Aneurysm Developing from IgG4-Related Periaortitis during Corticosteroid Therapy.", "title_normalized": "endovascular repair of a false aneurysm developing from igg4 related periaortitis during corticosteroid therapy" }	[ { "companynumb": "PHHY2015JP123078", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "80339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/D", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "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": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "80339", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/D", "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "20", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vascular pseudoaneurysm", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "IKEDA A, MITOMI K, KONISHI T, MATSUZAKI K, JIKUYA T, HIRAMATSU Y.. ENDOVASCULAR REPAIR OF A FALSE ANEURYSM DEVELOPING FROM IGG4-RELATED PERIAORTITIS DURING CORTICOSTEROID THERAPY. ANN-VASC-SURG. 2015?29 (7):1452.E5-1", "literaturereference_normalized": "endovascular repair of a false aneurysm developing from igg4 related periaortitis during corticosteroid therapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151014", "receivedate": "20151014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11629747, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "JP-MYLANLABS-2015M1035484", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTITIS", "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": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/DAY", "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." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vascular pseudoaneurysm", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "IKEDA A, MITOMI K, KONISHI T, MATSUZAKI K, JIKUYA T, HIRAMATSU Y. ENDOVASCULAR REPAIR OF A FALSE ANEURYSM DEVELOPING FROM IGG4-RELATED PERIAORTITIS DURING CORTICOSTEROID THERAPY. ANN-VASC-SURG 2015; 29(7):1452.E5-1.. 2015;29(7):1452.E5-1", "literaturereference_normalized": "endovascular repair of a false aneurysm developing from igg4 related periaortitis during corticosteroid therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160527", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11650700, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]
{ "abstract": "Radiation necrosis is a potentially debilitating side effect of therapy necessary to treat pediatric central nervous system tumors. Clinical signs of cerebral radiation necrosis (CRN) are similar to symptoms of disease progression and require close monitoring. The case of an infant diagnosed with a malignant rhabdoid tumor is presented to describe the medical and rehabilitation interventions implemented to address CRN. Rehabilitation providers should routinely be consulted in children with CRN as they fill a critical role in treatment, neurological symptom monitoring, and intervention planning to address family-centered functional goals.", "affiliations": "Department of Occupational Therapy, Washington University School of Medicine, St. Louis, Missouri.;Howard Head Sports Medicine, Edwards, Colorado.;Department Radiation Oncology, University of Colorado Anschutz, Aurora, Colorado.;Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado.;Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado.", "authors": "L'Hotta\|Allison J\|AJ\|0000-0001-7825-2492;Thomas\|Kristin M\|KM\|;Milgrom\|Sarah A\|SA\|;Hemenway\|Molly S\|MS\|;Levy\|Jean M Mulcahy\|JMM\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.28705", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "68(1)", "journal": "Pediatric blood & cancer", "keywords": "CNS tumors; neuro-oncology; radiation therapy; rehabilitation", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D016543:Central Nervous System Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D007223:Infant; D011379:Prognosis; D011832:Radiation Injuries", "nlm_unique_id": "101186624", "other_id": null, "pages": "e28705", "pmc": null, "pmid": "32985070", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Medical and rehabilitation interventions in pediatric central nervous system radiation necrosis: A case report.", "title_normalized": "medical and rehabilitation interventions in pediatric central nervous system radiation necrosis a case report" }	[ { "companynumb": "US-PFIZER INC-2021377688", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "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": "CYCLOPHOSPHAMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOTEPA" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "THIOTEPA." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "CARBOPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "METHOTREXATE SODIUM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "VINCRISTINE SULFATE." } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Radiation necrosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "L^HOTTA, A.. MEDICAL AND REHABILITATION INTERVENTIONS IN PEDIATRIC CENTRAL NERVOUS SYSTEM RADIATION NECROSIS: A CASE REPORT. PEDIATRIC BLOOD AND CANCER. 2021?68 (1):10.1002/PBC.28705", "literaturereference_normalized": "medical and rehabilitation interventions in pediatric central nervous system radiation necrosis a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210415", "receivedate": "20210415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19140556, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]
{ "abstract": "BACKGROUND\nPolyethylene glycols (PEGs) or macrogols are polyether compounds and are widely used as additives in pharmaceuticals, cosmetics, and food.\n\n\nMETHODS\nWe report on a Caucasian patient experiencing recurrent severe allergic reactions to several drugs. An extensive diagnostic workup including skin prick tests, intradermal tests (IDT) and a double-blind oral challenge was performed to identify the trigger of anaphylaxis. In the present case hypersensitivity to the additive polyethylene glycol was confirmed by an IDT suggesting an Immunoglobulin E-dependent mechanism as a cause of the reaction.\n\n\nCONCLUSIONS\nPotential life-threatening hypersensitivity reactions to hidden molecules like macrogol may be underdiagnosed. Cases of immediate-type PEG hypersensitivity were reported with increasing frequency. The awareness regarding the allergenic potential of PEG should be raised and a proper product labelling is crucial to prevent PEG mediated hypersensitivity.", "affiliations": "Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.;Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.;Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.", "authors": "Wylon\|Katharina\|K\|;Dölle\|Sabine\|S\|;Worm\|Margitta\|M\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13223-016-0172-7", "fulltext": "\n==== Front\nAllergy Asthma Clin ImmunolAllergy Asthma Clin ImmunolAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology1710-14841710-1492BioMed Central London 17210.1186/s13223-016-0172-7Case ReportPolyethylene glycol as a cause of anaphylaxis Wylon Katharina [email protected] Dölle Sabine [email protected] Worm Margitta [email protected] Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany 13 12 2016 13 12 2016 2016 12 6710 6 2016 29 11 2016 © The Author(s) 2016\nOpen 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\nPolyethylene glycols (PEGs) or macrogols are polyether compounds and are widely used as additives in pharmaceuticals, cosmetics, and food.\n\nCase report\nWe report on a Caucasian patient experiencing recurrent severe allergic reactions to several drugs. An extensive diagnostic workup including skin prick tests, intradermal tests (IDT) and a double-blind oral challenge was performed to identify the trigger of anaphylaxis. In the present case hypersensitivity to the additive polyethylene glycol was confirmed by an IDT suggesting an Immunoglobulin E-dependent mechanism as a cause of the reaction.\n\nConclusion\nPotential life-threatening hypersensitivity reactions to hidden molecules like macrogol may be underdiagnosed. Cases of immediate-type PEG hypersensitivity were reported with increasing frequency. The awareness regarding the allergenic potential of PEG should be raised and a proper product labelling is crucial to prevent PEG mediated hypersensitivity.\n\nKeywords\nAnaphylaxisDrug additivesHypersensitivityMacrogolPolyethylene glycolissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\n\nPolyethylene glycol (PEG) or macrogol is a polyether compound. It is widely used as an additive in pharmaceuticals, cosmetics and food [1]. Different types of macrogol exist according to their molecular weight from 300 g/mol to 10,000,000 g/mol [2]. Anaphylactic reactions to macrogol are rarely reported. However, in recent years more reports appeared in the literature with macrogol induced hypersensitivities due to drugs, personal hygiene products, dental products, lozenges and lubricants [3, 4]. Here we report on a female with a history of three immediate type reactions triggered by macrogol 3350.\n\nCase report\nA 46-year-old Caucasian female with no known allergies received an intraarticular injection with a local anesthetic (Xylonest®: prilocaine, sodium chloride, sodium hydroxide/hydrochloric acid 7%). Eight hour after the injection she experienced nausea and a generalized pruritus. The symptoms resolved the next day without any medical treatment. One day later the patient was given an injection with medroxyprogesteronacetate (Clinovir®: medroxyprogesteronacetate, methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate, macrogol 3350, polysorbate 80, sodium chloride) from her gynecologist. Five minutes after the injection she developed generalized pruritus, sneezing, nausea and tachycardia. Previous injections with medroxyprogesteronacetate and prilocaine were well tolerated.\n\nOne year later the patient received an injection to treat a lumbar intervertebral disc prolapse containing lidocaine, bupivacaine hydrochloride, triamcinolone acetonide (Triamhexal®: triamcinolonacetonide, benzyl alcohol, macrogol 4000, sodium chloride, sodium dihydrogen phosphate-dihydrate, sodium hydrogen carbonate, polysorbate 80). Within 5 min the patient developed systemic anaphylactic symptoms, including pruritus, nausea, tachycardia and flush.\n\nThe patient presented to our outpatient clinic 4 months after the first incident and 3 days after the third reaction. We initiated an allergological work-up including skin prick tests with macrogol, Clinovir®, latex, benzyl alcohol, paraben mix, sodium-benzoate, p-hydroxybenzate acid, sodium-metabisulfite, local anesthetics (procaine 1%, lidocaine 1%, bupivacaine 0.5%, prilocaine 1%, articaine 1%, mepivacaine 1%, scandicaine 1%, xylocaine 1%, ultracaine 1%, novocaine 1%), glucocorticosteroids (dexamethasone, prednisolone, triamcinolone, methylprednisolone) which were negative for all tested substances (Table 1). A negative control (sodium chloride 0.9%) and a positive control (histamine 10 mg/ml) were included. Total immunoglobulin E (IgE) was 93.5 kU/l and tryptase was 1.8 µg/l. A double-blind, placebo-controlled oral challenge with the additives which are in the preparations of Clinovir® and Triamhexal® (sodium-benzoate 250 mg and p-hydroxybenzoic acid 250 mg) was negative (Table 2). An intradermal test was performed with local anesthetics and additives of the suspected trigger substances (1% macrogol 3350, 10% macrogol 3350, polysorbate 80, scandicaine, xylocaine, ultracaine, bupivacaine, prilocaine, novocaine). After injecting 1% macrogol 3350 intradermal a 6 mm wheel was seen. 15 min later we carried out a second intradermal test with 10% macrogol 3350 which showed a 6 mm wheel diameter (Table 3). Consecutively the patient developed a systemic reaction with generalized pruritus and a generalized urticaria. The wheel diameter enlarged up to 12 mm, 5 min after the application.Table 1 Skin prick test (interpretation after 15 min)\n\nNegative control\tSodium chloride 0.9%\t0 mm\t\nPositive control\tHistamine\t4 mm\t\nLocal anesthetics\tProcaine 1%, lidocaine 1%, bupivacaine 0,5%, prilocaine 1%, articaine 1%, mepivacaine 1%, scandicaine 1%, xylocaine 1%, ultracaine 1%, novocaine 1%\t0 mm\t\nGlucocorticosteroids\tDexamethasone, prednisolone, triamcinolone, methylprednisolone \t0 mm\t\nOthers\tMacrogol 3350 1%, macrogol 3350 10%, Depot Clinovir®, latex, benzyl alcohol 1%, paraben mix 16%, sodium-benzoate 5%, p-hydroxybenzate acid, sodium-metabisulfite\t0 mm\t\nPositive test result: wheel diameter >3 mm\n\n\nTable 2 Double-blind oral challenge\n\nAdditives\tNa-benzoate 250 mg, p-hydroxybenzoic acid 250 mg\tNegative\t\n\nTable 3 Intradermal test (interpretation after 15 min)\n\nNegative control\tNaCl\t0 mm\t\nPositive control\tHistamine\t4 mm\t\nAdditives\tMacrogol 3350 1%\t6 mm\t\n\tMacrogol 3350 10%\t6 mm\t\n\tPolysorbate 80 1%\t0 mm\t\nLocal anesthetics\tScandicaine 1%, xylocaine 1%, ultracaine 1%, bupivacaine 0,5%, prilocaine 1%, novocaine 1%\t0 mm\t\nPositive test result: wheel diameter >3 mm\n\n\n\n\nBased on the history and the obtained skin test results our patient was diagnosed with an immediate type reaction to macrogol. We suspect that the first severe allergic reaction our patient experienced was not solely induced by prilocaine but another local anesthetic or an unknown additive containing macrogol. We prescribed an emergency kit containing an epinephrine auto-injector, a glucocorticosteroid and an antihistamine. The patient received an allergy pass and was instructed to avoid PEG analogues when taking new, over-the-counter drugs prescription drugs, personal hygiene products, dental products and other potentially PEG containing products.\n\nTwo years after the diagnosis of the hypersensitivity to macrogol the patient ingested WICK Medinait® (paracetamol, dextromethorphan hydrobromide, doxylaminsuccinate, sucrose, glycerol, macrogol 6000, sodium citrate, sodium benzoate, potassium sorbate) treating a common cold. Again, she developed dyspnea and a generalized rash.\n\nConclusions\nHowever, data from the European anaphylaxis-registry with currently 7935 registered anaphylactic cases only three were induced by macrogol. These findings may imply that polyethylene glycol hypersensitivity is potentially life-threatening but probably underdiagnosed as many drugs and food items contain macrogol [4–6]. Handling patients with macrogol hypersensitivity can be challenging because of the extensive allergologic work up, the necessity of the physician’s expertise and the limited avoidance options because many drugs, including those used for the treatment of allergic reactions such as antihistamines may contain macrogol as an additive [5]. Therefore, specific product labeling and awareness is required. Patients should be educated about drugs which may contain PEGs, but also other products like lubricants or ultrasound gels. Our case indicated the need for an increased patient and physician awareness to the allergic potential of macrogol.\n\nConcerning the mechanism of anaphylaxis mediated by PEGs different mechanisms have been proposed. Our case supports the assumption of cross-reactivity between PEGs of different molecular weights and polyethylene glycol analogues [7, 8]. Like other authors have previously shown, the positive intradermal test suggests an IgE-dependent mechanism, although no control tests were performed on healthy individuals to rule out unspecific reactivity [9]. However, even after a 1:10 dilution a positive intradermal test was observed. Other methods besides an oral challenge test to confirm the diagnosis may be by basophil activation test or western blot to show specific IgE binding [9].\n\nIn conclusion, cases of immediate-type PEG hypersensitivity are reported with increasing frequency, therefore, awareness of PEG’s allergenic potential should be raised and better product labeling should be discussed.\n\nAbbreviations\nIgEimmunoglobulin E\n\nIDTintradermal test\n\nPEGpolyethylene glycol\n\nAuthors’ contributions\nKW collected the data and wrote the manuscript. SD provided and analyzed the data from the anaphylaxis registry. MW coordinated and edited the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nAll data is stored and available in the patients case files and may be requested to see a copy at any stage.\n\nConsent for publication\nWritten and oral informed consent for publication has been obtained from the patients and stored in the case files and may be requested to see a copy at any stage.\n\nEthics approval and consent to participate\nWritten and oral informed consent to participate has been obtained from the patients and stored in the case files and may be requested to see a copy at any stage.\n\nFunding\nThe publication fee will be funded by NORA eV (Network for Online-Registration of Anaphylaxis).\n==== Refs\nReferences\n1. Pizzimenti S Heffler E Gentilcore E Raie A Bussolino C Nebiolo F Macrogol hypersensitivity reactions during cleansing preparation for colon endoscopy J Allergy Clin Immunol Pract 2014 2 3 353 354 10.1016/j.jaip.2014.01.017 24811032 \n2. Jakasa I Verberk MM Esposito M Bos JD Kezic S Altered penetration of polyethylene glycols into uninvolved skin of atopic dermatitis patients J Invest Dermatol 2007 127 1 129 134 10.1038/sj.jid.5700582 17039242 \n3. Bordere A Stockman A Boone B Franki AS Coppens MJ Lapeere H A case of anaphylaxis caused by macrogol 3350 after injection of a corticosteroid Contact Dermat 2012 67 6 376 378 10.1111/j.1600-0536.2012.02104.x \n4. Wenande E Garvey LH Immediate-type hypersensitivity to polyethylene glycols: a review Clin Exp Allergy 2016 46 7 907 922 10.1111/cea.12760 27196817 \n5. Hyry H Vuorio A Varjonen E Skytta J Makinen-Kiljunen S Two cases of anaphylaxis to macrogol 6000 after ingestion of drug tablets Allergy 2006 61 8 1021 10.1111/j.1398-9995.2006.01083.x 16867059 \n6. Schuman E Balsam PE Probable anaphylactic reaction to polyethylene glycol electrolyte lavage solution Gastrointest Endosc 1991 37 3 411 10.1016/S0016-5107(91)70761-X 2071010 \n7. Fisher AA Immediate and delayed allergic contact reactions to polyethylene glycol Contact Dermat 1978 4 3 135 138 10.1111/j.1600-0536.1978.tb03759.x \n8. Yamasuji Y Higashi Y Sakanoue M A case of anaphylaxis caused by polyethylene glycol analogues Contact Dermat 2013 69 183 185 10.1111/cod.12084 \n9. Wenande EC Inhibition of polyethylene glycol-induced histamine release by monomeric ethylene and diethylene glycol: a case of probable polyethylene glycol allergy Allergy Clin Immunol 2013 131 1425 10.1016/j.jaci.2012.09.037\n\n", "fulltext_license": "CC BY", "issn_linking": "1710-1484", "issue": "12()", "journal": "Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology", "keywords": "Anaphylaxis; Drug additives; Hypersensitivity; Macrogol; Polyethylene glycol", "medline_ta": "Allergy Asthma Clin Immunol", "mesh_terms": null, "nlm_unique_id": "101244313", "other_id": null, "pages": "67", "pmc": null, "pmid": "27999603", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "27196817;23151193;668343;23228247;23948038;17039242;24811032;2071010;16867059", "title": "Polyethylene glycol as a cause of anaphylaxis.", "title_normalized": "polyethylene glycol as a cause of anaphylaxis" }	[ { "companynumb": 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POLYETHYLENE GLYCOL AS A CAUSE OF ANAPHYLAXIS. ALLERG-ASTH-CLIN-IMMUNOL. 2016?1267", "literaturereference_normalized": "polyethylene glycol as a cause of anaphylaxis", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180319", "receivedate": "20180319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14657333, "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": "Reporting of adverse incidents is mandatory in Denmark. All reported adverse incidents are made anonymously, and stored in an encrypted database. It is the purpose of this descriptive study to describe the severity of adverse medication incidents caused by oral anticoagulants in hospitals. All moderate, severe and fatal reports concerning non-vitamin K antagonist oral anticoagulants were analyzed from date of marketing until July 8 2014. The data collection for warfarin was from January 1 2014 until July 8 2014. Three independent specialists in clinical pharmacology evaluated the severity of incident outcomes. A total of 147 adverse medication incidents were analyzed, and showed that de facto or potentially fatal and serious incidents were most frequently associated with sector change (admission to or discharge from hospital, or undergoing surgery) and resulted from insufficient or excess dosing. Physicians should be aware when prescribing and changing anticoagulant therapy to avoid severe or fatal incidents.", "affiliations": "Department of Clinical Pharmacology Aarhus University Hospital Aarhus Denmark.;Department of Clinical Pharmacology Aarhus University Hospital Aarhus Denmark.;Unit for Quality and Patient Safety Capital Region of Denmark Copenhagen Denmark.;Department of Clinical Pharmacology Aarhus University Hospital Aarhus Denmark.", "authors": "Henriksen\|Jakob Nørgaard\|JN\|0000-0003-0784-3206;Nielsen\|Lars Peter\|LP\|;Hellebek\|Annemarie\|A\|;Poulsen\|Birgitte Klindt\|BK\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/prp2.307", "fulltext": "\n==== Front\nPharmacol Res PerspectPharmacol Res Perspect10.1002/(ISSN)2052-1707PRP2Pharmacology Research & Perspectives2052-1707John Wiley and Sons Inc. Hoboken 10.1002/prp2.307PRP2307Original ArticleOriginal ArticlesMedication errors involving anticoagulants: Data from the Danish patient safety database J. N. Henriksen et al.Henriksen Jakob Nørgaard http://orcid.org/[email protected] \n1\nNielsen Lars Peter \n1\nHellebek Annemarie \n2\nPoulsen Birgitte Klindt \n1\n1 Department of Clinical PharmacologyAarhus University HospitalAarhusDenmark2 Unit for Quality and Patient SafetyCapital Region of DenmarkCopenhagenDenmark* Correspondence\n\nJakob Nørgaard Henriksen, Department of Clinical Pharmacology, Aarhus University Hospital, Wilhelm Meyers Alle 4, DK‐8000 Aarhus C, Denmark.\n\nTel: +4540438804; Fax: +4586128804;\n\nE‐mail: [email protected]\n03 4 2017 6 2017 5 3 10.1002/prp2.2017.5.issue-3e0030713 2 2017 14 2 2017 © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nReporting of adverse incidents is mandatory in Denmark. All reported adverse incidents are made anonymously, and stored in an encrypted database. It is the purpose of this descriptive study to describe the severity of adverse medication incidents caused by oral anticoagulants in hospitals. All moderate, severe and fatal reports concerning non‐vitamin K antagonist oral anticoagulants were analyzed from date of marketing until July 8 2014. The data collection for warfarin was from January 1 2014 until July 8 2014. Three independent specialists in clinical pharmacology evaluated the severity of incident outcomes. A total of 147 adverse medication incidents were analyzed, and showed that de facto or potentially fatal and serious incidents were most frequently associated with sector change (admission to or discharge from hospital, or undergoing surgery) and resulted from insufficient or excess dosing. Physicians should be aware when prescribing and changing anticoagulant therapy to avoid severe or fatal incidents.\n\nAdverse incidentsanticoagulant therapyclinical pharmacologyDanish patient safety database source-schema-version-number2.0component-idprp2307cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:02.06.2017\n\n\nJ. N. \nHenriksen \n, \nL. P. \nNielsen \n, \nA. \nHellebek \n, \nB. K. \nPoulsen \n. Medication errors involving anticoagulants: Data from the Danish patient safety database , Pharma Res Per , 5 (3 ), 2017 , e00307, doi: 10.1002/prp2.307\n==== Body\nAbbreviations\nDPSDDanish Patient Safety Database\n\nINRinternational normalized ratio\n\nNOACnon‐vitamin K antagonist oral anticoagulant\n\nTTRtherapeutic range\n\nIntroduction\nAnticoagulant drugs are widely used for both treatment and prophylaxis of thrombotic diseases (Adelborg et al. 2016), and are some of the drugs that most frequently cause medication errors, as demonstrated by previous data (Runciman et al. 2003; Hardmeier et al. 2004). These drugs often cause serious or fatal events (Runciman et al. 2003; Hardmeier et al. 2004; Saedder et al. 2014), and are therefore considered to be high risk medication (Danish Medicines Agency 2011). In particular, when patients are transferred from one sector to the other, unintended incidents related to medication can happen (Bell et al. 2011).\n\nWarfarin was one of the first anticoagulant drugs on the market, and has been available since 1964 (Mercury Pharma Group Ltd 2016). In 2014, a total of 88.158 patients were treated with warfarin in Denmark (Sundhedsdatastyrelsen 2016). In March 2008, the first non‐vitamin K antagonist oral anticoagulant (NOAC), Pradaxa® (dabigatran), was released (Boehringer Ingelheim 2016). Three more NOACs have since been introduced to the market; Xarelto® (rivaroxaban) in September 2008, Eliquis® (apixaban) in May 2011 and Lixiana® (edoxoban) in June 2015 (Bayer Pharma AG 2015; Bristol‐Myers Squibb/Pfizer EEIG 2016; Daiichi Sankyo Europe BmgH 2016). As of 2014 in Denmark, a total of 23.466 patients were treated with dabigatran, 16.085 patients with rivaroxaban and 8.024 patients with apixaban (Sundhedsdatastyrelsen 2016).\n\nThe Danish Patient Safety Database (DPSD) is a national database containing all reported adverse incidents in Danish Health Care since 2004, when it was made mandatory for all health care personnel in the hospital sector to report adverse incidents (Ministry of Health/Jens Kristian Gøtrik 2003). The definition of an adverse incident is an incident or error that is unassociated to the patient's disease, but could have or, in fact, has caused harm to the patient (Government Agency of Patient Safety 2016). The reported adverse incidents are made anonymously and filed in an encrypted database, the DPSD. The purpose of this database is to generate information and provide learning objectives, thereby identifying ways to improve medication safety. Strict policy regarding the anonymity of the person making the report is formulated (Government Agency of Patient Safety 2016), and access to the information in the database is restricted.\n\nWe chose anticoagulant drugs because of an increasing use and the association with serious adverse medication incidents. Unlike earlier reports (Zaidenstein et al. 2002; Fanikos et al. 2004; Piazza et al. 2011), our data material contained NOACs as well as warfarin. It is the purpose of this study to describe the severity rather than the extent of adverse medication incidents and the circumstances that led to them, in order to provide learning objectives.\n\nMaterials and Methods\nDesign\nDescriptive study.\n\nSetting and data source\nReports to the Patient Safety Database are free‐text fields with no minimum amount of information required to complete the reporting process.\n\nAccess to the database was obtained on July 8 2014. On this date, one abstracter manually retrieved all adverse incidents reported as moderate, serious or fatal from the hospital sector concerning dabigatran, rivaroxaban and apixaban, and manually transcribed them to a Microsoft Excel®‐file in anonymous form. The marketing date of these three drugs therefore became the first possible entry point into the database. For warfarin, all reported moderate, serious and fatal adverse incidents from January 1 2014 until July 8 2014 were collected. As warfarin has been marketed for several years and by far is the most commonly used anticoagulant in Denmark, adverse incidents reporting was assumed to be stable, and therefore no reports were included before January 2014. We did, however, add fatal cases concerning warfarin prior to 2014 not to miss valuable information. This added though only two more reports. Reports on incidents occurring in primary care were excluded. In some reports more than one anticoagulant was reported.\n\nClassification of adverse medication incidents\nWe sorted available information for every adverse incident into categories consisting of gender (male, female or unknown), age (0–50, 50–75, >75 or unknown), reported drug (warfarin, dabigatran, rivaroxaban, apixaban or unknown), medication process (prescribing, administering, dispensing or unknown), type of problem (excess dose, insufficient dose, other1 or unknown), hospitalization process (admission, in hospital, discharge, surgery, unknown) and specific clinical situation (bridging, medication review, monitoring and other; see Table 2 for definitions).\n\nThis supported analysis of the involved drug, the specific process of medication and the situation during hospitalization, where the adverse incidents were most harmful. Incidents that did not fit into a category were labeled unknown.\n\nAnalysis\nEvery adverse incident was graded according to severity by three independent specialists in Clinical Pharmacology. They graded incidents with both known and unknown outcomes according to the definitions in Table 1.\n\nTable 1 Definitions of severity of the adverse incidents\n\nCategory\tKnown outcome (Government Agency of Patient Safety 2016)\tUnknown outcome (Lisby et al. 2005)\t\nNo harm/mild/potentially nonsignificant\tNo harm/minor harm that does not require additional treatment or care.\tMedication error that is judged without clinical risk for the patient.\t\nModerate/potentially significant\tTransient harm that requires admission to hospital, treatment by a physician, increased level of care or additional treatment for hospitalized patients.\tMedication error that is judged to pose a potential clinical risk of being inconvenient to the patient, without permanently harming the patient.\t\nSerious/potentially serious\tPermanent harm that requires admission to hospital, treatment by a physician, increased level of care or additional treatment for hospitalized patients. This includes harms that require acute, life‐saving treatment.\tMedication error that is judged to be able to cause a potential clinical risk of harming the patient.\t\nFatal/potentially fatal\tFatal\tMedication error that is judged to pose a potential clinical risk of leading to a fatal outcome.\t\nJohn Wiley & Sons, LtdAdverse medication incidents with a known outcome (an actual harm to the patient) was described as a “de facto” harm, whereas adverse medication incidents with an unknown outcome (and a potential for harming the patient) was described as a potential harm. If grading differed among the clinical pharmacologists, the reported adverse incident was reviewed again by the group to achieve consensus. We chose to pool both de facto and potentially nonsignificant, significant, serious or fatal to increase the strength of the data.\n\nThus, an adverse incident with a known outcome described in the database as “A 48‐year old woman with known systemic lupus erythematosus and antiphospholipid antibody syndrome had previously been switched from warfarin to dabigatran due to compliance problems. She was admitted due to bleeding and dabigatran was discontinued. This was not reinstated upon discharge. Seven days later, the patient was admitted to hospital with pulmonary embolism” would be categorized as follows: (1) Age = 48; (2) gender = female; (3) reported drug = dabigatran; (4) medication process = prescribing; (5) type of problem = no anticoagulant therapy; (6) location in the health care sector = discharge; (7) specific clinical situation = medication review; (8) outcome = 7 days later admitted with a lung embolus. This case was judged by the clinical pharmacologists as serious.\n\nAn adverse incident with an unknown outcome described in the database as “An 88‐year old woman was admitted with suspected deep vein thrombosis. The ultrasound was negative. She was discharged with both dabigatran and low molecular weight heparin” would be categorized as follows: (1) Age = 88; (2) gender = female; (3) reported drug = dabigatran; (4) medication process = prescribing; (5) type of problem = excess anticoagulant therapy; (6) location in the health care sector = discharge; (7) specific clinical situation = medication review; (8) outcome = unknown. This case was judged by the clinical pharmacologists to be potentially serious.\n\nResults\nA total of 148 adverse incidents were included in the study. One was omitted due to lack of information, and was therefore not possible to grade. Of the remaining 147, the outcome was known in 65 incidents (44%) and unknown in 82 (56%). In total, there were (de facto or potentially) seven fatal, 83 serious, 52 significant and five nonsignificant adverse medication incidents (Fig. 1).\n\nFigure 1 Reported drug and associated severity. Direct comparisons between individual drugs should be avoided, as the basis for data could be different.\n\nIn the medication process, an adverse medication incident occurred during prescription in 115 of the total 147 incidents (78%). All the seven fatal adverse medication incidents occurred in this part of the medication process and also accounted for 70 of the total 83 serious adverse medication incidents (84%). Vice versa, there were no fatal incidents due to administration and dispensation, and only one and six, respectively, were graded as serious.\n\nExcess or insufficient dosing was associated with all the seven fatal adverse medication incidents in our data material, with most being caused by excess doses (5 of 7). In the subcategories of excess or insufficient dosing, 33 (40%) and 23 (28%), respectively, of a total of 83 were graded as de facto or potentially serious.\n\nIn the hospitalization process, described as sector change (admission, discharge and surgery) was associated with a total of 116 of 147 adverse medication incidents (79%) as well as all the fatal (100%) and 68 out of the total 83 serious (82%) adverse medication incidents.\n\nImportant parts of the physician's task when handling patients during sector change (bridging, monitoring and medication review) was associated with all seven fatal (100%) and 70 of 83 serious adverse medication incidents (84%). Two of these 70 serious adverse medication incidents were thus not related to sector change (3%).\n\nCompared to admission and surgery, the discharge phase of the hospitalization process was associated with more adverse medication incidents (63 of 147 = 43%) than the two others (22 and 31 of 147 respectively = 15 and 21%). Only three of the 147 adverse medication incidents (2%) in the category “hospitalisation process” did not contain sufficient information to fit into a subcategory. It therefore became the most reliable category in terms of amount of data therein.\n\nWhere information in the reports about dosing errors was available, the adverse medication incident in the admission phase was due to excess anticoagulant in seven of 11 incidents (64%) and insufficient anticoagulant in the remaining four (36%). During surgery, the adverse medication incident was due to excess anticoagulant in 17 of the 28 incidents (61%) with insufficient anticoagulant accounting for the remaining 11 (39%). During discharge, the numbers were 19 of 43 (44%) and 24 of 43 (56%), respectively (results not shown Fig. 2).\n\nFigure 2 The situation in which the adverse incident happened related to severity of outcome.\n\nDiscussion\nOur data showed that all fatal and almost all serious adverse medication incidents were associated with the prescribing phase of the medication process. Unlike an American study looking at reported adverse incidents over a 3‐year period in the national database (Santell et al. 2003), we did not find a similar association with neither administering nor dispensing. This indicates a problem related to physicians rather than the nursing staff. It poses a question whether better decision‐making support, more education or other actions are necessary when trying to minimize adverse medication incidents. In some regions of Denmark, the electronic patient chart allows the physician to use a function called “anticoagulation” to evaluate international normalized ratio (INR) values and warfarin given while the patient is in hospital. This helps to regulate anticoagulant therapy with warfarin while the patient is hospitalized. However, this feature only includes patients treated with warfarin and no information about doses prior to admission is given.\n\nThis leads to our second major finding. Sector change (i.e., admission, discharge and surgery) was associated with the highest number of serious and fatal adverse medication incidents. This is supported by the adverse medication incidents related to prescribing situations such as bridging, critical evaluation of the patients' medication in a medication review and monitoring anticoagulant therapy. During admission and surgery, prescribing excess anticoagulant was the most frequent problem. During discharge, the reverse was true with prescribing insufficient anticoagulant being the most frequent problem.\n\nWith recent data showing no increased benefit of bridging low to moderate risk patients on warfarin, but instead an increased risk of bleeding (Douketis et al. 2015), fewer patients are expected to be offered bridging with low molecular weight heparin and thereby reducing the risk of adverse medication incidents.\n\nWe know there is an increased risk of unintended discontinuation of evidence‐based therapy in patients admitted to hospital (Bell et al. 2011), and it has also been demonstrated, that among the five categories of drugs studied, anticoagulant therapy had the highest adjusted odds ratio of unintended discontinuation (Bell et al. 2011). Likewise, it has been documented, that adverse incidents related to medication increase with a patient's admittance to hospital for any reason (Cornish et al. 2005). Work is being done to implement an electronic information system showing a patient's current medication that is accessible to physicians in both primary care and hospitals. However, it is not yet fully implemented among all general practitioners and is not yet fully equipped to handle information about varying doses of warfarin for example.\n\nWhile it has been shown that anticoagulant therapy along with cardiovascular and antiasthmatic therapy were the most frequent medications to cause fatalities among hospitalized patients (Ebbesen et al. 2001), there were no fatalities among hospitalized patients in our data set.\n\nOur data was not able to support NOACs being associated with different risk patterns compared with warfarin, and data were too limited to report on their own. This was not only due to the low number of events for NOACs, but also because of the quality of the reported incidents. In almost all the reports, we had no information about who prescribed the medication, the time in therapeutic range (TTR) for warfarin, patients' co‐morbidity and co‐medication. An attempt to do a head to head comparison between warfarin and NOACs would only be associated with a strong possibility of misinterpretation without bringing clinically relevant data. The data on NOACs merely confirm that the risk of harming patients with anticoagulants is increased in specific clinical situations such as sector change, particularly during discharge.\n\nA major challenge in our data material proved to be the level of information contained in the reports. When reporting an adverse incident to the Patient Safety Database, a health care person is prompted to choose either a known or an anticipated degree of severity as well as to provide information regarding the location and time of the incident. The options for harm are none, mild, moderate, serious or fatal (Table 1). Although a description of events prior to the adverse incident is required, there are no requirements about the quality or extent of the description. The level of information regarding the patient and the incident therefore varies significantly between reports. Therefore, we were unable to fully characterise all adverse incidents according to predefined categories. Naturally, this inconsistency of information, tended to inflict and to some degree incapacitate the severity analysis.\n\nFurthermore, more than half the incidents had an unknown outcome, and analysis depended on anticipation of a certain outcome rather than on a factual outcome.\n\nDue to these limitations, we were not able to distinguish between the different classes of drugs in terms of severity or to draw any conclusions about the individual drugs and the individual characteristics about the problem (for example, which drugs were insufficiently dosed, did the patient have renal impairment or when were INR‐values insufficiently handled). Concerning warfarin, though, we know that from a combined retrospective and prospective Danish study that disease and drug‐drug interactions were the two most common reasons for patients treated with warfarin being admitted to hospital due to elevated INR‐values with or without an active bleeding (Meegaard et al. 2012).\n\nAlthough reporting of serious adverse effects as well as adverse medication incidents are mandatory in Denmark, we must assume some degree of underreporting. In a randomized controlled trial of patients with atrial fibrillation for example, 2,71% and 3,36% of patients on dabigatran and warfarin, respectively experienced a major bleeding event per year as an adverse effect of their treatment (Connolly et al. 2009). However, postmarketing reporting of these adverse effects is much lower. When comparing the presumed annual major bleeding events rate in patients on warfarin using the data from the above‐mentioned trial with actual reporting to the Federal Drug Administration in the United States, only about a third of these events are reported (Moore and Bennett 2012). Therefore, the full scope of adverse medication incidents with anticoagulants might very well be larger than our data indicate.\n\nWe chose not to look at the extent but rather the severity of the adverse medication incidents, and therefore only included adverse incidents related to warfarin from January 2014 until July 2014 with the addition of two, fatal incidents before that. This created a longer period for adverse incidents to be recorded for NOACs relative to warfarin. However, warfarin was up until July 2014 still used substantially more than NOACs (Sundhedsdatastyrelsen 2016) and the relative longer time span of possible reported adverse incidents with NOACs is likely balanced by the much higher consumption of warfarin. We have attempted to highlight this in Table 2. Whether a change in the type and severity of adverse incidents has changed in the years leading up to 2014 is unknown, but since warfarin has been marketed for decades, this would not seem likely.\n\nTable 2 Number of adverse incidents divided into categories, subcategories as well as severity\n\nCategories\tTotal number within the subgroup (%)\tDe facto or potentially fatal (%)\tDe facto or potentially serious (%)\tDe facto or potentially significant+nonsignificant (%)\t\nGender\t\nMale\t55 (37%)\t3 (6%)\t31 (56%)\t21 (38%)\t\nFemale\t62 (42%)\t2 (3%)\t40 (65%)\t20 (32%)\t\nUnknown\t30 (21%)\t2 (7%)\t12 (40%)\t16 (53%)\t\nAge\t\n0–50\t9 (6%)\t0\t5 (56%)\t4 (44%)\t\n51–75\t43 (29%)\t1 (3%)\t26 (60%)\t16 (37%)\t\n75+\t60 (41%)\t4 (7%)\t37 (62%)\t19 (31%)\t\nUnknown\t35 (24%)\t2 (6%)\t16 (46%)\t17 (48%)\t\nReported drug\t\nWarfarin\t96 (65%)\t4 (4%)\t50 (52%)\t42 (44%)\t\nDabigatran\t30 (21%)\t2 (7%)\t19 (63%)\t9 (30%)\t\nHeparin\t11 (7%)\t1 (9%)\t8 (73%)\t2 (18%)\t\nRivaroxaban\t6 (4%)\t0\t5 (83%)\t1 (17%)\t\nUnknown\t4 (3%)\t0\t1 (25%)\t3 (75%)\t\nMedication process\t\nPrescribing\t115 (78%)\t7 (6%)\t70 (61%)\t38 (33%)\t\nAdministering\t4 (3%)\t0\t1 (25%)\t3 (75%)\t\nDispensing\t16 (11%)\t0\t6 (38%)\t10 (62%)\t\nUnknown\t12 (8%)\t0\t6 (50%)\t6 (50%)\t\nType of problem\t\t\t\t\t\nExcess anticoagulant\t51 (35%)\t5 (10%)\t33 (65%)\t13 (25%)\t\nInsufficient anticoagulant\t50 (34%)\t2 (4%)\t23 (46%)\t25 (50%)\t\nOthera\n\t9 (6%)\t0\t6 (67%)\t3 (33%)\t\nUnknown\t37 (25%)\t0\t21 (57%)\t16 (43%)\t\nHospitalization process\t\nAdmission\t22 (15%)\t3 (14%)\t14 (64%)\t5 (22%)\t\nIn hospital\t28 (19%)\t0\t12 (43%)\t16 (57%)\t\nDischarge\t63 (43%)\t2 (3%)\t36 (57%)\t25 (40%)\t\nSurgery\t31 (21%)\t2 (6%)\t18 (58%)\t11 (36%)\t\nUnknown\t3 (2%)\t0\t3 (100%)\t0\t\nSpecific clinical situation\t\nBridgingb\n\t25 (17%)\t2 (8%)\t16 (64%)\t7 (28%)\t\nMedication reviewc\n\t61 (41%)\t2 (3%)\t36 (59%)\t23 (38%)\t\nMonitoringd\n\t22 (15%)\t3 (14%)\t18 (82%)\t1 (4%)\t\nOthere\n\t39 (27%)\t0\t13 (33%)\t26 (67%)\t\nThe numerals state the number of adverse incidents in the listed category. Percentages in the second column from the left are percent within the category. Percentages in the third, fourth and fifth column from the left are percentages in the subcategory.\n\na I.e. Patient given one anticoagulant, but should have been given another or not giving antidote to warfarin with a high INR.\n\nb Bridging was defined as changing anticoagulant therapy for a short while (i.e. during surgery) from one anticoagulant to another.\n\nc Medication review consisted of: Physician's review and prescribing of patient's medicine at admission, during hospital stay or discharge.\n\nd Monitoring was defined as reacting to an international normalized ratio (INR)‐value.\n\ne Missing or incorrect information in the electronic patient chart, lack of compliance or dispensing error.\n\nJohn Wiley & Sons, LtdInstead of highlighting differences between the drugs, our data showed anticoagulants as a whole to be associated with serious and fatal harm to patients during sector change, particularly during discharge. Our data showed that the fatal and serious problems were with prescribing rather than administering and dispensing the drugs.\n\nWith the purpose of providing learning points to the health care system, the Danish Patient Safety Database should support extra careful attention when prescribing anticoagulants and caring for patients treated with them during admission, discharge and surgery.\n\nConclusion\nAdverse incidents on anticoagulant therapy are associated with serious and even fatal harm to patients. In our dataset, we identified two main areas that caused serious and fatal outcomes. First of all, the prescription phase of the medication process proved to be the clinically most important in causing harm. We did not find similar relationship to administering and dispensing phases. Secondly, sector transfer, that is, admission, discharge and surgery, was associated with the majority of fatal and serious incidents. Our data do not support that the introduction of NOACs has influenced this significantly.\n\nIn all, anticoagulants have to be considered as risk medication in general, and patients treated with such drugs warrant increased attention.\n\nDisclosure\nDr. Henriksen reports nonfinancial support from LEO Pharma, outside the submitted work.\n\nAcknowledgements\nThe staff at “Learning” and “The Advisory council on Medication” under the Danish Patient Safety Authority for devising the project and granting access to the Danish Patient Safety Database.\n==== Refs\nReferences\n\n\nAdelborg \nK \n, \nGrove \nEL \n, \nSundboll \nJ \n, \nLaursen \nM \n, \nSchmidt \nM \n (2016 ). Sixteen‐year nationwide trends in antithrombotic drug use in denmark and its correlation with landmark studies . Heart \n102 : 1883 –1889 .27406838 \n\n\nBayer \nPharma AG \n (2015 ) Summary of product characteristics, xarelto [homepage on the Internet] . 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Pharmacoepidemiol Drug Saf \n11 : 235 –238 .12051123\n\n", "fulltext_license": "CC BY", "issn_linking": "2052-1707", "issue": "5(3)", "journal": "Pharmacology research & perspectives", "keywords": "Adverse incidents; Danish patient safety database; anticoagulant therapy; clinical pharmacology", "medline_ta": "Pharmacol Res Perspect", "mesh_terms": null, "nlm_unique_id": "101626369", "other_id": null, "pages": "e00307", "pmc": null, "pmid": "28603628", "pubdate": "2017-06", "publication_types": "D016428:Journal Article", "references": "11606147;24671697;12856391;15668306;12051123;19717844;14660523;15738372;26095867;23086541;21862745;15611888;27406838;22293053;28603628;15325949;22114827", "title": "Medication errors involving anticoagulants: Data from the Danish patient safety database.", "title_normalized": "medication errors involving anticoagulants data from the danish patient safety database" }	[ { "companynumb": "DK-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-035078", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "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": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACETYLSALICYLIC ACID" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "PRADAXA" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "TICAGRELOR" }, "drugadditional": null, "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": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TICAGRELOR" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Death", "reactionmeddraversionpt": "20.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HENRIKSEN J, NIELSEN L, HELLEBEK A, POULSEN B. 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MEDICATION ERRORS INVOLVING ANTICOAGULANTS: DATA FROM THE DANISH PATIENT SAFETY DATABASE. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2017;5:3:.", "literaturereference_normalized": "medication errors involving anticoagulants data from the danish patient safety database", "qualification": "5", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170628", "receivedate": "20170628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13699350, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "DK-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-034431", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NIELSEN L, HELLEBEK A, POULSEN B. MEDICATION ERRORS INVOLVING ANTICOAGULANTS: DATA FROM THE DANISH PATIENT SAFETY DATABASE. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2017;5(3):E00307.", "literaturereference_normalized": "medication errors involving anticoagulants data from the danish patient safety database", "qualification": "5", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170628", "receivedate": "20170628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13699340, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "DK-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-035327", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NIELSEN P, HELLEBEK A, POULSEN K. MEDICATION ERRORS INVOLVING ANTICOAGULANTS: DATA FROM THE DANISH PATIENT SAFETY DATABASE. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2017;5:3:E00307.", "literaturereference_normalized": "medication errors involving anticoagulants data from the danish patient safety database", "qualification": "5", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170628", "receivedate": "20170628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13699255, "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": "Although poisoning with calcium channel blocking agents is frequent, to our knowledge no cases involving amlodipine have been published. We describe here a case of amlodipine intoxication, in which protracted hypotension did not respond to vasopressor therapy alone. After the addition of continuous calcium chloride and glucagon infusion, blood pressure was restored and vasopressor therapy could be tapered off substantially. When calcium and glucagon were interrupted because of severe hypercalcemia and hyperglycemia, the patient developed irreversible hypotension and died. Either glucagon or calcium or both, and to some extent vasopressors, seem to have constituted effective treatment of hypotension in this case.", "affiliations": "Department of Intensive Care, University Hospital, Ghent, Belgium.", "authors": "Koch\|A R\|AR\|;Vogelaers\|D P\|DP\|;Decruyenaere\|J M\|JM\|;Callens\|B\|B\|;Verstraete\|A\|A\|;Buylaert\|W A\|WA\|", "chemical_list": "D017311:Amlodipine; D010076:Oxazepam", "country": "United States", "delete": false, "doi": "10.3109/15563659509017993", "fulltext": null, "fulltext_license": null, "issn_linking": "0731-3810", "issue": "33(3)", "journal": "Journal of toxicology. Clinical toxicology", "keywords": null, "medline_ta": "J Toxicol Clin Toxicol", "mesh_terms": "D017311:Amlodipine; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007022:Hypotension; D008875:Middle Aged; D010076:Oxazepam", "nlm_unique_id": "8213460", "other_id": null, "pages": "253-6", "pmc": null, "pmid": "7760451", "pubdate": "1995", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Fatal intoxication with amlodipine.", "title_normalized": "fatal intoxication with amlodipine" }	[ { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03023", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG, 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": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KOCH AR, VOGALAERS DP, DECRUYENAERE JM, CALLENS B AND ET. AL.. FATAL INTOXICATION WITH AMLODIPINE. CLIN TOXICOL.. 1995?33:253?256", "literaturereference_normalized": "fatal intoxication with amlodipine", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14900086, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "BE-LUPIN PHARMACEUTICALS INC.-2015-03589", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078043", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXAZEPAM." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KOCH A, VOGELAERS D, DECRUYENAERE J, CALLENS B, VERSTRAETE A, BUYLAERT W. FATAL INTOXICATION WITH AMLODIPINE. CLINICAL TOXICOLOGY. 1995?33 (3):253-256.", "literaturereference_normalized": "fatal intoxication with amlodipine", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151117", "receivedate": "20151117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11745090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]
{ "abstract": "Anti-synthetase syndrome is an autoimmune disorder characterized by the presence of autoantibodies against aminoacyl transfer RNA (tRNA) synthetases, and myositis, interstitial lung disease (ILD), arthritis, fever and Raynaud's phenomenon (RP). We present a 54-year-old woman, who complained of fatigue, low-grade fever, myalgias, arthralgias, RP and dyspnoea on exertion. Chest CT scan revealed features of interstitial lung disease. Due to rapid deterioration of her lung function, she required oxygen support. The patient did not respond to empiric treatment with antibiotics. Autoantibody testing was remarkable for ANA positivity (1/160) and high-titre anti-Jo1 positivity. A diagnosis of anti-synthetase syndrome was made and the patient was placed on high-dose corticosteroids and rituximab with significant improvement. At 1-year follow up, she remains in good condition, without the need for oxygen supplementation.", "affiliations": "Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Respiratory Medicine, University General Hospital of Larissa, Faculty of Medicine, University of Thessaly, Larissa, Greece.;Department of Respiratory Medicine, University General Hospital of Larissa, Faculty of Medicine, University of Thessaly, Larissa, Greece.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.", "authors": "Kourkouni\|Evangelia\|E\|;Mitsogiannis\|Georgios\|G\|;Simopoulou\|Theodora\|T\|;Liaskos\|Christos\|C\|;Katsiari\|Christina G\|CG\|;Daniil\|Zoi\|Z\|;Gourgoulianis\|Konstantinos\|K\|;Bogdanos\|Dimitrios P\|DP\|;Sakkas\|Lazaros I\|LI\|", "chemical_list": null, "country": "Greece", "delete": false, "doi": "10.31138/mjr.30.3.186", "fulltext": "\n==== Front\nMediterr J Rheumatol\nMediterr J Rheumatol\nMJR\nMediterranean Journal of Rheumatology\n2529-198X The Mediterranean Journal of Rheumatology (MJR) \n\n10.31138/mjr.30.3.186\nMJR-30-3-186\nCase Report\nInterstitial Lung Disease in Anti-Synthetase Syndrome\nKourkouni Evangelia 1 Mitsogiannis Georgios 1 Simopoulou Theodora 1 Liaskos Christos 1 Katsiari Christina G. 1 Daniil Zoi 2 Gourgoulianis Konstantinos 2 Bogdanos Dimitrios P. 1 Sakkas Lazaros I. 1 1 Department of Rheumatology and Clinical Immunology;\n2 Department of Respiratory Medicine, University General Hospital of Larissa, Faculty of Medicine, University of Thessaly, Larissa, Greece\nCorresponding Author: Lazaros I. Sakkas, Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece, Tel.: +302413502813, Fax: +202413501014, E-mail:[email protected]\n9 2019 \n30 9 2019 \n30 3 186 189\n12 4 2019 25 6 2019 09 7 2019 © 2019 The Mediterranean Journal of Rheumatology (MJR)2019This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Anti-synthetase syndrome is an autoimmune disorder characterized by the presence of autoantibodies against aminoacyl transfer RNA (tRNA) synthetases, and myositis, interstitial lung disease (ILD), arthritis, fever and Raynaud’s phenomenon (RP). We present a 54-year-old woman, who complained of fatigue, low-grade fever, myalgias, arthralgias, RP and dyspnoea on exertion. Chest CT scan revealed features of interstitial lung disease. Due to rapid deterioration of her lung function, she required oxygen support. The patient did not respond to empiric treatment with antibiotics. Autoantibody testing was remarkable for ANA positivity (1/160) and high-titre anti-Jo1 positivity. A diagnosis of anti-synthetase syndrome was made and the patient was placed on high-dose corticosteroids and rituximab with significant improvement. At 1-year follow up, she remains in good condition, without the need for oxygen supplementation.\n\nanti-synthetase syndromeanti-Jo1interstitial lung diseaseRaynaud’s phenomenon\n==== Body\nINTRODUCTION\nAnti-synthetase syndrome (aSS) is a rare autoimmune disorder characterized by the presence of antibodies against aminoacyl-transfer RNA synthetase (ARS) and a variable constellation of manifestations; most commonly interstitial lung disease (ILD), myositis, and arthritis. These manifestations occur in 60–95% of cases, whereas other, less common manifestations occurring in ∼40% of cases include Raynaud’s phenomenon (RP), fever and mechanic’s hands.1 By far the most common ARS antibody is anti-Jo1, which targets histidyl-tRNA synthetase (histidyl-RS) and occurs in 73% of aSS patients.2 Other less common ARS antibodies are against PL-12 (alanyl-RS) (in 14% of patients), PL-7 (threonyl-RS) (in 9% of patients), OJ (isoleucyl-RS), and EJ (glycyl-RS), KS (asparaginyl-RS), Zo (phenylalanyl-RS), and YRS/Tyr (tyrosyl-RS).3 Patients with anti-synthetase syndrome often suffer from severe and rapidly progressive ILD. In fact, life expectancy is curtailed in aSS and the major cause of death is ILD and pulmonary hypertension. The 5-year survival is 90% in anti-Jo-1-positive patients and 75% in non-Jo-1-positive patients but the 5-year survival can be as low as 31%.4 Thus, it is important to recognize the syndrome early and promptly institute immunosuppressive treatment. Herein, we describe a patient with anti-synthetase syndrome with rapidly progressive and severe ILD.\n\nCASE PRESENTATION\nA 54-year-old Caucasian woman presented to a private physician with a twenty days history of fatigue, low grade fever, myalgias, arthralgias, Raynaud’s phenomenon and dyspnoea on exertion. She was initially treated with 20mg of methylprednisolone as undifferentiated arthritis, and symptoms were improved. Attempts to taper down steroids led to relapse of manifestations. A new chest X-ray revealed increased lineal markings in lower lung fields (Figure 1) and a chest CT scan showed linear markings, ground glass opacities and mild bronchiectasis (Figure 2). Laboratory tests were remarkable for increased inflammation indices (CRP 3.5mg/dL [normal, <0.5 mg/dL], ESR 42 mm]), mild creatinine kinase elevation (CPK 185 U/L, normal, <145) and a positive ANA test (1/160, normal <1:80). Methylprednisolone was discontinued and empiric antibiotics (clarithromycin, moxifloxacin), antiviral (oseltamivir) and bronchodilators were prescribed, for presumed respiratory infection, without benefit.\n\nFigure 1. Chest x-rays showing increased markings in lower lung fields.\n\nFigure 2. Chest CT scan showing thickened linear markings, ground glass opacities, and mild bronchiectasis.\n\nShe was referred to the Emergency department of our Hospital and admitted to the Department of Rheumatology and Clinical Immunology for further evaluation and treatment.\n\nOn admission, she had mild hypoxia with reduced arterial oxygen saturation (SaO2 saturation, 90%–92%, pO2 65 mmHg on FiO2 21%), and arterial blood pressure was normal. The patient had low-grade fever up to 38° C (two spikes per day). Inflammation markers were elevated (CRP 2.2 mg/dL, ESR 23mm). The rest of the basic laboratory work-up is shown in Table 1. Pulmonary function tests revealed mildly restricted pattern with forced vital capacity (FVC) 74%, forced expiratory volume in 1s (FEV1) 73%, and FEV1/FVC 100%.\n\nTable 1. Laboratory tests during hospital stay.\n\nTest\tAt admission\tAt exit\t\nHaematocrit (%)\t40\t39\t\nWBC (×103/μL)\t8800\t14300\t\nPLT (×103/μL)\t367\t364\t\nCRP (mg/dL, normal <0,5)\t2,2\t0,7\t\nESR (mm)\t35\t23\t\nLactate dehydrogenase (IU/L, normal <245)\t377\t273\t\nCreatine phosphokinase (U/L, normal <145)\t241\t88\t\nDifferential diagnosis of diffuse pulmonary infiltrates, fever, hypoxia and elevated inflammatory markers included respiratory infections, and autoimmune pulmonary/rheumatic diseases. The latter included hypersensitivity pneumonitis, sarcoidosis, systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, rheumatoid arthritis, vasculitis, and myositis. An autoantibody panel with RF, anti-CCP, ANCA, and ANA was ordered.\n\nLegionella and Pneumococcal antigen urinary tests, serological tests for EBV, CMV, HIV, Parvo B19, myco-plasma and brucellosis, and Mantoux skin test were negative. Blood and urine cultures were sterile. The patient could not provide sputum for culture or immunofluorescence for Pneumocystis jirovecii. Beta D-glucan test for fungal infection was not available as a routine test in the microbiology laboratory of the hospital. The patient was empirically treated with broad spectrum antibiotics (intravenous piperacillin-tazobactam) without response. She progressively deteriorated with dyspnoea, tachypnoea, low pO2 (49 mmHg) requiring nasal oxygen supplementation, and rising CRP (6.3 mg/dl). Pulmonary embolism and acute heart failure were ruled out. Pneumocystis jirovecii pneumonia could not be excluded, and empirical treatment with co-trimoxazole (15 mg/kg/day) plus prednisone according to the treatment guidelines was initiated. Initially, the patient’s clinical status and laboratory findings (CRP 0.7 mg/dl) were improved, but with prednisolone tapering, fever reappeared, and oxygen supplementation was again needed. Therefore, the possibility of an ILD associated with immune-mediated rheumatic diseases was very likely. Systemic sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, and vasculitis were unlikely, since there was no other feature of these diseases. Rheumatoid arthritis was still a possibility, but anti-synthetase syndrome became the most likely diagnosis. In our department, we perform an autoantibody profile for myositis-anti-synthetase syndrome by line immunoassay (Figure 3). This multiplex test revealed very strong positivity for anti-Jo-1 (82 Arbitrary units, AU, cut off, 10) and anti-Ro52 antibodies (101 AU, cut off, 10). Antibodies against Mi-2 alpha, Mi-2 beta, TIF1γ, MDA5, NXP2, SAE1, Ku, PM-Scl100, PM-Scl75, SRP, PL-7, PL-12, EJ, and OJ) were all negative. Serum creatine phosphokinase (CPK) levels and electromyography were normal. Therefore, a diagnosis of anti-synthetase syndrome was made on the basis of ILD, fever, arthralgias, RP, and anti-Jo1 autoantibodies. High dose prednisolone was initiated along rituximab (1g on day 0 and day 15). The patient exhibited a quick improvement which continued during the following months with tapering of corticosteroids. At 1-year follow up, the patient is on 5 mg of prednisolone per day and rituximab (day 0–day 15) every six months. She is in good health, without the need of oxygen, and has started her work again. Chest x-rays and pulmonary function tests were normal.\n\nFigure 3. Line immunoblot assay showing positivity for Jo-1 and Ro52 autoantibodies.\n\nDISCUSSION\nOur case highlights the need for early recognition and treatment of aSS-ILD. Although aSS is associated with myositis, a patient may initially present with no myositis.1 On the other hand, ILD is the most prevalent manifestation of aSS occurring in 86–95% of patients.5,6 ILD frequently dominates the clinical picture at presentation and may rapidly progress to pulmonary failure. In fact, aSS-ILD is more prevalent and severe rather than myositis-associated ILD.4 ILD is more severe in anti-PL12/PL7 patients rather than anti-Jo-1 patients.4 In fact, patients with anti-PL12/PL7 antibodies have predominant ILD, often without muscle involvement, whereas patients with anti-Jo-1 antibodies have more diffuse phenotype.2,5 The presence of anti-Ro52 antibody in patients with aSS may be associated with rapidly progressive ILD6,7 and cancer.7 It should be noted that patients with ILD should also be tested for associated anti-signal recognition particle antibodies, including anti-MDA-5 (RNA helicase) and anti-Mi-2 (nuclear helicase). CT findings of aSS-ILD mostly include areas of ground glass opacities and reticulation, predominantly in lower lung lobes, and peribronchial lesions. Less frequently (∼35%) there is organizing pneumonia with fibrosis.8 Patients with aSS may also have myocarditis and pulmonary hypertension.4 Myocarditis occurs in 34% of aSS patients and may be asymptomatic or present with acute/subacute heart failure.9\n\nNo randomized control trials have been conducted in aSS, current therapy is off-label and based on case series and case reports, and includes corticosteroids along with an immunosuppressant, such as azathioprine, mycophenolate mofetil, calcineurin inhibitors (tacrolimus), rituximab and cyclophosphamide.4 Rituximab seems to be a very effective option with marked improvement in FVC in patients with connective tissue disease and ILD, who have anti-Jo1 antibodies.10 Significant improvement after treatment with rituximab is noted more frequently in anti-Jo1 antibody-positive compared to anti-Jo1 antibody-negative patients with inflammatory myopathies. In our case, an improvement in CT imaging features, as well as at FVC and DLCO tests, was observed over time. It must be noted that the greatest benefit was seen at the 3-year follow-up.\n\nIn conclusion, early recognition of aSS and investigation for major organ involvement is required for the optimal outcome of patients with this syndrome.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1. Bartoloni E Gonzalez-Gay MA Scirè C Castaneda S Gerli R Lopez-Longo FJ \nClinical follow-up predictors of disease pattern change in anti-Jo1 positive anti-synthetase syndrome: Results from a multicenter, international and retrospective study\n. Autoimmun Rev \n2017 ;16 (3 ):253 –7\n. [10.1016/j.autrev.2017.01.008 ] [PMID: ]28147261 \n2. Pinal-Fernandez I Casal-Dominguez M Huapaya JA Albayda J Paik JJ Johnson C \nA longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies\n. Rheumatology (Oxford) \n2017 ;56 (6 ):999 –1007\n. [10.1093/rheumatology/kex021 ] [PMID: ] [PMCID: ]28339994 \n3. Gallay L Gayed C Hervier B \nAntisynthetase syndrome pathogenesis: knowledge and uncertainties\n. Curr Opin Rheumatol \n2018 ;30 :664 –73\n. [10.1097/BOR.0000000000000555 ] [PMID: ]30239350 \n4. Witt LJ Curran JJ Strek ME \nThe Diagnosis and Treatment of Anti-synthetase Syndrome\n. Clin Pulm Med \n2016 ;23 (5 ):218 –26\n. [10.1097/CPM.0000000000000171 ] [PMID: ] [PMCID: ]27594777 \n5. Hervier B Devilliers H Stanciu R Meyer A Uzunhan Y Masseau A \nHierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity\n. Autoimmun Rev \n2012 ;12 (2 ):210 –7\n. [10.1016/j.autrev.2012.06.006 ] [PMID: ]22771754 \n6. Shi J Li S Yang H Zhang Y Pang Q Lu X Wang G \nClinical Profiles and Prognosis of Patients with Distinct Antisynthetase Autoantibodies\n. J Rheumatol \n2017 ;44 (7 ):1051 –7\n. [10.3899/jrheum.161480 ] [PMID: ]28461650 \n7. Marie I Hatron PY Dominique S Cherin P Mouthon L Menard JF \nShort-term and long-term outcome of anti-Jo1-positive patients with anti-Ro52 antibody\n. Sem Arthritis Rheum \n2012 ;41 (6 ):890 –9\n. [10.1016/j.semarthrit.2011.09.008 ] [PMID: ]22078416 \n8. Waseda Y Johkoh T Egashira R Sumikawa H Saeki K Watanabe S \nAntisynthetase syndrome: Pulmonary computed tomography findings of adult patients with antibodies to aminoacyl-tRNA synthetases\n. Eur J Radiol \n2016 ;85 :1421 –26\n. [10.1016/j.ejrad.2016.05.012 ] [PMID: ]27423682 \n9. Dieval C Deligny C Meyer A Cluzel P Champtiaux N Lefevre G \nMyocarditis in Patients With Antisynthetase Syndrome: Prevalence, Presentation, and Outcomes\n. Medicine \n2015 ;94 (26 ):e798 . [10.1097/MD.0000000000000798 ] [PMID: ] [PMCID: ]26131832 \n10. Doyle TJ Dhillon N Madan R Cabral F Fletcher EA Koontz DC \nRituximab in the Treatment of Interstitial Lung Disease Associated with Antisynthetase Syndrome: A Multicenter Retrospective Case Review\n. J Rheumatol \n2018 ;45 (6 ):841 –50\n. [10.3899/jrheum.170541 ] [PMID: ] [PMCID: ]29606668\n\n", "fulltext_license": "CC BY", "issn_linking": "2529-198X", "issue": "30(3)", "journal": "Mediterranean journal of rheumatology", "keywords": "Raynaud’s phenomenon; anti-Jo1; anti-synthetase syndrome; interstitial lung disease", "medline_ta": "Mediterr J Rheumatol", "mesh_terms": null, "nlm_unique_id": "101730166", "other_id": null, "pages": "186-189", "pmc": null, "pmid": "32185363", "pubdate": "2019-09", "publication_types": "D002363:Case Reports", "references": "22078416;27423682;26131832;27594777;22771754;29606668;28461650;28147261;30239350;28339994", "title": "Interstitial Lung Disease in Anti-Synthetase Syndrome.", "title_normalized": "interstitial lung disease in anti synthetase syndrome" }	[ { "companynumb": "GR-MYLANLABS-2020M1004249", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CLARITHROMYCIN" }, "drugadditional": null, 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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": "MOXIFLOXACIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "drugadministrationroute": null, "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": "RITUXIMAB." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "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": "PIPERACILLIN/TAZOBACTAM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": null, "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": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KOURKOUNI E, MITSOGIANNIS G, SIMOPOULOU T, LIASKOS C, KATSIARI CG, DANIIL Z ET.AL. INTERSTITIAL LUNG DISEASE IN ANTI-SYNTHETASE SYNDROME.. MEDITERRANEAN J. RHEUMATOLOGY. 2019?30(3):186-9", "literaturereference_normalized": "interstitial lung disease in anti synthetase syndrome", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17274414, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]
{ "abstract": "Giant cell arteritis is a common systemic vasculitis affecting the elderly, with maximum prevalence in the 7th decade of age, targeting aortic derived medium and large vessels of the neck and head. Diagnosis is established on a biopsy specimen of the temporal artery wall, through pathological confirmation of panarteritis, typically characterized by mononuclear cell infiltrate, with the 1990 ACR criteria often used in clinical practice. We present the case of a patient with a new onset headache and systemic inflammation, who did not fulfil the classical diagnostic criteria, nor did the temporal artery biopsy (TAB) provide a positive result. However, the ultrasonographical features, clinical evolution and response to corticosteroid therapy confirmed the diagnosis. This patient had bilateral presence of the halo sign on color duplex ultrasonography (CDUS), cited as a highly specific feature, when compared to the ACR criteria as a standard reference. We employed its positive likelihood-ratio (LR+) of 43 as previously estimated, while considering a low pre-test probability for a positive diagnosis (15%), to calculate a post-test probability of 88%, leading to our decision to treat him as having giant cell arteritis. Remission of the headache and rebound phenomena when tapered off steroid therapy substantially contributed to the positive diagnosis, underlining the importance of future studies needing to use clinical evolution as a reference standard.", "affiliations": "Colentina Clinical Hospital, Department of Neurology, Bucharest, Romania.;Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest, Romania.;Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest, Romania.", "authors": "Chiriac\|Andra\|A\|;Badea\|Camelia\|C\|;Băicuș\|Cristian\|C\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D011241:Prednisone", "country": "Germany", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1220-4749", "issue": "57(4)", "journal": "Romanian journal of internal medicine = Revue roumaine de medecine interne", "keywords": "compression sign; giant cell arteritis; halo sign; ultrasonography", "medline_ta": "Rom J Intern Med", "mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D013700:Giant Cell Arteritis; D006801:Humans; D008297:Male; D011241:Prednisone; D014463:Ultrasonography", "nlm_unique_id": "9304507", "other_id": null, "pages": "341-344", "pmc": null, "pmid": "31120860", "pubdate": "2019-12-01", "publication_types": "D002363:Case Reports", "references": null, "title": "Will imaging change the diagnosis and management of giant cell arteritis?", "title_normalized": "will imaging change the diagnosis and management of giant cell arteritis" }	[ { "companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-237346", "fulfillexpeditecriteria": "1", "occurcountry": "RO", "patient": { "drug": [ { "actiondrug": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.75 MILLIGRAM/KILOGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".75", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "GABAPENTIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "77525", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIINFLAMMATORY THERAPY", "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": "3", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MILLIGRAM", "drugenddate": null, "drugenddateformat": null, "drugindication": "EAR INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "83", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Myopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Steroid diabetes", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CHIRIAC A, BADEA C, BAICUS C. WILL IMAGING CHANGE THE DIAGNOSIS AND MANAGEMENT OF GIANT CELL ARTERITIS. ROMANIAN JOURNAL OF INTERNAL MEDICINE. 2019?57 (4):341-344", "literaturereference_normalized": "will imaging change the diagnosis and management of giant cell arteritis", "qualification": "3", "reportercountry": "RO" }, "primarysourcecountry": "RO", "receiptdate": "20201021", "receivedate": "20200220", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17439006, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]
{ "abstract": "Acute liver failure (ALF) in neonates is rare. Although the incidence is reported to be rare, neonatal hemochromatosis (NH) has to be considered as one of the causes of neonatal ALF. We present a pair of dichorionic twin who had a diverse clinical presentation of NH. One twin passed away despite medical treatment with exchange transfusion and intravenous immunoglobulin (IVIg), whereas the other twin suffered from only mildly deranged liver function, which normalized spontaneously. Early identification of liver failure and clinical awareness of this disease entity are essential to its timely diagnosis and treatment. Antenatal management using IVIg prevents the recurrence of NH in subsequent pregnancies.", "affiliations": "Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong.;Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong.;Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong.", "authors": "Chee\|Yee Yuet\|YY\|;Wong\|Siu Chun Mabel\|SCM\|;Wong\|Ming Sum Rosanna\|MSR\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1055/s-0038-1675335", "fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0038-1675335180007Case ReportHeterogeneous Presentation of Neonatal Hemochromatosis in Dichorionic Twins Chee Yee Yuet FHKAM1Wong Siu Chun Mabel FHKAM1Wong Ming Sum Rosanna FHKAM11 Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong KongAddress for correspondence Yuet Yee Chee, FHKAM Department of Paediatrics and Adolescent MedicineUniversity of Hong Kong, 102 Pokfulam Road, Queen Mary Hospital, Hong KongHong [email protected] 2018 20 11 2018 8 4 e332 e334 31 1 2018 19 6 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.Acute liver failure (ALF) in neonates is rare. Although the incidence is reported to be rare, neonatal hemochromatosis (NH) has to be considered as one of the causes of neonatal ALF. We present a pair of dichorionic twin who had a diverse clinical presentation of NH. One twin passed away despite medical treatment with exchange transfusion and intravenous immunoglobulin (IVIg), whereas the other twin suffered from only mildly deranged liver function, which normalized spontaneously. Early identification of liver failure and clinical awareness of this disease entity are essential to its timely diagnosis and treatment. Antenatal management using IVIg prevents the recurrence of NH in subsequent pregnancies.\n\nKeywords\nneonatal hemochromatosisgestational alloimmune liver diseaseliver failure\n==== Body\nCase Report\nClinical Presentation\nA dichorionic diamniotic male twin was born at 35 weeks of gestation with a birth weight of 1.6 kg (small for gestational age). The baby presented with recurrent hypoglycemia shortly after birth. Blood tests on the second day of life showed cholestasis (up to 145 umol/L), hypoalbuminemia, hyperammonemia (up to 453 umol/L), and coagulopathy, which progressively worsened throughout the first week of life. Work-up for neonatal liver failure was negative for metabolic disease, and surgical and infective causes.\n\n\nFerritin level was elevated at 8,397 umol/L. Biopsy of the liver and buccal mucosa was performed. This demonstrated hepatic and extrahepatic iron deposition (\nFig. 1\n) and confirmed the diagnosis of neonatal hemochromatosis (NH; likely due to gestational alloimmune liver disease, GALD). Medical treatment was given with exchange transfusion and intravenous immunoglobulin (IVIg). However, he failed to respond to medical treatment and developed worsening liver failure. Liver transplantation was considered but deemed not an option due to the low body weight and unavailability of living-related liver donor. After extensive discussion with the parents, the decision for redirection of care was made. The baby was electively extubated and eventually succumbed on day 33 of life.\n\n\nFig. 1 \nLiver biopsy showing hepatocellular siderosis (left) and abnormal iron deposition in salivary gland (right), demonstrating iron in blue by Perl's stain.\n\n\nOn the contrary, the other twin girl was born with a birth weight of 2.4 kg and suffered only from mildly deranged liver function only. Her liver function test showed mildly elevated liver enzymes (peak aspartate aminotransferase [AST] of 371 U/L and alanine aminotransferase [ALT] of 162 U/L at around 3 weeks of life) and conjugated bilirubin (11 umol/L), with normal ammonia level and clotting profile all along. Metabolic, surgical, and infective work-ups were negative. Ferritin level was high at 9,801 umol/L. Liver function test subsequently normalized spontaneously upon follow-up.\n\nFamily was counseled on the importance of antenatal treatment with IVIg in future pregnancies to prevent the recurrence of NH.\n\nDiscussion\n\nAlthough neonatal liver failure is rarely encountered, one of the most important diagnoses to consider is NH. NH is a rare condition. The exact incidence of the disorder is unknown. Fetal liver injury causes disturbed fetal iron homeostasis, resulting in fetal iron overload. NH is characterized by severe liver injury with the accumulation of iron in hepatic and extrahepatic tissues. The most common cause of fetal liver injury leading to the NH phenotype is a gestational alloimmune disorder called GALD.\n1\n2\nIt results from the transplacental transfer of maternal immunoglobulin G (IgG) directed against an antigen on the fetal hepatocyte, with fetal complement activation and formation of membrane attack complex, resulting in fetal hepatocyte injury and death (with congenital cirrhosis and siderosis of extrahepatic tissues). Once a woman has become sensitized, transplacental passage of IgG can occur in subsequent pregnancy, causing immune-mediated liver injury in the fetus.\n\n\n\nDiagnosis of NH is by the demonstration of iron accumulation in the extrahepatic tissues, usually through the biopsy of oral mucosal salivary glands or using T2-weighed magnetic resonance imaging (MRI) demonstrating the accumulation of iron in the pancreas, heart, or adrenal glands.\n1\nAntibodies to C5b-9 complex, a neoantigen created during the activation of terminal complement cascade, are used to demonstrate the accumulation of membrane attack complex in liver biopsy.\n2\nHowever, this immunohistochemical staining for C5b-9 complex is not available in our locality.\n\n\n\nTreatment for NH includes exchange transfusion (by removing existing reactive antibodies) and IVIg (blocking antibody action and interfering with complement activation).\n3\n4\nSurvival with medical treatment (without liver transplantation) is reported to be at around 75%.\n4\nIf medical treatment fails, liver transplantation remains to be the last therapeutic option.\n\n\n\nNH presentation could be quite heterogeneous, as shown in this pair of twins. The twin boy was being affected antenatally with growth restriction and early presentation with hypoglycemia within few hours after birth followed by liver failure. Without the frank presentation of liver failure in one of the index twin, the other twin would have been managed as a case of neonatal hepatitis, and the diagnosis of NH would be missed. With antenatal IVIg treatment, outcome of future pregnancy in our index family is expected to be good.\n5\n6\n\n\n\nTable 1\nsummarizes the clinical characteristics of published cases of twins pregnancy affected by NH in the literature.\n7\n8\n9\n10\n11\n\n\nTable 1 Summary of twins pregnancy affected by NH\n\tNormal values\tTwin set 1 (index)\t\t\nTwin set 2\n7\n\t\t\nTwin set 3\n8\n\t\t\nTwin set 4\n9\n\t\nTwin set 5\n9\n\t\t\nTwin set 6\n10\n\t\t\nTwin set 7\n11\n\t\t\n Twin set 8\n11\n\t\t\n\t\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin B\t\n\nPregnancy\n\t\tDCDA\tDCDA\tMC\tMC\tMC\tMC\tN/A\tMCDA\tMCDA\tMC\tMC\tDCDA\tDCDA\tDCDA\tDCDA\t\n\nGender\n\t\tMale\tFemale\tMale\tMale\tFemale\tFemale\tMale\tMale\tMale\tMale\tMale\tMale\tFemale\tFemale\tFemale\t\n\nGestational age (weeks)\n\t\t35\t35\t37\t37\t34\t34\t27\t26\t26\t33\t33\t35\t35\t37\t37\t\n\nBirth weight (kg)\n\t\t1.6\t2.4\t2.49\t2.5\t1.83\t1.95\t0.92\t0.82\t0.9\t2.4\t2.1\tAGA\tAGA\tAGA\tAGA\t\n\nTotal bilirubin (umol/L)\n\t<24\t368\t169\t154\t197\t36\tN/A\t149\t71\t476\t–\tN/A\t231\t67\t91\t238\t\n\nDirect bilirubin (umol/L)\n\t<10\t145\t11\t32\t21\t19\tN/A\tN/A\tN/A\tN/A\t–\tN/A\t113\t9\t7\t80\t\n\nAST (U/L)\n\t<60\t146\t371\t502\t133\t34\tN/A\tN/A\tN/A\tN/A\t–\tN/A\tN/A\tN/A\tN/A\tN/A\t\n\nALT (U/L)\n\t<53\t56\t162\t78\t23\t101\tN/A\t98\t25\t306\t–\t5\t27\t41\t21\t38\t\n\nINR\n\t<2\t4.5\t1.2\t2.8\t1.5\t3\tN/A\t1.5\t1.2\t1.6\t–\t1.37\t4.7\t1\t2.2\t3.4\t\n\nFerritin (pmol/L)\n\t275–831\t8,397\t9,801\t62,115\t5,643\t3,596\tN/A\t2,663\t5,443\t6,625\t–\t1,180\t2,609\t1,539\t3,762\t8,865\t\n\nNH Treatment\n\t\tIVIG, ET\tNot required\tIVIG\tNot required\tAntioxidant–chelation therapy\tN/A\tAntioxidant therapy\tNot required\tAntioxidant therapy\t–\tAntioxidant therapy\tAntioxidant–chelation therapy\tAntioxidant therapy\tAntioxidant–chelation therapy\tAntioxidant–chelation therapy\t\n\nOutcome\n\t\tDied on day 33 of life\tHealthy at 10 mo\tHealthy at 1.5 y\tHealthy at 1.5 y\tHealthy at 1 y\tDied on day 12 of life\tAlive\tAlive\tAlive\tIUD\tHealthy at 6 mo\tHealthy at 1 y\tHealthy at 1 y\tHealthy at 10 mo\tHealthy at 10 mo\t\nAbbreviations: AGA, appropriate for gestational age; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCDA, dichorionic–diamniotic; ET, exchange transfusion; INR, international normalized ratio; IUD, intrauterine demise; IVIG, intravenous immunoglobulin; MC, monochorionic; MCDA, monochorionic-diamniotic; N/A, not available; NH, neonatal hemochromatosis .\n\nConclusion\nIn conclusion, a high index of suspicion of NH in babies presenting with cholestasis and deranged liver function is important so as to facilitate its early diagnosis and management. It has a high recurrence in subsequent pregnancies, and antenatal IVIg treatment can greatly reduce this chance.\n\nConflicts of Interest All contributing authors declare no conflicts of interest.\n==== Refs\nReferences\n1 Whitington PF Gestational alloimmune liver disease and neonatal hemochromatosis Semin Liver Dis 2012 32 04 325 332 23397533 \n2 Heissat S Collardeau-Frachon S Baruteau J Neonatal hemochromatosis: diagnostic work-up based on a series of 56 cases of fetal death and neonatal liver failure J Pediatr 2015 166 01 66 73 25444000 \n3 Lopriore E Mearin ML Oepkes D Devlieger R Whitington PF Neonatal hemochromatosis: management, outcome, and prevention Prenat Diagn 2013 33 13 1221 1225 24030714 \n4 Rand EB Karpen SJ Kelly S Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin J Pediatr 2009 155 04 566 571 19560784 \n5 Whitington PF Hibbard JU High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis Lancet 2004 364 (9446):1690 1698 15530630 \n6 Whitington PF Kelly S Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin Pediatrics 2008 121 06 e1615 e1621 18474533 \n7 Midorikawa H Mizuochi T Okada JI Hisano T Disparate clinical findings in monochorionic twins with neonatal hemochromatosis Pediatr Int 2017 59 11 1215 1216 29359379 \n8 Korkmaz L Baştuğ O Daar G Doğanay S Deniz K Kurtoğlu S Neonatal hemochromatosis in monochorionic twins J Neonatal Perinatal Med 2015 8 04 413 416 26836824 \n9 Isa HM Mohamed AM Neonatal hemochromatosis. Case series from Bahrain Saudi Med J 2013 34 12 1274 1280 24343468 \n10 Vanden Eijnden S Hassoun M Donner C Iron overload in gestational alloimmune liver disease: still more questions than answers Prenat Diagn 2012 32 08 810 812 22566027 \n11 Ekong UD Kelly S Whitington PF Disparate clinical presentation of neonatal hemochromatosis in twins Pediatrics 2005 116 06 e880 e884 16291733\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2157-7005", "issue": "8(4)", "journal": "AJP reports", "keywords": "gestational alloimmune liver disease; liver failure; neonatal hemochromatosis", "medline_ta": "AJP Rep", "mesh_terms": null, "nlm_unique_id": "101569862", "other_id": null, "pages": "e332-e334", "pmc": null, "pmid": "30464860", "pubdate": "2018-10", "publication_types": "D002363:Case Reports", "references": "29359379;24030714;25444000;26836824;22566027;24343468;15530630;19560784;18474533;23397533;16291733", "title": "Heterogeneous Presentation of Neonatal Hemochromatosis in Dichorionic Twins.", "title_normalized": "heterogeneous presentation of neonatal hemochromatosis in dichorionic twins" }	[ { "companynumb": "HK-BEH-2021129455", "fulfillexpeditecriteria": "1", "occurcountry": "HK", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "125201", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEONATAL HAEMOCHROMATOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HUMAN IMMUNOGLOBULIN (INN)" } ], "patientagegroup": "2", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "1.6", "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "CHEE Y.Y., WONG S.C.M., WONG M.S.R.. HETEROGENEOUS PRESENTATION OF NEONATAL HEMOCHROMATOSIS IN DICHORIONIC TWINS. AJP REPORTS. 2018?8(4):E332?E334", "literaturereference_normalized": "heterogeneous presentation of neonatal hemochromatosis in dichorionic twins", "qualification": "3", "reportercountry": "HK" }, "primarysourcecountry": "HK", "receiptdate": "20210319", "receivedate": "20210319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19027454, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210420" } ]

{ "abstract": "OBJECTIVE\nThe aim of this study was to explore the effects of early oral ibuprofen administration on the incidence of hemodynamically significant patent ductus arteriosus (hsPDA) and define the association between serum ibuprofen levels and ductal closure.\n\n\nMETHODS\nPreterm infants with a gestational age of <28 weeks and/or birth weight of <1,000 g were randomized either to the intervention (ibuprofen prophylaxis) or control group. The intervention group received oral ibuprofen 10 mg/kg within 12-24 h after birth followed by 5 mg/kg at 24 and 48 h. Serum ibuprofen levels after the treatment were analyzed in the intervention group, and the incidence of hsPDA and complication rates were compared between two groups.\n\n\nRESULTS\nNineteen infants who received one course (three doses) of prophylactic ibuprofen in the intervention group and 17 infants in the control group who underwent an echocardiographic examination on the fourth day of life were analyzed. hsPDA was observed in five (26 %) infants in the intervention group and ten (58 %) infants in the control group (p = 0.09). In the intervention group two infants experienced gastrointestinal bleeding two infants had spontaneous intestinal perforation, and two infants developed acute kidney failure. Mean serum ibuprofen level was 28.7 ± 16.9 mg/L in the intervention group, and there was no correlation between ibuprofen level obtained on the fourth day and ductal closure.\n\n\nCONCLUSIONS\nOral ibuprofen prophylaxis reduces the rates of hsPDA even it is not statistically significant. The ductal closure rate did not correlate with serum ibuprofen levels. Due to high prevalence of adverse events observed, our data do not support the use of oral ibuprofen for prophylaxis of hsPDA.", "affiliations": "Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey. [email protected]", "authors": "Kanmaz|Gozde|G|;Erdeve|Omer|O|;Canpolat|Fuat Emre|FE|;Oğuz|Serife Suna|SS|;Uras|Nurdan|N|;Altug|Nahide|N|;Greijdanus|Ben|B|;Dilmen|Uğur|U|", "chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen", "country": "Germany", "delete": false, "doi": "10.1007/s00228-012-1438-8", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-6970", "issue": "69(5)", "journal": "European journal of clinical pharmacology", "keywords": null, "medline_ta": "Eur J Clin Pharmacol", "mesh_terms": "D000284:Administration, Oral; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004374:Ductus Arteriosus, Patent; D005260:Female; D006801:Humans; D007052:Ibuprofen; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D008297:Male", "nlm_unique_id": "1256165", "other_id": null, "pages": "1075-81", "pmc": null, "pmid": "23128963", "pubdate": "2013-05", "publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial", "references": "22147286;2007940;11673749;9099319;1972434;21840880;12774141;22794156;413500;8397375;15001951;17564958;18307541;17768157;21089127;16696414;10974138;10693094;20876595;16322158;6909683;21094951;12971028;19620202;3516077;19255990", "title": "Serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus.", "title_normalized": "serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus" }

[ { "companynumb": "US-JNJFOC-20150219051", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017463", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PATENT DUCTUS ARTERIOSUS", "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": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intestinal perforation", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KANMAZ G, ERDEVE O, CEANPOLAT FE, DGUZ SS, URAS, N, ALTUG N, ET AL. SERUM IBUPROFEN LEVELS OF EXTREMELY PRETERM INFANTS TREATED PROPHYLACTICALLY WITH ORAL IBUPROFEN TO PREVENT PATENT DUCTUS ARTERIOSUS. EUR.J CUN PHARMACAL 2013;69(5):1075-81.", "literaturereference_normalized": "serum ibuprofen levels of extremely preterm infants treated prophylactically with oral ibuprofen to prevent patent ductus arteriosus", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150226", "receivedate": "20150226", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10870885, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "Cystic fibrosis (CF) patients receive many antibiotic treatments for recurrent respiratory infections and frequently report antibiotic hypersensitivity reactions (HSRs). In this retrospective study, medical records of CF patients were reviewed to clarify the clinical features, the culprit antibiotics, and the prevalence of antibiotic HSRs in the CF population. From 601 CF patients, 95 suspected antibiotic HSRs occurred in 60 patients (prevalence of 10.0%). β-Lactams were the most common inducers, but cotrimoxazole was also frequently involved. Seventy-six of 95 suspected HSRs were assessed by allergy workup including skin tests (43/76 reactions) and/or drug reintroduction as a full course of the culprit antibiotic (73 of 76 reactions). From the 43 suspected HSRs that were skin-tested, only three had positive skin tests and were not subjected to drug readministration. All the other 73 suspected HSRs received a full course of the culprit antibiotic: HSR symptoms recurred in 10 of 73 cases and therefore were considered as confirmed antibiotic HSRs; for the remaining 63 suspected HSRs that did not relapse after drug readministration, the diagnosis of antibiotic HSRs was excluded. In summary, 13 of 76 suspected HSRs were confirmed as antibiotic HSRs. The prevalence of suspected and confirmed antibiotic HSRs in CF patients appears similar to that reported in the general population. Of note, most of the antibiotic suspected HSRs are not confirmed after allergology workup. A complete allergy workup appears therefore crucial to make a correct diagnosis and to avoid unnecessary contraindication of major antibiotics.", "affiliations": "University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;Internal Medicine and Vascular Pathology Department, Adult Cystic Fibrosis Center, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Internal Medicine and Vascular Pathology Department, Adult Cystic Fibrosis Center, Groupement Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Pediatric Pulmonology and Allergology Department, Pediatric Cystic Fibrosis Center, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;Pediatric Pulmonology and Allergology Department, Pediatric Cystic Fibrosis Center, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.;University of Lyon 1 Claude Bernard, Villeurbanne, France.", "authors": "Braun|Camille|C|0000-0001-9260-8977;Reix|Philippe|P|;Durieu|Isabelle|I|;Nove-Josserand|Raphaele|R|;Durupt|Stéphane|S|;Ohlmann|Camille|C|;Mainguy|Catherine|C|;Nicolas|Jean-François|JF|;Nosbaum|Audrey|A|;Jubin|Virginie|V|", "chemical_list": "D000900:Anti-Bacterial Agents; D047090:beta-Lactams", "country": "England", "delete": false, "doi": "10.1111/pai.13206", "fulltext": null, "fulltext_license": null, "issn_linking": "0905-6157", "issue": "31(4)", "journal": "Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology", "keywords": "allergy workup; antibiotic; cystic fibrosis; hypersensitivity", "medline_ta": "Pediatr Allergy Immunol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D002648:Child; D003550:Cystic Fibrosis; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D012882:Skin Tests; D055815:Young Adult; D047090:beta-Lactams", "nlm_unique_id": "9106718", "other_id": null, "pages": "396-404", "pmc": null, "pmid": "31880334", "pubdate": "2020-05", "publication_types": "D016428:Journal Article", "references": null, "title": "The diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work-up in cystic fibrosis patients.", "title_normalized": "the diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work up in cystic fibrosis patients" }

[ { "companynumb": "FR-TEVA-2020-FR-1503934", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "73303", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIVE PULMONARY EXACERBATION OF CYSTIC FIBROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Type I hypersensitivity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRAUN C, REIX P, DURIEU I, NOVE?JOSSERAND R, DURUPT S, OHLMANN C, ET AL. THE DIAGNOSIS OF HYPERSENSITIVITY TO ANTIBIOTICS IS RARELY CONFIRMED BY ALLERGY WORK?UP IN CYSTIC FIBROSIS PATIENTS. PEDIATR?ALLERGY?IMMUNOL 2020?31(4):396?404.", "literaturereference_normalized": "the diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work up in cystic fibrosis patients", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210628", "receivedate": "20200617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17906264, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20210717" }, { "companynumb": "FR-TEVA-2020-FR-1503959", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "73303", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIVE PULMONARY EXACERBATION OF CYSTIC FIBROSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "COTRIMOXAZOLE" } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Type I hypersensitivity", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BRAUN C, REIX P, DURIEU I, NOVE?JOSSERAND R, DURUPT S, OHLMANN C, ET AL. THE DIAGNOSIS OF HYPERSENSITIVITY TO ANTIBIOTICS IS RARELY CONFIRMED BY ALLERGY WORK?UP IN CYSTIC FIBROSIS PATIENTS. PEDIATR?ALLERGY?IMMUNOL 2020?31(4):396?404.", "literaturereference_normalized": "the diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work up in cystic fibrosis patients", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20210628", "receivedate": "20200617", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17906265, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20210717" } ]

{ "abstract": "The long-term efficacy of infliximab in patients with Crohn's disease is suboptimal.\n\n\n\nTo study prognostic factors for real-life long-term effcacy of infliximab in Crohn's disease.\n\n\n\nAll consecutive Crohn's disease patients treated with infliximab at a tertiary centre were retrospectively analysed. Only patients who received scheduled infliximab maintenance treatment were considered. Patient- and disease-related factors were used to identify independent predictors of infliximab failure-free survival using Cox proportional hazards regression.\n\n\n\nOf 1031 patients with Crohn's disease, 261 were eligible for inclusion. Median time on infliximab was 2.4 [IQR 1.4-4.7] years, and 65 (24.9%) patients experienced infliximab failure. Estimated 5-year infliximab failure-free survival was 65.9% (95% CI 58.3-73.5). Multivariate Cox regression identified disease duration ≥1 year (HR 2.5 (95% CI 1.2-5.2), P = 0.02), L1 disease location [HR 2.0 (1.1-3.5), P = 0.02], prior anti-TNF use [HR 2.3 (1.1-4.8), P = 0.03], haemoglobin <13.5 g/dL [HR 2.3 (1.2-4.4), P = 0.02], not using therapeutic drug monitoring [HR 8.0 (4.1-15.6), P = 1 × 10(-9) ], and first dose optimisation within first year [HR 3.7 (2.1-6.6), P = 5 × 10(-6) ] as independent predictors of infliximab failure-free survival. Stratifying patients into risk groups resulted in estimated 3-year infliximab failure-free survival rates ranging from 95.3% (94.2-96.4) to 26.3% (8.6-44.0) depending on the number of risk factors (P = 8 × 10(-13) ).\n\n\n\nThis study identified several easy to obtain predictors of infliximab failure in patients with Crohn's disease, and these are in line with previous reports. Those with a high-risk profile for infliximab failure in whom infliximab initiation is considered, should be treated as early as possible making use of therapeutic drug monitoring.", "affiliations": "Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.;Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.;Department of Clinical and Experimental Medicine, Translational Research Center for GastroIntestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.", "authors": "Billiet|T|T|;Cleynen|I|I|;Ballet|V|V|;Ferrante|M|M|;Van Assche|G|G|;Gils|A|A|;Vermeire|S|S|", "chemical_list": "D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab", "country": "England", "delete": false, "doi": "10.1111/apt.13754", "fulltext": null, "fulltext_license": null, "issn_linking": "0269-2813", "issue": "44(7)", "journal": "Alimentary pharmacology & therapeutics", "keywords": null, "medline_ta": "Aliment Pharmacol Ther", "mesh_terms": "D000328:Adult; D003424:Crohn Disease; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult", "nlm_unique_id": "8707234", "other_id": null, "pages": "673-83", "pmc": null, "pmid": "27502581", "pubdate": "2016-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Prognostic factors for long-term infliximab treatment in Crohn's disease patients: a 20-year single centre experience.", "title_normalized": "prognostic factors for long term infliximab treatment in crohn s disease patients a 20 year single centre experience" }

[ { "companynumb": "BE-JNJFOC-20160913574", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "103772", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "LYOPHILIZED POWDER", "drugdosagetext": "WEEK 0, 2 AND 6 FOLLOWED BY AT LEAST TWO??ADDITIONAL INFUSIONS AT WEEK 14 AND WEEK 22", "drugenddate": null, "drugenddateformat": null, "drugindication": "CROHN^S DISEASE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Therapeutic response decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthropathy", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin reaction", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug specific antibody present", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm malignant", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug level decreased", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BILLIET T, CLEYNEN I, BALLET V, FERRANTE M, ASSCHE GV, GILS A, ET AL. PROGNOSTIC FACTORS FOR LONG-TERM INFLIXIMAB TREATMENT IN CROHN^S DISEASE PATIENTS: A 20-YEAR SINGLE CENTRE EXPERIENCE. ALIMENT PHARMACOL THER 09-AUG-2016;44:673-683.", "literaturereference_normalized": "prognostic factors for long term infliximab treatment in crohn s disease patients a 20 year single centre experience", "qualification": "3", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20160927", "receivedate": "20160921", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12767175, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20161109" } ]

{ "abstract": "In 2003, van Grotel and colleagues reported an infant suffering a chemotherapy-resistant eRMS of the tongue, that was treated with subtotal tumor resection and brachytherapy after major medical ethical discussions. As no long-term sequelae of such a procedure have been described, perspectives were uncertain at that time. Now, after 15 years, we describe hypoplasia of the mandibula, compromised dentation, osteopenia, neuropsychological deficits, and moderate speech impairment as the most prominent late effects. Also, mandibular cysts and basal cell carcinomas in the irradiated area, eventually led to the diagnosis Gorlin syndrome.", "affiliations": "*Princess Máxima Center for Pediatric Oncology §Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands †Department of Pediatrics, Erasmus MC-Sophia Children's Hospital ‡Department of Radiotherapy, Erasmus MC ∥Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital ¶Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.", "authors": "van Rijswijk|Petra M|PM|;van den Heuvel-Eibrink|Marry M|MM|;van den Akker|Erica L T|ELT|;Slagter|Cleo|C|;Lequin|Maarten H|MH|;Aarsen|Femke K|FK|;van Atteveld|Jenneke E|JE|;Wagner|Anja|A|;van Grotel|Martine|M|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MPH.0000000000000935", "fulltext": null, "fulltext_license": null, "issn_linking": "1077-4114", "issue": "39(7)", "journal": "Journal of pediatric hematology/oncology", "keywords": null, "medline_ta": "J Pediatr Hematol Oncol", "mesh_terms": "D000293:Adolescent; D001478:Basal Cell Nevus Syndrome; D001918:Brachytherapy; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007223:Infant; D008297:Male; D012208:Rhabdomyosarcoma; D018233:Rhabdomyosarcoma, Embryonal; D014062:Tongue Neoplasms", "nlm_unique_id": "9505928", "other_id": null, "pages": "566-569", "pmc": null, "pmid": "28859029", "pubdate": "2017-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Very Long-term Sequelae After Nonradical Surgery Combined With Brachytherapy in an Infant With a Chemotherapy-resistant Rhabdomyosarcoma of the Tongue.", "title_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue" }

[ { "companynumb": "NL-ACCORD-061501", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "133001", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "EPIRUBICIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "2007500240001", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "5", "drugcumulativedosageunit": "007", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "DACTINOMYCIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206775", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "34", "drugcumulativedosageunit": "007", "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "34", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN." } ], "patientagegroup": "4", "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM, VAN DEN HEUVEL-EIBRINK MM, VAN DEN AKKER ELT, SLAGTER C, LEQUIN MH, AARSEN FK, ET AL. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J PEDIATR HEMATOL ONCOL. 2017 OCT?39(7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180406", "receivedate": "20171130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14238178, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "NL-RECORDATI RARE DISEASES-NL-R13005-17-00262", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", 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null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": "TOTAL CUMULATIVE DOSE 5 MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" } ], 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VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. JOURNAL OF PEDIATRIC HEMATOLOGY/ONCOLOGY 2017;39(7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171229", "receivedate": "20171229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14335656, "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": "NL-BAXTER-2018BAX007362", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. JOURNAL OF PEDIATRIC HEMATOLOGY/ONCOLOGY. 2017?39(7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180313", "receivedate": "20180313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14628649, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 1, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180509" }, { "companynumb": "NL-MYLANLABS-2017M1073516", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { 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null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM, VAN DEN HEUVEL-EIBRINK MM, VAN DEN AKKER ELT, SLAGTER C, LEQUIN MH, AARSEN FK, ET AL. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J-PEDIATR-HEMATOL-ONCOL 2017;39(7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171121", "receivedate": "20171121", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14208529, "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": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-156448", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", 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"drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VICRISTINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 CYCLES", "drugenddate": null, 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ACTINOMYCIN D" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3 CYCLES", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IFOSFAMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPIRUBICIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/KG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tooth loss", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dental caries", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tooth disorder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM, VAN DEN HEUVEL-EIBRINK MM, VAN DEN AKKER ELT, SLAGTER C, LEQUIN MH, AARSEN FK, ET AL. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J-PEDIATR-HEMATOL-ONCOL. 2017;39(7):566-569", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171207", "receivedate": "20171207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14258019, "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": "NL-PFIZER INC-2017543145", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "IFOSFAMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "CARBOPLATIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "076517", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL CUMULATIVE DOSE 34MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "DACTINOMYCIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EPIRUBICIN HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "050778", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TOTAL CUMULATIVE DOSE 5MG/KG", "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "4", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "49", "reaction": [ { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Developmental delay", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK PM. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE.. J-PEDIATR-HEMATOL-ONCOL. 2017?39(7):566-569", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "1", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20180309", "receivedate": "20171228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14332812, "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" }, { "companynumb": "NL-FRESENIUS KABI-FK201710111", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CARBOPLATIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "077266", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CARBOPLATIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IFOSFAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "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": "EPIRUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "065411", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EPIRUBICIN (MANUFACTURER UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "074983", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "EMBRYONAL RHABDOMYOSARCOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Body height below normal", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Osteopenia", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Delayed puberty", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VAN RIJSWIJK P,VAN DEN HEUVEL-EIBRINK M,VAN DEN AKKER E,SLAGTER C,LEQUIN M,AARSEN F. VERY LONG-TERM SEQUELAE AFTER NONRADICAL SURGERY COMBINED WITH BRACHYTHERAPY IN AN INFANT WITH A CHEMOTHERAPY-RESISTANT RHABDOMYOSARCOMA OF THE TONGUE. J PEDIATR HEMATOL ONCOL 2017;39 (7):566-569.", "literaturereference_normalized": "very long term sequelae after nonradical surgery combined with brachytherapy in an infant with a chemotherapy resistant rhabdomyosarcoma of the tongue", "qualification": "3", "reportercountry": "NL" }, "primarysourcecountry": "NL", "receiptdate": "20171127", "receivedate": "20171127", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14226680, "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 17-year-old male subject with a history of deep venous thrombosis presented with acute unilateral severe chest pain. His examination was nonspecific, and vital signs were normal. His initial laboratory evaluation revealed mild thrombocytopenia, elevated troponin levels, and critically elevated activated partial thromboplastin time. A computed tomography angiogram of the chest revealed a pulmonary embolus, and anticoagulation therapy was initiated. His course was complicated by the development of multiple thrombi and respiratory failure. Extensive evaluation revealed a rare, underlying diagnosis in time for life-saving treatment to be initiated.", "affiliations": "Children's National Health System, Washington, District of Columbia; and [email protected].;Department of Dermatology, Georgetown University-Washington Hospital Center, Washington, District of Columbia.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.;Children's National Health System, Washington, District of Columbia; and.", "authors": "Shah|Ankoor Y|AY|;Jamison|Megan|M|;Otero|Hansel J|HJ|;Jung|Lawrence|L|;Frank|Lowell H|LH|;Guerrera|Michael F|MF|;Kirkorian|A Yasmine|AY|", "chemical_list": "D016682:Lupus Coagulation Inhibitor; D014336:Troponin", "country": "United States", "delete": false, "doi": "10.1542/peds.2016-0794", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-4005", "issue": "139(3)", "journal": "Pediatrics", "keywords": null, "medline_ta": "Pediatrics", "mesh_terms": "D000293:Adolescent; D000307:Adrenal Gland Diseases; D016736:Antiphospholipid Syndrome; D002637:Chest Pain; D006470:Hemorrhage; D006801:Humans; D016682:Lupus Coagulation Inhibitor; D008297:Male; D010314:Partial Thromboplastin Time; D011655:Pulmonary Embolism; D013921:Thrombocytopenia; D014336:Troponin; D020246:Venous Thrombosis", "nlm_unique_id": "0376422", "other_id": null, "pages": null, "pmc": null, "pmid": "28159870", "pubdate": "2017-03", "publication_types": "D016429:Clinical Conference; D016428:Journal Article", "references": null, "title": "A 17-Year-Old With Chest Pain.", "title_normalized": "a 17 year old with chest pain" }

[ { "companynumb": "US-JNJFOC-20170526155", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIVAROXABAN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "022406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "DEEP VEIN THROMBOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIVAROXABAN" } ], "patientagegroup": "4", "patientonsetage": "17", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH A, JAMISON M, OTERO H, JUNG L, FRANK L, GUERRERA M, ET AL. A 17-YEAR-OLD WITH CHEST PAIN. PEDIATRICS 2017;139:3.", "literaturereference_normalized": "a 17 year old with chest pain", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170530", "receivedate": "20170530", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13592297, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" } ]

{ "abstract": "An increase in amoxicillin-induced crystal nephropathy (AICN) incidence has been recently suggested. The aims of this study were to investigate the trend of AICN incidence through Paris' regional centers of pharmacovigilance (Paris RCPVs) and better describe this rare adverse drug reaction. Forty-five AICN cases were identified between 1985 and 2016. All cases, except one, were reported since 2010. Amoxicillin (AMX) was administered intravenously (65 [interquartile range {IQR}, 43 to 110] mg/kg of body weight/day) in all patients, either for treating infection (n = 15) or as surgical prophylaxis (n = 30). Delay between AMX administration and AICN onset was 1 (IQR, 1 to 3) day; 30, 4, and 11 patients developed KDIGO stage 1, 2, and 3 acute kidney injury, respectively. Delay between AICN onset and kidney function recovery was 4 (IQR, 2 to 6) days. Precipitating factors were identified in only one-third of cases. Twelve patients required intensive care unit admission, and 8 needed renal replacement therapy. Neither chronic kidney disease nor death was observed. We confirmed the recent and dramatic increase of AICN in the Paris RCPVs since 2010. The absence of precipitating factors in the majority of cases and the onset of AICN in apparent routine indications, such as surgical prophylaxis, are alarming and justify a high vigilance from all AMX prescribers.", "affiliations": "Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France [email protected].;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Unité Transversale de Traitement des Infections, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France.;Département de Pharmacie Clinique, Institut Gustave Roussy, Villejuif, France.;Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.;Centre Régional de Pharmacovigilance, Assistance Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.;Service d'Anesthésie et des Réanimations Chirurgicales-DHU A-TVB, Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Créteil, France.", "authors": "Vodovar|Dominique|D|;Thomas|Laure|L|;Mongardon|Nicolas|N|;Lepeule|Raphaël|R|;Lebrun-Vignes|Bénédicte|B|;Biour|Michel|M|;Netzer|Florence|F|;Haouache|Hakim|H|;Le Beller|Christine|C|;Dhonneur|Gilles|G|", "chemical_list": "D000658:Amoxicillin", "country": "United States", "delete": false, "doi": "10.1128/AAC.01630-17", "fulltext": null, "fulltext_license": null, "issn_linking": "0066-4804", "issue": "62(3)", "journal": "Antimicrobial agents and chemotherapy", "keywords": "acute kidney injury; adverse drug reaction; amoxicillin; amoxicillin-induced crystal nephropathy; crystals", "medline_ta": "Antimicrob Agents Chemother", "mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000658:Amoxicillin; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D012189:Retrospective Studies", "nlm_unique_id": "0315061", "other_id": null, "pages": null, "pmc": null, "pmid": "29263078", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": "16863455;22418755;26926627;22257367;20067334;3712526;22903046;4025964;2750161;18042305;17162145;23603656;19414839;5114750;27330071;12350188;12897111;8275607;10405561;20610357;25680270;25360508;10082069;12480988;3986077;12834178;19555813;16011448;21143023;8584329;4688560;5913575;5047606;11072960", "title": "Dramatic Increase of Amoxicillin-Induced Crystal Nephropathy Found in a Cohort Study of French Pharmacovigilance Centers.", "title_normalized": "dramatic increase of amoxicillin induced crystal nephropathy found in a cohort study of french pharmacovigilance centers" }

[ { "companynumb": "FR-MICRO LABS LIMITED-ML2019-01275", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205707", "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": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMOXICILLIN/CLAVULANIC ACID" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMOXICILLIN" }, "drugadditional": "3", "drugadministrationroute": null, "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": "AMOXICILLIN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Crystal nephropathy", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VODOVAR D, THOMAS L, MONGARDON N, LEPEULE R, LEBRUN-VIGNES B, BIOUR M, NETZER F, HAOUACHE H, BELLER C, DHONNEUR G. DRAMATIC INCREASE OF AMOXICILLIN-INDUCED CRYSTAL NEPHROPATHY FOUND IN A COHORT STUDY OF FRENCH PHARMACOVIGILANCE CENTERS.. ANTIMICROB-AGENTS-CHEMOTHER. 2018?62:.", "literaturereference_normalized": "dramatic increase of amoxicillin induced crystal nephropathy found in a cohort study of french pharmacovigilance centers", "qualification": "3", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20190527", "receivedate": "20190527", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16357130, "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": "BACKGROUND\nThe aim of this paper is to report maternal and neonatal outcomes in pregnant women treated with escitalopram during pregnancy and breastfeeding.\n\n\nMETHODS\nWomen enrolled in the DEGRA Database at the Clinic of Affective Disorders in Pregnancy and Postpartum in Italy, treated during pregnancy with escitalopram and followed up throughout pregnancy, were included in this study. All patients provided written informed consent and the study was approved by the local ethics committee. Psychiatric diagnoses were assessed using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition) Axis I Disorders and symptoms were assessed using the Hamilton Rating Scale for Depression (17 items) and Hamilton Rating Scale for Anxiety (14 items). Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded.\n\n\nRESULTS\nThe case histories of seven pregnant women treated for depression and/or anxiety disorders with escitalopram were reported. Four women were also treated with benzodiazepines. All pregnancies were full-term and all newborns had normal Apgar scores. There were no major malformations or miscarriages following exposure to escitalopram. Mild withdrawal syndrome was reported only in a newborn who was also exposed to a benzodiazepine. Two infants exposed to escitalopram during breastfeeding did not show any health problems.\n\n\nCONCLUSIONS\nOur experience with use of escitalopram in pregnant women did not reveal any maternal or neonatal concerns. However, considering the few cases analyzed and the paucity of published literature, no conclusions can be drawn on its safety profile in pregnancy and breastfeeding.", "affiliations": "Psychiatric Unit and DEGRA Center, United Hospital and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy.", "authors": "Bellantuono|Cesario|C|;Bozzi|Francesca|F|;Orsolini|Laura|L|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/NDT.S45951", "fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S45951ndt-9-1333Case SeriesSafety of escitalopram in pregnancy: a case series Bellantuono Cesario Bozzi Francesca Orsolini Laura Psychiatric Unit and DEGRA Center, United Hospital and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, ItalyCorrespondence: Laura Orsolini, Psychiatric Unit and DEGRA Center, United Hospital and Academic Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Via Conca 71, 60020 Ancona, Italy, Tel +39 07 1596 3308, Fax +39 07 1596 3313, Email [email protected] 2013 09 9 2013 9 1333 1337 © 2013 Bellantuono et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2013The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.Background\nThe aim of this paper is to report maternal and neonatal outcomes in pregnant women treated with escitalopram during pregnancy and breastfeeding.\n\nMethods\nWomen enrolled in the DEGRA Database at the Clinic of Affective Disorders in Pregnancy and Postpartum in Italy, treated during pregnancy with escitalopram and followed up throughout pregnancy, were included in this study. All patients provided written informed consent and the study was approved by the local ethics committee. Psychiatric diagnoses were assessed using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition) Axis I Disorders and symptoms were assessed using the Hamilton Rating Scale for Depression (17 items) and Hamilton Rating Scale for Anxiety (14 items). Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded.\n\nResults\nThe case histories of seven pregnant women treated for depression and/or anxiety disorders with escitalopram were reported. Four women were also treated with benzodiazepines. All pregnancies were full-term and all newborns had normal Apgar scores. There were no major malformations or miscarriages following exposure to escitalopram. Mild withdrawal syndrome was reported only in a newborn who was also exposed to a benzodiazepine. Two infants exposed to escitalopram during breastfeeding did not show any health problems.\n\nConclusion\nOur experience with use of escitalopram in pregnant women did not reveal any maternal or neonatal concerns. However, considering the few cases analyzed and the paucity of published literature, no conclusions can be drawn on its safety profile in pregnancy and breastfeeding.\n\nKeywords\nescitaloprampregnancybreastfeedingmajor malformationsperinatal complications\n==== Body\nIntroduction\nMajor depressive disorder, in many cases in comorbidity with anxiety disorders, frequently occurs during pregnancy. Approximately 10%–15% of pregnant women experience these disorders,1,2 with clinically relevant consequences for the outcome of pregnancy. In fact, depressed women do not seek early prenatal care and are more likely to adopt other unsafe behaviors, such as inadequate diet and use of tobacco, alcohol, and other harmful substances. Further, women with untreated major depressive disorder can be at risk of self-harm or suicide.3 High rates of relapse were reported by women with depression who discontinued antidepressant therapy at the time of conception, compared with women who continued therapy throughout the pregnancy, in a study conducted by Cohen et al.4 There is an unwillingness among physicians and patients to use antidepressant drugs during the gestational period, because there are conflicting results about the use of such drugs, and the risk of major congenital malformations.5–8 The Canadian Paediatric Society recommends that satisfactory treatment of depression in pregnancy is important for the well-being of both the mother and infant, and that individual risk-benefit assessment must be made when a selective serotonin reuptake inhibitor needs to be prescribed during pregnancy.9\n\nNowadays, the selective serotonin reuptake inhibitor, escitalopram, is considered to be one of the most effective and well tolerated agents for the treatment of moderate and severe major depressive disorder,10 as well as for the treatment of anxiety disorders. Overall, the data available on its use during pregnancy and breastfeeding suggest a good safety profile.5 The aim of this paper is to report the maternal and neonatal outcomes of seven pregnant women treated with escitalopram during their pregnancy.\n\nMaterials and methods\nCases of women who were treated during pregnancy with escitalopram were drawn from a recently implemented database (www.degradatabase.it, September 2009). The DEGRA Database now includes 110 pregnant women who have been followed during their pregnancy at the Clinic of Affective Disorders in Pregnancy and Postpartum (DEGRA Center), Academic Psychiatric Unit, United Hospitals of Ancona, Italy. The psychiatric diagnosis of patients at their first visit was made using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual - Fourth Edition) Axis I Disorders,11 while severity was assessed using the Hamilton Rating Scale for Depression (HAM-D-17 items) and Hamilton Rating Scale for Anxiety (HAM-A-14 items). All patients were fully informed about the benefits, risks, and potential adverse effects of treatment with the drug during pregnancy and breastfeeding, as well as on the risks of untreated depression/anxiety disorder in pregnancy, by a senior psychiatrist (CB) before initiating treatment. Pregnant women were also asked to sign a consent form approved by the ethics committee.\n\nOnly pregnant women treated with escitalopram and followed up by our team throughout pregnancy and, in some cases, also during postpartum, were included in this study. Clinical and sociodemographic characteristics as well as maternal and neonatal outcomes were recorded during the study period. Neonatal outcomes were assessed in terms of mean birth weight, routine pediatric examination, Apgar scores, and examination for major congenital malformations or other minor anomalies.\n\nResults\nWe report seven cases of women treated with escitalopram during their pregnancy drawn from the DEGRA Database. Clinical and sociodemographic characteristics and neonatal outcomes of these seven cases are summarized in Table 1. Mean age (± standard deviation) at the time of presentation was 34.14 ± 3.76 (range 29–38) years. All women were of Caucasian ancestry, living with their partners, and currently working. For four women, this was their first pregnancy; three women had previously given birth to healthy babies after full-term pregnancies. Two patients were diagnosed with panic disorder, one with generalized anxiety disorder, and four with major depressive disorder (one of these also had panic disorder). Four patients were moderate smokers (5–10 cigarettes/day).\n\nSix women were exposed to escitalopram (10–20 mg/day) at conception; of these, two received escitalopram throughout their pregnancy, one discontinued treatment at week 8 and restarted at week 24 (up to delivery) due to a new severe episode of anxiety, and one was switched to paroxetine because of lack of efficacy of escitalopram at week 16. Two women decided to discontinue treatment at week 8 and 13, respectively. Only one patient was treated with escitalopram from week 21 to delivery. All cases but one showed a good clinical response to escitalopram.\n\nFour patients were also taking low doses of alprazolam, lorazepam, and clonazepam at bedtime. One patient, affected by thyroid disease, was exposed throughout pregnancy to L-thyroxine.\n\nAll pregnancies were full-term. The mean birth weight of the newborns was 2,870 ± 269.01 g (range 2,400–3,100 g), which is considered to be in the normal range (2,500–4,500 g); only one infant showed a low birth weight of 2,400 g. All newborns had normal Apgar scores at 1 and 5 minutes. We did not detect any major congenital malformations or other minor anomalies in the newborns.\n\nOne newborn also exposed to paroxetine (20–40 mg/day) and a benzodiazepine during late pregnancy developed a withdrawal reaction characterized by hypoglycemia (controlled with dextrose administration), lethargy, hypotonia, decreased primitive reflexes, and poor responsiveness to noxious stimuli. Symptoms improved within 48 hours and the newborn did not require any other medical intervention.\n\nDuring the postpartum period, all women and newborns were followed up for 6 months. Only two patients decided to continue drug treatment with escitalopram (10 mg/day) until 1 and 5 months after delivery, respectively, in order to prevent postpartum depression. All infants exposed to escitalopram showed no health problems during the follow-up period.\n\nDiscussion\nThe safety profile of escitalopram during the gestational period is an important topic for the health care community because the prescription of such drugs during pregnancy and in women of childbearing age affected by psychiatric illnesses is still up for debate. There is still some uncertainty about the relative risk concerning the use of escitalopram in pregnancy, as data on its safety are available only after the drug has been prescribed for many years. On the other hand, it is well documented that untreated maternal major depressive disorder and/or anxiety disorders, as well as other severe psychiatric illnesses, can have disruptive consequences on the outcome of pregnancy and on the safety of the newborn.3,4,9 In our case series, no major malformations were detected after exposure to escitalopram during early pregnancy. This is consistent with the available literature suggesting that escitalopram is not associated with an increased risk of major or minor abnormalities.5,7,12 We reported only one underweight newborn, a finding which is consistent with other evidence showing an increased risk of low birth weight of newborns exposed in utero to escitalopram.7 We also observed a case of withdrawal syndrome, even though the event occurred in a newborn whose exposure to escitalopram was stopped at 16 weeks but who was also exposed to paroxetine and clonazepam later during the pregnancy. Therefore, it is unlikely that escitalopram was responsible for this adverse effect, as this drug is not frequently associated with withdrawal reactions at therapeutic doses.13\n\nThis case series demonstrates the need for antidepressant therapy during pregnancy and provides valuable information on the use of escitalopram in pregnancy in a real-life clinical setting, with a range of depression-related diagnoses and exposure to escitalopram, concomitant use of other drugs, and in the presence of other risk factors. However, results from this case series should be interpreted with caution due to the low number of cases reported and the lack of controls. Due to these limitations, the causation, association, strength of association, and effect of confounders on the findings, eg, depression, maternal smoking, and socioeconomic status, are uncertain.\n\nOur findings are in agreement with evidence from large population-base studies reported in the literature, and provide data to support the safety of escitalopram in pregnancy in terms of no increased risk of major malformations.6,7,12 However, randomized controlled studies with a larger sample size are required in order to establish the safety profile of escitalopram in pregnancy and in breastfeeding women.\n\nA range of depression rating scales are available for assessment of symptom severity. We used the HAM-D-17 and HAM-A-14 scales to assess symptoms of depression and anxiety during the follow-up period. However, although beyond the scope of this study, other scales, such as the Montgomery-Åsberg Depression Rating Scale, may better differentiate biological and somatic symptoms of depression from symptoms commonly experienced during pregnancy.\n\nConclusion\nThe data from this small preliminary case series, together with the existing evidence, suggest that escitalopram does not appear to be associated with a higher risk of adverse maternal and neonatal outcomes when used by women during the gestational period, despite the fact that perinatal complications with other selective serotonin reuptake inhibitors have been reported in the literature. Given the paucity of data on the safety of escitalopram in pregnancy and the risk involved with nontreatment of major depressive disorder during pregnancy, any additional data are welcomed. However, considering the low number of cases and lack of controls in this series, it is prudent not to draw definitive conclusions on its safety during pregnancy and breastfeeding. These preliminary data are from a recently implemented database; therefore, future findings with larger patient numbers will add to the literature on the treatment of depression during pregnancy and the safety of escitalopram in the newborn.\n\nAuthor contributions\n\nCB, the senior psychiatrist responsible for treatment of patients afferent to the Clinic of Affective Disorders in Pregnancy and Postpartum, designed and planned the research. FB and LO performed the literature search and database analysis. All authors participated in drafting the manuscript and approving the final version for submission. The authors thank David Bellantuono for developing the online DEGRA Database used in this study.\n\nDisclosure\n\nEditorial assistance was provided by Raelene Simpson on behalf of inScience Communications, Springer Healthcare. This assistance was supported by Lundbeck. Otherwise, there are no potential conflicts of interest to disclose and no commercial support or funding was received for the study.\n\nTable 1 Maternal sociodemographic characteristics, drugs prescribed, and neonatal outcomes\n\nCase\tAge and demographic characteristics of women\tPrevious pregnancy\tDiagnosis\tHabits\tPsychotropic drug dosage in mg/day (weeks of exposure)\n\tDelivery\tBirth weight (g)\tApgar score (1/5 minutes)\tNeonatal outcomes\t\nAD\tBDZ\t\n1\t38, Caucasian, with partner, office worker\tOne miscarriage One healthy full-term pregnancy\tPD\tModerate alcohol use Smoker\tESC 10 (0–40)\tALP 0.25 (0–3)\tFull-term Natural\tLow (2,400)\t9/10\tHealthy\t\n2\t31, Caucasian, with partner, craftsman\tOne healthy full-term pregnancy\tComorbid PD and MDD\tModerate alcohol use Nonsmoker\tESC 10–20 (0–39)\tNone\tFull-term Cesarean\tNormal (3,100)\t9/10\tHealthy\t\n3\t29, caucasian, with partner, craftsman\tNonparous\tMDD\tNo alcohol use Nonsmoker\tESC 10 (0–13)\tNone\tFull-term Natural\tNormal (2,900)\t9/10\tHealthy\t\n4\t31, caucasian, with partner, craftsman\tNonparous\tMDD\tModerate alcohol use Nonsmoker\tESC 10–20 (21–38)\tNone\tFull-term Natural\tNormal (3,030)\t9/10\tHealthy\t\n5\t37, caucasian, with partner, office worker\tNonparous\tGAD\tNo alcohol use Smoker\tESC 20 (0–8 and 24–40)\tALP 1.25 (0–8 and 24–40)\tPost-term Natural\tNormal (3,100)\t9/10\tHealthy\t\n6\t38, caucasian, with partner, office worker\tTwo healthy full-term pregnancies\tPD\tNo alcohol use Smoker\tESC 10 (0–8)\tALP 1.25 (29–38)\tFull-term Natural\tNormal (2,600)\t10/10\tHealthy\t\n7\t35, caucasian, with partner, housewife\tNonparous\tMDD\tOccasional alcohol abuse Smoker\tESC 10 (0–16) PAR 20–40 (16–38)\tCLO 0.5 (0–11) LOR 1 (12–38)\tFull-term Natural\tNormal (2,960)\t8/10\tWithdrawal symptoms\t\nAbbreviations: PD, panic disorder; MDD, major depressive disorder; GAD, generalized anxiety disorder; AD, antidepressant; BDZ, benzodiazepine; ESC, escitalopram; ALP, alprazolam; PAR, paroxetine; CLO, clonazepam; LOR, lorazepam.\n==== Refs\nReferences\n1 Birndorf CA Madden A Portera L Leon AC Psychiatric symptoms, functional impairment, and receptivity toward mental health treatment among obstetrical patients Int J Psychiatry Med 2001 31 4 355 365 11949734 \n2 Grant BF Goldstein RB Chou SP Sociodemographic and psychopathologic predictors of first incidence of DSM-IV substance use, mood and anxiety disorders: results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions Mol Psychiatry 2009 14 11 1051 1066 18427559 \n3 Yonkers KA Wisner KL Stewart DE The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists Gen Hosp Psychiatry 2009 31 5 403 413 19703633 \n4 Cohen LS Altshuler LL Harlow BL Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment JAMA 2006 295 5 499 507 16449615 \n5 Bellantuono C Bozzi F Orsolini L Catena-Dell’Osso M The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review Hum Psychopharmacol 2012 27 6 534 539 23044635 \n6 Einarson A Choi J Einarson TR Koren G Incidence of major malformations in infants following antidepressant exposure in pregnancy: results of a large prospective cohort study Can J Psychiatry 2009 54 4 242 246 19321030 \n7 Klieger-Grossmann C Weitzner B Panchaud A Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study J Clin Pharmacol 2012 52 5 766 770 22075232 \n8 Diav-Citrin O Ornoy A Selective serotonin reuptake inhibitors in human pregnancy: to treat or not to treat? Obstet Gynecol Int 2012 2012 698947 22190957 \n9 Jefferies AL Canadian Paediatric Society, and Fetus and Newborn Committee Selective serotonin reuptake inhibitors in pregnancy and infant outcomes Paediatric Child Health 2011 16 9 562 563 \n10 Cipriani A Furukawa TA Salanti G Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis Lancet 2009 373 9665 746 758 19185342 \n11 First MB Spitzer RL Gibbon M Williams JBW Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-1-CV) New York, NY Biometrics Research Department, New York State Psychiatric Institute, Department of Psychiatry, Columbia University 1995 \n12 Kallen BA Otterblad OP Maternal use of selective serotonin re-uptake inhibitors in early pregnancy and infact congenital malformations Birth Defects Res A Clin Mol Teratol 2007 79 4 301 308 17216624 \n13 Tixier H Feyeux C Girod S Acute voluntary intoxication with selective serotonin reuptake inhibitors during the third trimester of pregnancy: therapeutic management of mother and fetus Am J Obstet Gynecol 2008 199 5 e9 e12 18984074\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6328", "issue": "9()", "journal": "Neuropsychiatric disease and treatment", "keywords": "breastfeeding; escitalopram; major malformations; perinatal complications; pregnancy", "medline_ta": "Neuropsychiatr Dis Treat", "mesh_terms": null, "nlm_unique_id": "101240304", "other_id": null, "pages": "1333-7", "pmc": null, "pmid": "24043940", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": "17216624;18984074;22190957;18427559;23115498;19703633;16449615;23044635;19321030;22075232;11949734;19185342", "title": "Safety of escitalopram in pregnancy: a case series.", "title_normalized": "safety of escitalopram in pregnancy a case series" }

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SAFETY OF ESCITALOPRAM IN PREGNANCY: A CASE SERIES. 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SAFETY OF ESCITALOPRAM IN PREGNANCY: A CASE SERIES. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2013 SEP 07;9:1333-1337.", "literaturereference_normalized": "safety of escitalopram in pregnancy a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20141007", "receivedate": "20141007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10501502, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20150528" }, { "companynumb": "IT-LUPIN PHARMACEUTICALS INC.-2014-01389", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "078169", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ALPRAZOLAM" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PANIC DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ALPRAZOLAM." } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": "2.4", "reaction": [ { "reactionmeddrapt": "Low birth weight baby", "reactionmeddraversionpt": "17.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ORSOLINI L, BOZZI F, BELLANTUONO C. SAFETY OF ESCITALOPRAM IN PREGNANCY: A CASE SERIES. NEUROPSYCHIATRIC DISEASE AND TREATMENT. 2013 SEP 07;9:1333-1337.", "literaturereference_normalized": "safety of escitalopram in pregnancy a case series", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20140731", "receivedate": "20140731", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 10353830, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "To illustrate that patients with diabetic retinopathy who are treated exclusively with anti-vascular endothelial growth factor (VEGF) therapy and have an interruption in treatment may experience marked progression of disease with potentially devastating visual consequences.\n\n\n\nRetrospective, multicenter, case series.\n\n\n\nRetrospective review of patients treated exclusively with anti-VEGF therapy for proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy (NPDR), with or without diabetic macular edema (DME), and temporarily lost to follow-up. Baseline disease characteristics, cause and duration of the treatment interruption, and resulting disease progression, complications, and outcomes were assessed.\n\n\n\nThirteen eyes of 12 patients with type 2 diabetes were identified. The mean age was 57 ± 10 years, and 50% were women. Anti-VEGF therapy was indicated for PDR with DME in 7 (54%) eyes, PDR without DME in 3 (23%) eyes, and moderate to severe NPDR with DME in 3 (23%) eyes. Eight eyes had visual acuity (VA) of 20/80 or better before treatment interruption. The median duration of treatment hiatus was 12 months. Reasons for treatment interruption included intercurrent illness (31%), noncompliance (31%), and financial issues (15%). Complications upon follow-up included vitreous hemorrhage (9 eyes), neovascular glaucoma (5 eyes), and traction retinal detachment (4 eyes). Despite treatment of these complications, 77% of eyes lost ≥3 lines of VA, with 46% of eyes having a final VA of hand motion or worse.\n\n\n\nDiabetic patients are subject to significant lapses in follow-up because of illness, financial hardship, or noncompliance. In patients with diabetic retinopathy, especially PDR, who are managed with anti-VEGF therapy alone, unintentional treatment interruptions can result in irreversible blindness.", "affiliations": "Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.;Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: [email protected].;Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.", "authors": "Wubben|Thomas J|TJ|;Johnson|Mark W|MW|;|||", "chemical_list": "D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab", "country": "United States", "delete": false, "doi": "10.1016/j.ajo.2019.03.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9394", "issue": "204()", "journal": "American journal of ophthalmology", "keywords": null, "medline_ta": "Am J Ophthalmol", "mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D003930:Diabetic Retinopathy; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D012160:Retina; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity", "nlm_unique_id": "0370500", "other_id": null, "pages": "13-18", "pmc": null, "pmid": "30878488", "pubdate": "2019-08", "publication_types": "D016428:Journal Article; D016448:Multicenter Study", "references": null, "title": "Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Retinopathy: Consequences of Inadvertent Treatment Interruptions.", "title_normalized": "anti vascular endothelial growth factor therapy for diabetic retinopathy consequences of inadvertent treatment interruptions" }

[ { "companynumb": "US-ROCHE-2414348", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFLIBERCEPT" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC RETINOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AFLIBERCEPT" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RANIBIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125156", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC RETINOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RANIBIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125085", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "DIABETIC RETINOPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Glaucoma", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tractional retinal detachment", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vitreous haemorrhage", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WUBBEN T, JOHNSON M, SOHN E, PEAIRS J, KAY C, KIM S ET AL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR DIABETIC RETINOPATHY: CONSEQUENCES OF INADVERTENT TREATMENT INTERRUPTIONS.. AMERICAN JOURNAL OF OPHTHALMOLOGY. 2019?204:13-8.", "literaturereference_normalized": "anti vascular endothelial growth factor therapy for diabetic retinopathy consequences of inadvertent treatment interruptions", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191007", "receivedate": "20191007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16889586, "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": "A 67-year-old gentleman developed persistent Staphylococcus epidermidis bacteraemia following transjugular intrahepatic portal shunting. 'Endotipsitis' was diagnosed. Conventional therapy with a vancomycin infusion, amikacin and rifampicin failed after 17 days. He was cured with a 6-week course of high-dose (8 mg/kg) daptomycin monotherapy.", "affiliations": "Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Trust, Oxford, UK. [email protected]", "authors": "Colston|Julia Marie|JM|;Scarborough|Matthew|M|;Collier|Jane|J|;Bowler|Ian C J W|IC|", "chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D000583:Amikacin; D017576:Daptomycin; D012293:Rifampin", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2013()", "journal": "BMJ case reports", "keywords": null, "medline_ta": "BMJ Case Rep", "mesh_terms": "D000368:Aged; D000583:Amikacin; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002405:Catheterization, Central Venous; D057785:Catheters; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D008297:Male; D012293:Rifampin; D013203:Staphylococcal Infections; D013212:Staphylococcus epidermidis; D017211:Treatment Failure; D014640:Vancomycin", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "23595199", "pubdate": "2013-04-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22100575;16353112;22160888;21731907;21923436;22908167;19929905;16914701;12567297;22985884;15183855;18591272;22931050", "title": "High-dose daptomycin monotherapy cures Staphylococcus epidermidis 'endotipsitis' after failure of conventional therapy.", "title_normalized": "high dose daptomycin monotherapy cures staphylococcus epidermidis endotipsitis after failure of conventional therapy" }

[ { "companynumb": "GB-MYLANLABS-2015M1010598", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "065421", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMIKACIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "STAPHYLOCOCCAL INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMIKACIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "050", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pathogen resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "COLSTON JM, SCARBOROUGH M, COLLIER J, BOWLER IC. HIGH-DOSE DAPTOMYCIN MONOTHERAPY CURES STAPHYLOCOCCUS EPIDERMIDIS ^ENDOTIPSITIS^ AFTER FAILURE OF CONVENTIONAL THERAPY. BMJ-CASE-REP 2013; :.", "literaturereference_normalized": "high dose daptomycin monotherapy cures staphylococcus epidermidis endotipsitis after failure of conventional therapy", "qualification": "1", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20150401", "receivedate": "20150401", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10975996, "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": "Wilkie's syndrome or superior mesenteric artery syndrome is an unusual cause of proximal intestinal obstruction, primarily attributed to recent weight loss. We report the case of a 19-year-old woman comes to our clinic and reports weight loss, abdominal pain, nausea, and vomiting. Laboratory tests revealed anemia, hypoalbuminemia, hypomagnesemia, and a suppressed thyroid stimulating hormone secondary to levothyroxine. A barium swallow test showed gastric dilatation, delayed gastric emptying and an axial computed tomography revealed an aortomesenteric angle of 11.7°. Conservative management with total parenteral and enteral nutrition was initiated, being the first-line treatment. In refractory cases surgery is a safe and effective option.", "affiliations": "Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México; Departamento de Bienestar y Desarrollo Sustentable, Centro Universitario del Norte, Universidad de Guadalajara. Colotlán, Jalisco, México.;Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México.;Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México.;Departamento de Nutriología Clínica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Ciudad de México, México.", "authors": "Cervantes Pérez|Enrique|E|;Martínez-Soto Holguín|Martha C|MC|;Diaz Juárez|Juan Pedro|JP|;Reyes Ramírez|Ana Luz Del C|ALDC|", "chemical_list": null, "country": "Peru", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1022-5129", "issue": "40(3)", "journal": "Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru", "keywords": null, "medline_ta": "Rev Gastroenterol Peru", "mesh_terms": "D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D006980:Hyperthyroidism; D013478:Superior Mesenteric Artery Syndrome; D055815:Young Adult", "nlm_unique_id": "9108294", "other_id": null, "pages": "274-277", "pmc": null, "pmid": "33181816", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Wilkie's syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism: a case report and literature review.", "title_normalized": "wilkie s syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism a case report and literature review" }

[ { "companynumb": "MX-LUPIN PHARMACEUTICALS INC.-2021-26755", "fulfillexpeditecriteria": "1", "occurcountry": "MX", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209713", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "Autoimmune hypothyroidism", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEVOTHYROXINE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "209713", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "25 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "25", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOTHYROXINE" } ], "patientagegroup": null, "patientonsetage": "19", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hyperthyroidism", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Superior mesenteric artery syndrome", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Perez EC, Martinez-Soto Holguin MC, Juarez JPD, Del C Reyes Ramirez AL. Wilkie^s syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism: A case report and literature review. Revista de Gastroenterolog?i del Peru. 2020;40 (3):274-277", "literaturereference_normalized": "wilkie s syndrome caused by exogenous hyperthyroidism in a patient with primary autoimmune hypothyroidism a case report and literature review", "qualification": "3", "reportercountry": "MX" }, "primarysourcecountry": "MX", "receiptdate": "20220324", "receivedate": "20220111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20323863, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" } ]

{ "abstract": "Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy.", "affiliations": "Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan.;Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Japan.;Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.;Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan.;Department of Nephrology, Tokyo Medical and Dental University, Japan.", "authors": "Suzuki|Soichiro|S|;Naito|Shotaro|S|;Numasawa|Yoshiyuki|Y|;Asada|Mizuho|M|;Shoji|Norikazu|N|;Zeniya|Moko|M|;Takahashi|Daiei|D|;Sato|Hidehiko|H|;Iimori|Soichiro|S|;Nomura|Naohiro|N|;Sohara|Eisei|E|;Okado|Tomokazu|T|;Ishiwata|Yasuyoshi|Y|;Nagata|Masashi|M|;Rai|Tatemitsu|T|;Yokota|Takanori|T|;Uchida|Shinichi|S|", "chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.1785-18", "fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3079933910.2169/internalmedicine.1785-18Case ReportEncephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient Suzuki Soichiro 1Naito Shotaro 1Numasawa Yoshiyuki 2Asada Mizuho 3Shoji Norikazu 1Zeniya Moko 1Takahashi Daiei 1Sato Hidehiko 1Iimori Soichiro 1Nomura Naohiro 1Sohara Eisei 1Okado Tomokazu 1Ishiwata Yasuyoshi 3Nagata Masashi 3Rai Tatemitsu 1Yokota Takanori 2Uchida Shinichi 1\n1 Department of Nephrology, Tokyo Medical and Dental University, Japan\n2 Department of Neurology and Neurological Science, Tokyo Medical and Dental University, Japan\n3 Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, JapanCorrespondence to Dr.　Shotaro Naito, [email protected]\n\n25 2 2019 15 6 2019 58 12 1775 1779 4 7 2018 4 12 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal 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/).Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy. \n\nceftriaxoneend-stage kidney diseaseencephalopathytriphasic waves\n==== Body\nIntroduction\nEncephalopathy is a rare side effect of cephalosporin treatment. Although encephalopathy caused by ceftriaxone, a third-generation cephalosporin, is particularly rare, several studies have reported this complication in patients with end-stage kidney disease (ESKD) (1, 2). Renal insufficiency is considered to be a predisposing factor for ceftriaxone neurotoxicity (1, 2); however, to date, no studies have evaluated the plasma and cerebral spinal fluid (CSF) concentrations of ceftriaxone in relation to encephalopathy. We herein present a case of encephalopathy in a hemodialysis patient who received intravenous ceftriaxone for Helicobacter cinaedi bacteremia. Our analysis revealed that the plasma and CSF concentrations of ceftriaxone were higher than the optimal range.\n\nCase Report\nAn 86-year-old woman on maintenance hemodialysis for ESKD due to benign nephrosclerosis presented to the emergency department with complaints of vomiting, diarrhea, and mild alteration of consciousness. Her medical history included rheumatoid arthritis, hypothyroidism, and hypertension. Her medications included prednisolone (5 mg), levothyroxine, rabeprazole, mosapride, butyric acid bacteria, and amezinium metilsulfate. A physical examination revealed soft abdomen; however, the patient complained of pain in her right lower abdomen. Although laboratory data showed leukocytosis and an elevated C-reactive protein level, the patient was afebrile and hemodynamically stable when she presented to the emergency department. She was sent home without any medication. One day later, she developed high fever with persistent abdominal pain and was admitted to our hospital. Her altered consciousness had improved at the time of admission. Intravenous ceftriaxone (1 g daily) was administered as an empirical treatment for bacterial enteritis. On the third day of admission, the presence of gram-negative bacteria was confirmed by blood culture, and the ceftriaxone dosage was increased to 2 g daily. Eventually, Helicobacter cinaedi was identified as the causative agent by blood culture.\n\nOn the 13th day of ceftriaxone treatment, the patient showed an altered mental state and a decreased level of consciousness as well as myoclonic jerks involving the right shoulder and arm. A neurological examination revealed roving eye movement and preserved light reflex. Brain magnetic resonance imaging did not reveal acute stroke or other focal findings that would account for her symptoms. No obvious abnormalities in the liver function or serum electrolyte levels were observed (Table). Hypoglycemia was not detected by capillary glucose monitoring. A CSF analysis revealed no elevated cell counts, and CSF cultures were negative. Electroencephalography (EEG) was performed, which showed generalized triphasic waves (TWs), predominantly in the frontal area (Fig. 1). Because the patient's symptoms were suspected to have been caused by ceftriaxone-induced encephalopathy, ceftriaxone was discontinued on the day after the onset of neurological symptoms. Consequently, a progressive improvement in the patient's neurological state was noted, and her consciousness completely recovered at four days after the discontinuation of ceftriaxone. Accordingly, she was diagnosed with ceftriaxone-induced encephalopathy. EEG performed seven days after the discontinuation of ceftriaxone revealed normal wave patterns and the absence of TWs.\n\nTable. Laboratory Data at the Onset of Neurological Symptoms.\n\nAlb\t2.6\tg/dL\tTSH\t5.03\tμIU/mL\t\nBUN\t26\tmg/dL\tFT3\t1.14\tpg/mL\t\nCr\t3.52\tmg/dL\tFT4\t1.25\tng/dL\t\nNa\t145\tmEq/L\tTPO-Ab\t9\tIU/mL\t\nK\t4.6\tmEq/L\tVit B1\t54\tng/mL\t\nCl\t106\t/mEq/L\tVit B12\t193\tpg/mL\t\nCa\t8.4\tmg/dL\t\t\t\t\nMg\t2.0\tmg/dL\tWBC\t10,700\t/μL\t\nGlucose\t84\tmg/dL\tHb\t11.0\tg/dL\t\nCRP\t0.64\tmg/dL\tPlt\t19.0\t/μL\t\nNH3\t12\tμmol/L\t\t\t\t\nT-Bil\t0.2\tmg/dL\tCerebrospinal fluid\t\t\t\nγ-GTP\t19\tU/L\tCell count\t1\tcell/μL\t\nAST\t15\tU/L\tGlucose\t48\tmg/dL\t\nALT\t13\tU/L\tProtein\t64\tmg/dL\t\nAlb: Albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, Ca: calcium, Cl: chloride, Cr: creatinine, CRP: C-reactive protein, FT3: free triiodothyronine, FT4: Free Thyroxin, γ-GTP: gamma-glutamyltransferase, K: potassium, LDH: lactate dehydrogenase, Mg: magnesium, NH3: ammonia, Plt: platelet, RBC: red blood cell, T-Bil: total bilirubin, TPO-Ab: thyroid peroxidase antibody, TSH: thyroid-stimulating hormone, Vit B1: vitamin B1, Vit B12: vitamin B12\n\nFigure 1. Electroencephalogram shows periodic generalized triphasic waves predominantly in the frontal area. EMG: electromyogram, EOG: electrooculogram, ECG: electrocardiogram\n\nThe differential diagnoses included other potential causes of disturbed consciousness (e.g., electrolyte disorders, metabolic alterations, cerebral hypoxia, infection, stroke, and medication use). However, no other factors that could possibly explain her neurological symptoms were identified, and hemodialysis did not improve her mental state. Retrospective measurement of plasma and CSF ceftriaxone concentrations was performed by high-performance liquid chromatography using specimens collected at the onset of her consciousness disturbance (Fig. 2). The plasma and CSF concentrations of ceftriaxone were both found to be high (>100 μg/mL and 10.2 μg/mL, respectively), indicating that ceftriaxone neurotoxicity was causally related to the adverse events in this case.\n\nFigure 2. The time course of the ceftriaxone concentration and administered dose. The concentrations were measured approximately 20 h after an infusion of ceftriaxone (2 g). The CTRX concentration rapidly decreased after discontinuation. CTRX: ceftriaxone, HD: hemodialysis\n\nDiscussion\nEncephalopathy is known as an infrequent adverse effect of ceftriaxone (1-4). The exact mechanism that leads to ceftriaxone-induced encephalopathy as a side effect is not completely understood; however, it has been presumed to be caused by competitive antagonism of brain γ-aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system (5), and increased excitatory amino acids (6).\n\nThe elimination half-life of ceftriaxone, which ranges from 6 to 9 hours in patients with a normal renal function, is longer than that of any other third-generation cephalosporin. Its elimination route is via kidney and biliary excretion; the half-life of ceftriaxone in hemodialysis patients was found to double from 8 to 16 hours in a previous study (7). Furthermore, unlike most cephalosporins that are highly dialyzable, ceftriaxone is not dialyzed during hemodialysis (8, 9). With renal failure, the accumulated toxic organic acids compete with cephalosporins for active transportation from the CSF to the blood, which increases the concentration of cephalosporin in the CSF (10).\n\nIn the present case, the patient presented with several risk factors for drug-induced neurotoxicity, including old age, renal impairment, and high-dose treatment (11). To clarify the association between ceftriaxone and encephalopathy, we measured the plasma and CSF concentrations of ceftriaxone. Although cefepime, a commonly used cephalosporin, is the only antibiotic mentioned in more than ten reports on the relationship between serum cephalosporin concentrations and neurotoxicity (12), no reports on ceftriaxone-induced encephalopathy have reported the drug concentrations associated with the condition. According to a previous report, after ceftriaxone (2 g, every 24 hours), the plasma trough levels ranged from 13 to 15 μg/mL in adults with a normal renal function (13). In the present case, the ceftriaxone plasma concentration before hemodialysis (approximately 20 hours after infusion of 2 g ceftriaxone) was >100 μg/mL. This value is far higher than that reported in a previous study (13), suggesting that a high plasma concentration of ceftriaxone was maintained ceftriaxone during administration. As already mentioned, the elimination half-life of ceftriaxone is longer in hemodialysis patients, which may lead to sustained high ceftriaxone concentrations in the plasma.\n\nIn the present case, the CSF ceftriaxone concentration was also high. Generally, the protein-unbound, free fraction of agents can freely penetrate the blood-brain/blood-CSF barrier (14). Approximately 90-95% of ceftriaxone is protein-bound and thus it can rarely penetrate the blood-CSF barrier (14). Nau et al. reported that the CSF concentrations of ceftriaxone after an infusion of ceftriaxone (2 g) in patients with uninflamed meninges ranged from 0.18 to 1.04 μg/mL (15), whereas the CSF ceftriaxone level in the current patient was 10.2 μg/mL even at more than 24 hours after the discontinuation of ceftriaxone. Furthermore, the free fraction of ceftriaxone is higher in patients with an abnormal renal function (4, 16). In the present case, the high proportion of unbound plasma ceftriaxone - due to the low albumin level and renal insufficiency - presumably made the CSF ceftriaxone concentration higher, resulting in neurotoxicity. The high proportion of unbound plasma ceftriaxone resulted in a relatively high rate of removal by dialysis; approximately 40% of ceftriaxone was dialyzed during hemodialysis.\n\nNeurological manifestations of ceftriaxone-associated encephalopathy, such as myoclonus, asterixis, seizures, and consciousness alteration, have been reported in patients with an impaired renal function (3, 17). Previous studies reported that EEG findings such as slow waves and TWs might be associated with cephalosporin neurotoxicity. TWs are defined by their typical morphology, characterized by a predominant surface positive wave, preceded and followed by smaller surface negative deflections, conferring them a triphasic appearance (18). However, non-epileptic TWs with a sharply contoured morphology may resemble epileptic patterns encountered during nonconvulsive status epilepticus (NCSE), thus leading to the misinterpretation and over-interpretation of this pattern as ictal, if the electroencephalogram is considered alone (19). According to a previous study that described the electroencephalographic differences between TWs and NCSE, amplitude predominance of phase two was more common with TWs than with NCSE (40.8% vs. 0%); and the frequency of epileptiform discharge with TWs was lower than that with NCSE (1.8 Hz vs. 2.4 Hz) (20). An electroclinical response to benzodiazepines and the evaluation of consciousness impairment should be considered to distinguish between TWs and NCSE (19).\n\nNeurological symptoms and EEG findings emerge at 1-10 days after the initiation of the cephalosporin treatment and resolve several days after discontinuation (1-3, 21-23). Thus, EEG might be beneficial in the diagnosis and management of ceftriaxone neurotoxicity. The neurotoxicity induced by cephalosporins is reported to be reversible (1-3, 21-23). In the present case, the discontinuation of ceftriaxone resulted in marked improvements in the clinical symptoms without any sequelae.\n\nIn conclusion, ceftriaxone might cause encephalopathy with manifestations such as myoclonus, an altered mental state, a decreased level of consciousness, and changes in EEG findings. Hemodialysis patients are particularly vulnerable to ceftriaxone-induced encephalopathy. This first reported case of high in plasma and CSF concentrations of ceftriaxone in a patient who developed neurological symptoms following ceftriaxone treatment suggests a causal relationship between the administration of ceftriaxone and the onset of encephalopathy. Patients with renal impairment who develop such symptoms during ceftriaxone treatment should be evaluated for potential ceftriaxone-induced encephalopathy, and drug discontinuation should be considered as the treatment of choice.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nSafadi S , Mao M , Dillon JJ \nCeftriaxone-induced acute encephalopathy in a peritoneal dialysis patient . Case Rep Nephrol \n2014 : 108185 , 2014 .25544915 \n2. \nRoncon-Albuquerque R Jr, Pires I , Martins R , Real R , Sousa G , von Hafe P \nCeftriaxone-induced acute reversible encephalopathy in a patient treated for a urinary tract infection . Neth J Med \n67 : 72 -75 , 2009 .19299850 \n3. \nKim KB , Kim SM , Park W , Kim JS , Kwon SK , Kim HY \nCeftriaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review . J Korean Med Sci \n27 : 1120 -1123 , 2012 .22969263 \n4. \nSutter R , Ruegg S , Tschudin-Sutter S \nSeizures as adverse events of antibiotic drugs: a systematic review . Neurology \n85 : 1332 -1341 , 2015 .26400582 \n5. \nWallace KL \nAntibiotic-induced convulsions . Crit Care Clin \n13 : 741 -762 , 1997 .9330839 \n6. \nDe Sarro A , Ammendola D , Zappala M , Grasso S , De Sarro GB \nRelationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats . Antimicrob Agents Chemother \n39 : 232 -237 , 1995 .7695312 \n7. \nCohen D , Appel GB , Scully B , Neu HC \nPharmacokinetics of ceftriaxone in patients with renal failure and in those undergoing hemodialysis . Antimicrob Agents Chemother \n24 : 529 -532 , 1983 .6316845 \n8. \nPatel IH , Sugihara JG , Weinfeld RE , Wong EG , Siemsen AW , Berman SJ \nCeftriaxone pharmacokinetics in patients with various degrees of renal impairment . Antimicrob Agents Chemother \n25 : 438 -442 , 1984 .6329080 \n9. \nGrill MF , Maganti R \nCephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring . Ann Pharmacother \n42 : 1843 -1850 , 2008 .19033476 \n10. \nJoseph J , Vimala A \nCeftazidime-induced myoclonus and encephalopathy in hemodialysis patient . Indian J Nephrol \n25 : 61 -62 , 2015 .25684877 \n11. \nSchliamser SE , Cars O , Norrby SR \nNeurotoxicity of beta-lactam antibiotics: predisposing factors and pathogenesis . J Antimicrob Chemother \n27 : 405 -425 , 1991 .1856121 \n12. \nBhattacharyya S , Darby RR , Raibagkar P , Gonzalez Castro LN , Berkowitz AL \nAntibiotic-associated encephalopathy . Neurology \n86 : 963 -971 , 2016 .26888997 \n13. \nPollock AA , Tee PE , Patel IH , Spicehandler J , Simberkoff MS , Rahal JJ Jr \nPharmacokinetic characteristics of intravenous ceftriaxone in normal adults . Antimicrob Agents Chemother \n22 : 816 -823 , 1982 .6295268 \n14. \nNau R , Sorgel F , Eiffert H \nPenetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections . Clin Microbiol Rev \n4 : 858 -883 , 2010 .\n15. \nNau R , Prange HW , Muth P , et al \nPassage of cefotaxime and ceftriaxone into cerebrospinal fluid of patients with uninflamed meninges . Antimicrob Agents Chemother \n37 : 1518 -1524 , 1993 .8363385 \n16. \nJoynt GM , Lipman J , Gomersall CD , Young RJ , Wong EL , Gin T \nThe pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients . J Antimicrob Chemother \n47 : 421 -429 , 2001 .11266414 \n17. \nSato Y , Morita H , Wakasugi H , et al \nReversible choreoathetosis after the administration of ceftriaxone sodium in patients with end-stage renal disease . Am J Med Sci \n340 : 382 -384 , 2010 .20724905 \n18. \nAdriana Bermeo-Ovalle \nTriphasic waves: swinging the pendulum back in this diagnostic dilemma . Epilepsy Curr \n17 : 40 -42 , 2017 .28331470 \n19. \nBrigo F , Storti M \nTriphasic waves . Am J Electroneurodiagnostic Technol \n51 : 16 -25 , 2011 .21516927 \n20. \nBoulanger JM , Deacon C , Lécuyer D , Gosselin S , Reiher J \nTriphasic waves versus nonconvulsive status epilepticus: EEG distinction . Can J Neurol Sci \n33 : 175 -180 , 2006 .16736726 \n21. \nMartinez-Rodriguez JE , Barriga FJ , Santamaria J , et al \nNonconvulsive status epilepticus associated with cephalosporins in patients with renal failure . Am J Med \n111 : 115 -119 , 2001 .11498064 \n22. \nLam S , Gomolin IH \nCefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review . Pharmacotherapy \n26 : 1169 -1174 , 2006 .16863493 \n23. \nThabet F , Al Maghrabi M , Al Barraq A , Tabarki B \nCefepime-induced nonconvulsive status epilepticus: case report and review . Neurocrit Care \n10 : 347 -351 , 2009 .19034700\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "0918-2918", "issue": "58(12)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": "ceftriaxone; encephalopathy; end-stage kidney disease; triphasic waves", "medline_ta": "Intern Med", "mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001927:Brain Diseases; D002443:Ceftriaxone; D004569:Electroencephalography; D005260:Female; D016481:Helicobacter Infections; D006801:Humans; D006435:Renal Dialysis", "nlm_unique_id": "9204241", "other_id": null, "pages": "1775-1779", "pmc": null, "pmid": "30799339", "pubdate": "2019-06-15", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11266414;11498064;16736726;16863493;1856121;19033476;19034700;19299850;20724905;20930076;21516927;22969263;25544915;25684877;26400582;26888997;28331470;6295268;6316845;6329080;7695312;8363385;9330839", "title": "Encephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient.", "title_normalized": "encephalopathy induced by high plasma and cerebrospinal fluid ceftriaxone concentrations in a hemodialysis patient" }

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"reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SUZUKI, S.. ENCEPHALOPATHY INDUCED BY HIGH PLASMA AND CEREBROSPINAL FLUID CEFTRIAXONE CONCENTRATIONS IN A HEMODIALYSIS PATIENT. INTERNAL MEDICINE. 2019?58 (12):1775-1779", "literaturereference_normalized": "encephalopathy induced by high plasma and cerebrospinal fluid ceftriaxone concentrations in a hemodialysis patient", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20190815", "receivedate": "20190305", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16035698, "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" }, { "companynumb": "JP-ATLANTIDE PHARMACEUTICALS AG-2022ATL000028", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065180", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 GRAM PER DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "Gastroenteritis bacterial", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065180", "drugbatchnumb": "UNK", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFTRIAXONE" } ], "patientagegroup": null, "patientonsetage": "86", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic encephalopathy", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Suzuki S, Naito S, Numasawa Y, Asada M, Shoji N, Zeniya M,etal. Encephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient. Intern Med. 2019;58:1775-1779", "literaturereference_normalized": "encephalopathy induced by high plasma and cerebrospinal fluid ceftriaxone concentrations in a hemodialysis patient", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20220509", "receivedate": "20220509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20800419, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]

{ "abstract": "Introduction Amplitude-integrated electroencephalography (aEEG) is one of the most widely used neuromonitoring tools in neonatology today. However, little is known about its clinical indications and potential benefits in pediatric intensive care patients. Based on limited experience, its impact on therapeutic decision-making in this patient population is unclear. Case Description We report the case of a 16-year-old boy who, after a pansinusitis, developed a severe meningoencephalitis and intracranial empyema with increased intracranial pressure that required drainage and decompressive craniectomy. He subsequently developed status epilepticus despite a combination of various anticonvulsants. Only after the initialization of an aEEG, we were able to adequately diagnose and continuously monitor his seizure activity and titrate the effect of the antiepileptic drugs. During his hospital stay, we were able to clearly monitor and guide our therapy by accurately identifying the termination of status epilepticus and the recurrence of seizures. Discussion With the help of aEEG, it was easy to identify the nonconvulsive status epilepticus (NCSE) and the ongoing seizure activity in this teenage patient. NCSE is a clinical problem with an effect on the outcome of the patient and is often underdiagnosed. AEEG enabled a rapid detection and management of seizure activity and thereby reduced the overall seizure burden, which was associated with better neurologic outcome.", "affiliations": "Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.;Department of Pediatric Cardiology and Pediatric Intensive Care, Campus Grosshadern of the Ludwig Maximilians University, Munich, Germany.", "authors": "Schettler|Karl F|KF|;Heineking|Beatrice|B|;Fernandez-Rodriguez|Silvia|S|;Pilger|Angelika|A|;Haas|Nikolaus Alexander|NA|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1055/s-0036-1587328", "fulltext": null, "fulltext_license": null, "issn_linking": "2146-4626", "issue": "6(2)", "journal": "Journal of pediatric intensive care", "keywords": "amplitude-integrated EEG; antiepileptic therapy; meningoencephalitis; neuromonitoring; nonconvulsive status epilepticus", "medline_ta": "J Pediatr Intensive Care", "mesh_terms": null, "nlm_unique_id": "101592756", "other_id": null, "pages": "136-141", "pmc": null, "pmid": "31073438", "pubdate": "2017-06", "publication_types": "D002363:Case Reports", "references": "11571331;14556030;16162436;17188917;17805245;19150756;19585276;20234318;22797054;23318514;23653183;23690296;23876221;24083894;24236076;24401298;24955189;25129228;25524842;26348553;26719828;26816961;26833985;26889778;26928665;26933532;5354856", "title": "Guiding Antiepileptic Therapy in a Pediatric Patient with Severe Meningoencephalitis and Decompressive Craniectomy with the Use of Amplitude-Integrated Electroencephalography.", "title_normalized": "guiding antiepileptic therapy in a pediatric patient with severe meningoencephalitis and decompressive craniectomy with the use of amplitude integrated electroencephalography" }

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null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CEFOTAXIME SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNKNOWN DOSE", "drugenddate": null, "drugenddateformat": null, "drugindication": "MENINGITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CEFOTAXIME" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": 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"reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SCHETTLER KF, HEINEKING B, FERNANDEZ-RODRIGUEZ S, PILGER A, HAAS NA. GUIDING ANTIEPILEPTIC THERAPY IN A PEDIATRIC PATIENT WITH SEVERE MENINGOENCEPHALITIS AND DECOMPRESSIVE CRANIECTOMY WITH THE USE OF AMPLITUDE-INTEGRATED ELECTROENCEPHALOGRAPHY. 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{ "abstract": "An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.", "affiliations": "Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, Oxfordshire, UK [email protected].;Department of Geratology, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.;Department of Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.;Department of Geratology, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK.", "authors": "Attwood|Jonathan E|JE|http://orcid.org/0000-0002-0452-4077;Naseer|Saniya|S|;Michael|Sophia|S|;Riley|Josie|J|", "chemical_list": "D001323:Autoantibodies; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D008775:Methylprednisolone", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-237398", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "14(1)", "journal": "BMJ case reports", "keywords": "epilepsy and seizures; geriatric medicine; immunology; memory disorders", "medline_ta": "BMJ Case Rep", "mesh_terms": "D061605:Administration, Intravenous; D000369:Aged, 80 and over; D001323:Autoantibodies; D060825:Cognitive Dysfunction; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins; D020363:Limbic Encephalitis; D008032:Limbic System; D008775:Methylprednisolone; D010951:Plasma Exchange; D049268:Positron-Emission Tomography; D012640:Seizures; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33431450", "pubdate": "2021-01-11", "publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media", "references": null, "title": "Clinical diagnosis of LGI1 antibody encephalitis in an 83-year-old woman.", "title_normalized": "clinical diagnosis of lgi1 antibody encephalitis in an 83 year old woman" }

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CLINICAL DIAGNOSIS OF LGI1 ANTIBODY ENCEPHALITIS IN AN 83?YEAR?OLD WOMAN. BMJ?CASE?REP 2021?14:NO. 1.", "literaturereference_normalized": "clinical diagnosis of lgi1 antibody encephalitis in an 83 year old woman", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20210312", "receivedate": "20210312", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19002253, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]

{ "abstract": "American trypanosomiasis, also named Chagas disease (CD), is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi. The disease affects millions of people worldwide, leading yearly to approximately 50,000 deaths. COVID-19, generated by SARS-CoV-2, can lead to lymphopenia and death. We hereby describe the first report of two patients with CD and COVID-19 coinfection, from hospitalization until patients' death.", "affiliations": "Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Technical Division of Medical Biology, Adolfo Lutz Institute, Immunology Center, São Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.;Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil.", "authors": "Alberca|Ricardo Wesley|RW|;Yendo|Tatiana Mina|TM|;Leuzzi Ramos|Yasmim Álefe|YÁ|;Fernandes|Iara Grigoletto|IG|;Oliveira|Luana de Mendonça|LM|;Teixeira|Franciane Mouradian Emidio|FME|;Beserra|Danielle Rosa|DR|;de Oliveira|Emily Araujo|EA|;Gozzi-Silva|Sarah Cristina|SC|;Andrade|Milena Mary de Souza|MMS|;Branco|Anna Cláudia Calvielli Castelo|ACCC|;Pietrobon|Anna Julia|AJ|;Pereira|Nátalli Zanete|NZ|;de Brito|Cyro Alves|CA|;Orfali|Raquel Leão|RL|;Aoki|Valéria|V|;Duarte|Alberto José da Silva|AJDS|;Benard|Gil|G|;Sato|Maria Notomi|MN|", "chemical_list": "D012367:RNA, Viral", "country": "United States", "delete": false, "doi": "10.4269/ajtmh.20-1185", "fulltext": "\n==== Front\nAm J Trop Med Hyg\nAm J Trop Med Hyg\ntpmd\ntropmed\nThe American Journal of Tropical Medicine and Hygiene\n0002-9637 1476-1645 The American Society of Tropical Medicine and Hygiene \n\n33025877\ntpmd201185\n10.4269/ajtmh.20-1185\nArticles\nCase Report: COVID-19 and Chagas Disease in Two Coinfected Patients\nAlberca Ricardo Wesley 1* Yendo Tatiana Mina 1 Leuzzi Ramos Yasmim Álefe 1 Fernandes Iara Grigoletto 1 Oliveira Luana de Mendonça 12 Teixeira Franciane Mouradian Emidio 12 Beserra Danielle Rosa 1 de Oliveira Emily Araujo 1 Gozzi-Silva Sarah Cristina 12 Andrade Milena Mary de Souza 1 Branco Anna Cláudia Calvielli Castelo 12 Pietrobon Anna Julia 12 Pereira Nátalli Zanete 1 de Brito Cyro Alves 3 Orfali Raquel Leão 1 Aoki Valéria 1 Duarte Alberto José da Silva 1 Benard Gil 1 Sato Maria Notomi 1 1 Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil;\n2 Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil;\n3 Technical Division of Medical Biology, Adolfo Lutz Institute, Immunology Center, São Paulo, Brazil\n* Address correspondence to Ricardo Wesley Alberca, Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Av. Dr. Enéas Carvalho de Aguiar, 470, São Paulo, 05403-000 Brazil. E-mail: [email protected]’ addresses: Ricardo Wesley Alberca, Tatiana M. Yendo, Yasmim Álefe Leuzzi Ramos, Iara Grigoletto Fernandes, Luana de Mendonça Oliveira, Franciane Mouradian Emidio Teixeira, Danielle Rosa Beserra, Emily Araujo, Sarah Cristina Gozzi-Silva, Milena Mary de Souza Andrade, Anna Cláudia Calvielli Castelo Branco, Anna Julia Pietrobon, Nátalli Zanete Pereira, Raquel Leao Orfali, Valeria Aoki, Alberto Jose da Silva Duarte, Gil Benard, and Maria Notomi Sato, Departamento de Dermatologia, Faculdade de Medicina FMUSP, Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Universidade de Sao Paulo, Sao Paulo, Brazil, E-mails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], and [email protected]. Cyro Alves de Brito, Technical Division of Medical Biology, Adolfo Lutz Institute, Immunology Center, São Paulo, Brazil, E-mail: [email protected].\n\n\n12 2020 \n06 10 2020 \n06 10 2020 \n103 6 2353 2356\n11 9 2020 29 9 2020 © The American Society of Tropical Medicine and Hygiene2020This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Abstract.\nAmerican trypanosomiasis, also named Chagas disease (CD), is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi. The disease affects millions of people worldwide, leading yearly to approximately 50,000 deaths. COVID-19, generated by SARS-CoV-2, can lead to lymphopenia and death. We hereby describe the first report of two patients with CD and COVID-19 coinfection, from hospitalization until patients’ death.\n==== Body\nINTRODUCTION\nChagas disease (CD) is a vector-borne disease transmitted mainly by the bloodsucking bug from subfamily Triatominae.1 Chagas disease is named after Carlos Chagas, a Brazilian researcher who described the life cycle of the parasite Trypanosoma cruzi. The disease was first described in Latin America,1 but currently it is a neglected health problem, affecting approximately 7 million people worldwide.2\n\nChagas disease presents two distinct clinical phases: an acute one, associated with a strong type 1 immune response,3 and a chronic phase, which may endure for the rest of the patients’ life.3 The chronic phase may evolve to different degrees of severity in 30% of the cases, leading to dilated cardiomyopathy, arrhythmia, cardioembolism, heart failure, and death.3,4 Systemic arterial hypertension (SAH) and dyslipidemia are also common features among elderly CD patients.5\n\nA Trypanosoma cruzi–infected person can also progress to an indeterminate form, in which the patient has no symptoms or signs of the disease, presenting no alteration in gastrointestinal and myocardial functions.6 Nevertheless, coinfections can lead to CD reactivation and influence the overall prognoses of the patient.7,8\n\nCOVID-19 is a disease caused by SARS-CoV-2 infection that leads to high rates of respiratory illness and death.9 Several risk factors have been investigated, such as obesity, type 2 diabetes mellitus, and SAH.10\n\nSARS-CoV-2 infection mainly affects the respiratory tract11 but recently has been associated with significant multiple organ dysfunction syndrome.12 One of the most common critical complications during COVID-19 is myocardial injury,13,14 especially in patients with a higher inflammatory profile.13\n\nAs the pandemic is still ongoing, it is impossible to precise the impact of SARS-CoV-2 infection in the overall population, but to the moment, COVID-19 has caused almost 1 million deaths worldwide. Although CD affects millions, to the moment, there is no report of CD and COVID-19 coinfection in the literature.\n\nWe analyzed two CD-infected patients (aged 69 and 74 years), with confirmed SARS-CoV-2 infection by nasopharyngeal detection of SARS-CoV-2 RNA, using reverse transcriptase–PCR and negative results for influenza and respiratory syncytial virus. The patients were hospitalized in a special ward for COVID-19 patients at the university hospital (Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo[HCFMUSP]) with approval for the usage of data from patients. We hereby describe laboratory data from day one until both patients passed away. The study was approved by the local Ethics Committee (HCFMUSP no. 30800520.7.0000.0068-2020) and was carried out in conformity with the 2013 revision of the Declaration of Helsinki.\n\nCASE PRESENTATIONS\nThe first patient was a woman, aged 74 years, who had COVID-19–associated symptoms on May 26, tested positive for SARS-CoV-2 on May 30, and hospitalized. She had a past diagnosis of CD, with chronic CD cardiomyopathy (Figure 1A) and a pacemaker since 2013 (Figure 1A) for a total atrioventricular block, and, on admission, atrial fibrillation with dilatation of the pulmonary artery trunk (43 mm). Additional past clinical history included a stroke in 2010 and a unilateral mastectomy of the left side due to breast cancer in 2011. The patient’s regular medications were hydralazine, atenolol, losartan, omeprazole, amiodarone, atorvastatin, and isosorbide. On admission, the patient presented dyspnea but not cough, fever, or myalgia. Chest radiography revealed pulmonary ground-glass opacities affecting 50% of the lungs (Figure 1B and C). The level of N-terminal pro–b-type natriuretic peptide (NT-proBNP) was 1,319 pg/mL (reference value of < 125 pg/mL), but D-dimer was below detection, but peaked in 1738 ng/mL in fibrinogen equivalent units (FEUs) on the 10th day at the hospital. Total bilirubin and fractions as well as total protein levels and fractions (albumin and globulin) were within reference levels. No alteration in the levels in serum alanine transaminase or aspartate transaminase was detected during hospitalization. As part of the COVID treatment protocol, she received ceftriaxone from June 1 to 6, methylprednisolone 40 mg on June 7, azithromycin from June 1 to 2, and warfarin on June 7.\n\nFigure 1. Chest X-ray and thoracic computerized tomography scan of patient #1. (A) X-ray from 2015 pre–COVID-19 hospitalization showing the marked cardiomegaly, (B) X-ray from June 2020, and (C) tomography from June 2020 during COVID-19 hospitalization showing COVID-19 ground-glass opacity.\n\nPatient #1 showed normal levels of red blood count, hemoglobin, and hematocrit, but a platelet count reduction since day 1 of hospitalization (Figure 2A–D). White blood counts were normal in the first week, with an increase in neutrophils and monocytes by the end of the second week of hospitalization (Figure 2E–J). The neutrophil-to-lymphocyte ratio remained at normal levels during hospitalization due to the reduced lymphocyte cell count, a common feature in COVID-19 (Figure 2J).15\n\nFigure 2. Daily clinical features of patients. Blood levels of (A) erythrocytes, (B) hemoglobin, (C) hematocrit, (D) platelets, (E) leukocytes, (F) neutrophils, (G) eosinophils, (H) lymphocytes, (I) monocytes, (J) neutrophil-to-lymphocyte ratio, (K) creatinine, (L) glucose, (M) C-reactive protein, (N) urea, (O) pO2, (P) pCO2, (Q) pH, (R) oxygen peripheral saturation, (S) prothrombin time, (T) activated partial thromboplastin time, (U) sodium, (V) potassium, and (X) magnesium. Gray box represents reference values; dot line represents the date the patients passed away.\n\nThere was also a sustained elevation of creatinine levels, C-reactive protein, and urea (Figure 2K, M, and N). On day 8, the patient developed blood glucose alterations, probably caused by SARS-CoV-2 infection, as previously proposed (Figure 2L).16\n\nOther findings included low pO2, but normal levels of pCO2 and pH, with a variable oxygen peripheral saturation (Figure 2O–R). High prothrombin time during COVID-19 was also verified (Figure 2Q). From day 10 onward, the patient presented altered sodium, potassium, and magnesium serum levels (Figure 2U–X). The patient’s clinical situation rapidly deteriorated, evolving into SARS. The patient was transferred to the ICU, and despite all efforts, the patient passed away on day 17 (June 17) because of refractory circulatory shock.\n\nThe second patient was a man, aged 69 years, weighing 62 kg, who had COVID-19–associated symptoms on May 7. He sought the hospital 2 weeks later, and tested positive on May 22 and hospitalized. He was a heavy smoker and has been followed at the HCFMUSP for indeterminate CD. Chest radiography revealed pulmonary ground-glass opacities in 50% of the parenchyma. On admission, the level of NT-proBNP was 458 pg/mL and of D-dimer was 88,868 ng/mL FEUs. Blood troponin T levels were within the normal range during admission (< 0.014 ng/mL), but increased to 0.193 ng/mL on the ninth day. Total bilirubin and fractions as well as total protein levels and fractions (albumin and globulin) were within reference levels. No alteration in the levels in serum alanine transaminase or aspartate transaminase was detected during hospitalization. During hospitalization, he received azithromycin and ceftriaxone from May 22 to 27, enoxaparin, methylprednisolone 30 mg on May 27, piperacillin/tazobactam from May 27 to 31, vancomycin from May 31 until death, and meropenem on May 31.\n\nPatient #2 was admitted already with respiratory distress and immediately transferred to the ICU. Laboratory findings showed normal levels of erythrocytes and hemoglobin, and high levels of platelet since day 1 (Figure 2A–D). High counts on leukocytes, especially on neutrophils, were seen since day 5, with the maintenance of low lymphocyte counts (Figure 2E–J). Creatinine and urea levels were stable, with an abrupt spike on day 10 (Figure 2K and N). Interestingly, C-reactive protein levels were constantly high, and pO2 levels were regularly low, with pCO2 and pH levels under normal levels (Figure 2M and O–Q), but oxygen saturation was regularly below reference values (Figure 2R). Prothrombin time and activated partial prothrombin time increased on day 13 (Figure 2S and T). Sodium and potassium serum levels were always normal during hospitalization time, but the magnesium levels increased rapidly in the last couple of days in the hospital (Figure 2U–X). On day 8, there was an increase in the glucose serum levels, probably related to the SARS-CoV-2 infection (Figure 2L), as previously proposed.16\n\nThe patient progressed with pulmonary thromboembolism and SARS, followed by hypotension and cardiac arrest. Despite all efforts, the patient passed away on day 13 (June 3).\n\nDISCUSSION\nWe hereby describe two patients with CD and SARS-CoV-2 coinfection. Both patients were hospitalized in a reference center for COVID-19 treatment in the metropolitan region of São Paulo, a city in the Southeast of Brazil. The southeast region comprises less than 5% of the CD cases in Brazil. We hypothesize that CD and COVID-19 coinfection may be an important noninvestigated cause of death in regions with a higher incidence of CD.17\n\nChagas disease can manifest as a severe, life-threatening opportunistic infection in patients with immune deficiencies such as HIV.18 COVID-19 may lead to lymphopenia, which could curb the anti–T. cruzi immune response, similar to what is seen in HIV patients.18 Elderly CD patients are also prone to develop SAH and dyslipidemia,5 therefore being at higher risk group for COVID-19.11,19\n\nSome patients with COVID-19 develop severe disease characterized by respiratory and systemic syndromes.20 Chronic underdiagnosed diseases, such as indeterminate form CD, and other coinfections,21–23 may alter the disease course and represent a significant risk factor for poor COVID-19 outcomes.\n\nNevertheless, advanced age in these two case reports could be an additional risk factor, reducing the immune response against CD and COVID-19.5,24 These may be due to SARS-CoV-2 cell entry receptor expression, angiotensin-converting enzyme-2, immunosenescence, or a larger number of medical comorbidities.25\n\nThis report highlights the first report of CD and COVID-19 coinfection. Patients presented a rapid disease progression, and despite all efforts of the medical team, both patients died. We believe that CD may be an important and underrated risk factor for developing severe COVID-19, especially those with chronic CD with cardiomyopathy that may be prone to have poor outcomes, especially in endemic areas with underreported CD infection and/or underreported SARS-CoV-2 infection.\n\nAcknowledgments:\nPublication charges for this article were waived because of the ongoing pandemic of COVID-19.\n==== Refs\nREFERENCES\n1. Lidani KCF Andrade FA Bavia L Damasceno FS Beltrame MH Messias-Reason IJ Sandri TL , 2019 \nChagas disease: from discovery to a worldwide health problem\n. Front Public Health \n7 : 166 .31312626 \n2. World Health Organization , 2020 \nChagas Disease (Also Known as American Trypanosomiasis). Chagas Disease Fact Sheets . Available at: https://www.who.int/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)%0Ahttps://www.who.int/en/news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis). Accessed August 30, 2020 .\n3. Boscardin SB Torrecilhas ACT Manarin R Revelli S Rey EG Tonelli RR Silber AM , 2010 \nChagas’ disease: an update on immune mechanisms and therapeutic strategies\n. J Cell Mol Med \n14 : 1373 –1384\n.20070438 \n4. MacHado FS \n2012 \nChagas heart disease: report on recent developments\n. Cardiol Rev \n20 : 53 –65\n.22293860 \n5. Alves RMDA Thomaz RP De Almeida EA Wanderley JDS Guariento ME , 2009 \nChagas’ disease and ageing: the coexistence of other chronic diseases with Chagas’ disease in elderly patients\n. Rev Soc Bras Med Trop \n42 : 622 –628\n.20209343 \n6. Issa VS , 2018 \nThe indeterminate form of chagas disease\n. 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Signal Transduct Target Ther \n5 : 33 .32296069 \n16. Rubino F \n2020 \nNew-onset diabetes in COVID-19\n. N Engl J Med \n383 : 789 –790\n.32530585 \n17. Santos EF \n2020 \nAcute Chagas disease in Brazil from 2001 to 2018: a nationwide spatiotemporal analysis\n. PLoS Negl Trop Dis \n14 : e0008445 .32745113 \n18. Vaidian AK Weiss LM Tanowitz HB , 2004 \nChagas’ disease and AIDS\n. Kinetoplastid Biol Dis \n3 : 2 .15142278 \n19. Wu C \n2020 \nRisk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China\n. JAMA Intern Med \n180 : 934 –943\n.32167524 \n20. Jose RJ Manuel A , 2020 \nCOVID-19 cytokine storm: the interplay between inflammation and coagulation\n. Lancet Respir Med \n8 : e46 –e47\n.32353251 \n21. Chauhdary WA Chong PL Mani BI Asli R Momin RN Abdullah MS Chong VH , 2020 \nPrimary respiratory bacterial coinfections in patients with COVID-19\n. Am J Trop Med Hyg \n103 : 917 –919\n.32500854 \n22. Khaddour K Sikora A Tahir N Nepomuceno D Huang T , 2020 \nCase report: the importance of novel coronavirus disease (COVID-19) and coinfection with other respiratory pathogens in the current pandemic\n. Am J Trop Med Hyg \n102 : 1208 –1209\n.32314699 \n23. Lier AJ Tuan JJ Davis MW Paulson N McManus D Campbell S Peaper DR Topal JE , 2020 \nCase report: disseminated strongyloidiasis in a patient with COVID-19\n. Am J Trop Med Hyg \n103 : 1590 –1592\n.32830642 \n24. Liu K Chen Y Lin R Han K , 2020 \nClinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients\n. J Infect \n80 : e14 –e18\n.\n25. Perrotta F Corbi G Mazzeo G Boccia M Aronne L D’Agnano V Komici K Mazzarella G Parrella R Bianco A , 2020 \nCOVID-19 and the elderly: insights into pathogenesis and clinical decision-making\n. Aging Clin Exp Res \n32 : 1599 –1608\n.32557332\n\n", "fulltext_license": "CC BY", "issn_linking": "0002-9637", "issue": "103(6)", "journal": "The American journal of tropical medicine and hygiene", "keywords": null, "medline_ta": "Am J Trop Med Hyg", "mesh_terms": "D000368:Aged; D001938:Brazil; D000086382:COVID-19; D000086742:COVID-19 Testing; D002598:Chagas Cardiomyopathy; D060085:Coinfection; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D010138:Pacemaker, Artificial; D012367:RNA, Viral; D000086402:SARS-CoV-2; D014057:Tomography, X-Ray Computed; D014349:Trypanosoma cruzi", "nlm_unique_id": "0370507", "other_id": null, "pages": "2353-2356", "pmc": null, "pmid": "33025877", "pubdate": "2020-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "32745113;20070438;31986264;32539446;32426374;32171866;15142278;32314699;22293860;32733921;32500854;22231251;32530585;33195443;31312626;20209343;32296069;32353251;32830642;32557332;29561988;32167524;32077115;21633036", "title": "Case Report: COVID-19 and Chagas Disease in Two Coinfected Patients.", "title_normalized": "case report covid 19 and chagas disease in two coinfected patients" }

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CASE REPORT: COVID?19 AND CHAGAS DISEASE IN TWO COINFECTED PATIENTS. 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{ "abstract": "Despite the successes of tyrosine kinase inhibitors (TKIs) in improving outcomes in patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), allogeneic hematopoietic stem cell transplantation (HSCT) continues to be an important and potentially curative option for selected patients with either disease. After HSCT, TKIs are increasingly being used to treat or prevent disease relapse, and practice patterns suggest that these TKIs are often chosen empirically without regard to pre-HSCT mutation status. We investigated whether ABL kinase domain mutations persist after transplantation and, thus, whether pre-HSCT mutation status should inform the selection of post-HSCT TKIs in these patients. We retrospectively analyzed adults who underwent allogeneic HSCT for CML and Ph + ALL at our institution between 2000 and 2010, and we identified subjects who had detectable BCR-ABL transcripts by polymerase chain reaction (PCR), as well as available RNA for Sanger sequencing of the ABL kinase domain, in both the pre- and post-HSCT settings. In total, 95 CML and 20 Ph + ALL patients with positive PCR transcripts were identified, of which 10 (10.5%) and 4 (20.0%), respectively, were found to have pre-HSCT ABL kinase mutations known to confer TKI resistance. In 9 (64.2%) of these 14 patients, the same kinase mutation was also detectable at an average time of 191 days after HSCT. Seven (50.0%) of the 14 harboring mutations had relapsed/refractory disease by last follow-up, of which, in retrospect, 6 had received a predictably ineffective TKI within the first 100 days after transplantation based on our mutation analysis. These data support the idea that pre-existing mutations in the ABL kinase domain, frequently associated with resistance to TKIs and prevalent in a transplantation population, are persistently detectable in the majority of patients after transplantation. We propose that such resistance patterns should be considered when selecting TKIs in the post-HSCT setting, including clinical trials of post-HSCT TKI prophylaxis.", "affiliations": "Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington. Electronic address: [email protected].;Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.;Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, Washington.", "authors": "Egan|Daniel N|DN|;Beppu|Lan|L|;Radich|Jerald P|JP|", "chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "21(1)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Allogeneic hematopoietic stem cell transplantation; BCR-ABL kinase mutations; Chronic myeloid leukemia; Philadelphia-chromosome acute lymphoblastic leukemia", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors", "nlm_unique_id": "9600628", "other_id": null, "pages": "184-9", "pmc": null, "pmid": "25300870", "pubdate": "2015-01", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "19602874;17881635;15570257;15817679;16533723;22240733;17211436;18615627;19885746;19652056;15747376;21156844;20005967;21193419;23223358;17008892;18471874;21508120;19539217;17119111;16234522;19075254;23212150;12623848;21134983;23794064;15297408;12970768;20460883;1586748;16627254;24382642;17405907;19204710;17664354;16855631;12176876;12399961", "title": "Patients with Philadelphia-positive leukemia with BCR-ABL kinase mutations before allogeneic transplantation predominantly relapse with the same mutation.", "title_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation" }

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PATIENTS WITH PHILADELPHIA-POSITIVE LEUKEMIA WITH BCR-ABL KINASE MUTATIONS BEFORE ALLOGENEIC TRANSPLANTATION PREDOMINANTLY RELAPSE WITH THE SAME MUTATION. 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PATIENTS WITH PHILADELPHIA-POSITIVE LEUKEMIA WITH BCR-ABL KINASE MUTATIONS BEFORE ALLOGENEIC TRANSPLANTATION PREDOMINANTLY RELAPSE WITH THE SAME MUTATION. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2015;172-195", "literaturereference_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10679240, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" }, { "companynumb": "PHHY2014US167145", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "IMATINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "021588", "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": "IMATINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukaemia recurrent", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oncologic complication", "reactionmeddraversionpt": "18.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "EGAN DN, BEPPU L, RADICH JP. PATIENTS WITH PHILADELPHIA-POSITIVE LEUKEMIA WITH BCR-ABL KINASE MUTATIONS BEFORE ALLOGENEIC TRANSPLANTATION PREDOMINANTLY RELAPSE WITH THE SAME MUTATION. BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION. 2015;172-195", "literaturereference_normalized": "patients with philadelphia positive leukemia with bcr abl kinase mutations before allogeneic transplantation predominantly relapse with the same mutation", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20141229", "receivedate": "20141229", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10679250, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150529" } ]

{ "abstract": "Glutamic acid decarboxylase antibodies (GAD-Abs) have been implicated in refractory epilepsy. The association with refractory status epilepticus in adults has been rarely described. We discuss our experience in managing three adult patients who presented with refractory status epilepticus associated with GAD-Abs. Case series with retrospective chart and literature review. Three patients without pre-existing epilepsy who presented to our institution with generalized seizures between 2013 and 2014 were identified. Seizures proved refractory to first and second-line therapies and persisted beyond 24 hours. Patient 1 was a 22-year-old female who had elevated serum GAD-Ab titres at 0.49 mmol/l (normal: <0.02) and was treated with multiple immuno- and chemotherapies, with eventual partial seizure control. Patient 2 was a 61-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l. EEG showed persistent generalized periodic discharges despite maximized therapy with anticonvulsants but no immunotherapy, resulting in withdrawal of care and discharge to nursing home. Patient 3 was a 50-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l, and was discovered to have pulmonary sarcoidosis. Treatment with steroids and intravenous immunoglobulin resulted in seizure resolution. Due to the responsiveness to immunotherapy, there may be an association between GAD-Abs and refractory seizures, including refractory status epilepticus. Causation cannot be established since GAD-Abs may be elevated secondary to concurrent autoimmune diseases or formed de novo in response to GAD antigen exposure by neuronal injury. Based on this report and available literature, there may be a role for immuno- and chemotherapy in the management of refractory status epilepticus associated with GAD-Abs.", "affiliations": "Department of Neurology.;Department of Neurology.;Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham Hospital, Birmingham, AL, USA.;Department of Neurology.;Department of Neurology.", "authors": "Khawaja|Ayaz M|AM|;Vines|Brannon L|BL|;Miller|David W|DW|;Szaflarski|Jerzy P|JP|;Amara|Amy W|AW|", "chemical_list": "D000927:Anticonvulsants; D001323:Autoantibodies; D005968:Glutamate Decarboxylase", "country": "France", "delete": false, "doi": "10.1684/epd.2016.0797", "fulltext": null, "fulltext_license": null, "issn_linking": "1294-9361", "issue": "18(1)", "journal": "Epileptic disorders : international epilepsy journal with videotape", "keywords": "NORSE; RSE; anti-GAD antibody; chemotherapy; glutamic acid decarboxylase; immunotherapy; refractory seizures; status epilepticus", "medline_ta": "Epileptic Disord", "mesh_terms": "D000927:Anticonvulsants; D001323:Autoantibodies; D004569:Electroencephalography; D005260:Female; D005968:Glutamate Decarboxylase; D006801:Humans; D008875:Middle Aged; D012189:Retrospective Studies; D012640:Seizures; D013226:Status Epilepticus; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "100891853", "other_id": null, "pages": "34-43", "pmc": null, "pmid": "26878120", "pubdate": "2016-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Refractory status epilepticus and glutamic acid decarboxylase antibodies in adults: presentation, treatment and outcomes.", "title_normalized": "refractory status epilepticus and glutamic acid decarboxylase antibodies in adults presentation treatment and outcomes" }

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"reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHAWAJA AM, VINES BL, MILLER DW, SZAFLARSKI JP, AMARA AW. REFRACTORY STATUS EPILEPTICUS AND GLUTAMIC ACID DECARBOXYLASE ANTIBODIES IN ADULTS: PRESENTATION, TREATMENT AND OUTCOMES. EPILEPTIC DISORD. 2016?18(1):34-43", "literaturereference_normalized": "refractory status epilepticus and glutamic acid decarboxylase antibodies in adults presentation treatment and outcomes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17208026, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-UCBSA-2016011588", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": 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null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LORAZEPAM." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "MIDAZOLAM HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INFUSION", "drugdosagetext": "14MG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MIDAZOLAM" }, { 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null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "3MG/KG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PENTOBARBITAL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PROPOFOL" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50MCG/KG/HR", "drugenddate": null, "drugenddateformat": null, "drugindication": "SEDATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PROPOFOL." } ], "patientagegroup": null, "patientonsetage": "61", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KHAWAJA AM, VINES BL, MILLER DW, SZAFLARSKI JP, AMARA AW. REFRACTORY STATUS EPILEPTICUS AND GLUTAMIC ACID DECARBOXYLASE ANTIBODIES IN ADULTS: PRESENTATION, TREATMENT AND OUTCOMES. EPILEPTIC DISORD. 2016?18(1):34-43", "literaturereference_normalized": "refractory status epilepticus and glutamic acid decarboxylase antibodies in adults presentation treatment and outcomes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17208025, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 2, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" } ]

{ "abstract": "BACKGROUND\nCollagenous colitis (CC) is a clinicopathologic syndrome characterized by chronic watery diarrhea and distinctive histopathologic features. Spontaneous perforation of CC is extremely rare, because CC is usually managed medically, and the need for surgical intervention is rare. We report a surgical case of spontaneous colonic perforation of CC with acute abdomen disease.\n\n\nMETHODS\nA 77-year-old man was admitted to our hospital for abdominal pain and watery diarrhea. Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the splenic flexure of the colon. Therefore, we performed emergency surgery with a diagnosis of colonic perforation. Intraoperative findings revealed colonic necrosis at the splenic flexure, so we performed a left hemicolectomy. Histopathological examination revealed typical findings of CC, a thick subepithelial collagenous band and deep ulcers with perforation. The postoperative course was uneventful, and the patient was discharged on the 28th postoperative day. After changing the proton pump inhibitor (PPI) from lansoprazole (LPZ) to rabeprazole (RPZ), he has not complained of diarrhea symptoms.\n\n\nCONCLUSIONS\nAlthough spontaneous perforation is a rare complication of CC, it is possible to be diagnosed by symptom of acute abdomen disease. This is the seventh case of spontaneous colonic perforation of CC worldwide.", "affiliations": "Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan. [email protected].;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.;Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga, 520-2192, Japan.", "authors": "Mori|Haruki|H|;Miyake|Toru|T|;Shimizu|Tomoharu|T|;Yamaguchi|Tsuyoshi|T|;Kaida|Sachiko|S|;Takebayashi|Katsushi|K|;Iida|Hiroya|H|;Otsuki|Akinori|A|;Inatomi|Osamu|O|;Kitoh|Katsuyuki|K|;Andoh|Akira|A|;Tani|Masaji|M|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1186/s40792-019-0647-0", "fulltext": "\n==== Front\nSurg Case RepSurg Case RepSurgical Case Reports2198-7793Springer Berlin Heidelberg Berlin/Heidelberg 64710.1186/s40792-019-0647-0Case ReportA case of spontaneous colonic perforation in collagenous colitis Mori Haruki [email protected] 1Miyake Toru 1Shimizu Tomoharu 1Yamaguchi Tsuyoshi 1Kaida Sachiko 1Takebayashi Katsushi 1Iida Hiroya 1Otsuki Akinori 2Inatomi Osamu 2Kitoh Katsuyuki 2Andoh Akira 2Tani Masaji 11 0000 0000 9747 6806grid.410827.8Department of Surgery, Shiga University of Medical Science, Setatsukinowa-chou, Otsu, Shiga 520-2192 Japan 2 Otsu, Japan to Setatsukinowa-chou, Otsu, Shiga 520-2192 Japan 31 5 2019 31 5 2019 12 2019 5 907 3 2019 20 5 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.Background\nCollagenous colitis (CC) is a clinicopathologic syndrome characterized by chronic watery diarrhea and distinctive histopathologic features. Spontaneous perforation of CC is extremely rare, because CC is usually managed medically, and the need for surgical intervention is rare. We report a surgical case of spontaneous colonic perforation of CC with acute abdomen disease.\n\nCase presentation\nA 77-year-old man was admitted to our hospital for abdominal pain and watery diarrhea. Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the splenic flexure of the colon. Therefore, we performed emergency surgery with a diagnosis of colonic perforation. Intraoperative findings revealed colonic necrosis at the splenic flexure, so we performed a left hemicolectomy. Histopathological examination revealed typical findings of CC, a thick subepithelial collagenous band and deep ulcers with perforation. The postoperative course was uneventful, and the patient was discharged on the 28th postoperative day. After changing the proton pump inhibitor (PPI) from lansoprazole (LPZ) to rabeprazole (RPZ), he has not complained of diarrhea symptoms.\n\nConclusions\nAlthough spontaneous perforation is a rare complication of CC, it is possible to be diagnosed by symptom of acute abdomen disease. This is the seventh case of spontaneous colonic perforation of CC worldwide.\n\nKeywords\nColonic perforationCollagenous colitisSpontaneousissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nCollagenous colitis (CC) is characterized by chronic diarrhea and usually occurs in middle-aged women. Endoscopic examinations are generally unremarkable [1], laboratory and radiological test results are usually normal, and stool cultures are sterile in many cases. Thus, there is not a reliable biomarker for CC diagnosis.\n\nEndoscopic evaluation of the colon is often normal, but erythema, edema, changes in blood vessels, and mucosal clefts may be observed [2]. Definitive diagnosis is established by the pathological diagnosis, an endoscopic biopsy revealing a thickened subepithelial collagenous band (10–30 μm) found in the wall of the colon with epithelial damage and chronic inflammation of the lamina propria [3].\n\nCC is a heterogeneous disorder and may have multiple etiologies making pathogenesis unclear. Several medications have been implicated as contributing factors, notably aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), histamine 2 receptor blockers, and proton pump inhibitors, such as lansoprazole and certain selective serotonin reuptake inhibitors [4]. Autoimmune conditions, including rheumatoid arthritis, thyroid disorders, ulcerative colitis, and celiac disease, are also associated with colitis. Furthermore, it has been reported that smoking and bacterial infections are associated with CC. But it is unclear that the family history and genetic abnormalities are risk factors for CC [5, 6]. CC is rarely associated with serious complications; however, spontaneous and post-colonoscopic perforated cases have been reported [3]. Mechanisms of rare spontaneous perforations in patients with CC remain unclear. We report herein an interesting and rare case of the above.\n\nCase presentation\nA 77-year-old man was admitted to Shiga University of Medical Science (SUMS) Hospital complaining of abdominal pain and frequent episodes of non-bloody watery diarrhea, lasting for 2 months. His past medical history included a gastric ulcer 40 years earlier, hypertension, and chemotherapy for multiple myeloma. His current medications were aspirin, prednisolone, melphalan, and lansoprazole (LPZ). His body temperature was within the normal range. Physical examination revealed acute left abdominal pain and muscular defense. Laboratory results revealed a white blood cell count of 2100/μl (normal range, 3000–8000/μl), and C-reactive protein (CRP) level was 0.19 mg/dl (normal range, < 0.30 mg/dl). Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the colonic splenic flexure, and ascites was found on the liver surface (Fig. 1a, b). The patient was diagnosed as having peritonitis with colonic perforation. Emergency laparotomy was performed, and it was observed that the ascites contained intestinal fluid. The colon around the splenic angle was necrotic and edematous. We performed a left hemicolectomy. Macroscopic findings (Fig. 2) showed edematous mucosa and tortuous longitudinal ulcer. Histopathological examination (Fig. 3) revealed typical findings of CC, with a thick subepithelial collagenous band and deep ulcers with perforation. Active lymphocyte infiltration was observed in all layers of the colon. There was no evidence of acute ischemic colitis or inflammatory bowel disease.Fig. 1 Abdominal computed tomography (CT). a Ascites around the liver (arrow). b, c Thickness in bowel wall and involving the free air around the colonic splenic flexure (arrow)\n\nFig. 2 Macroscopy of the resected colon: cross sections of the bowel show normal-appearing mucosa, markedly thickened edematous wall, and longitudinal ulcer. The arrow indicates the perforation site\n\nFig. 3 Histological examination. a Typical findings of collagenous colitis with a thick subepithelial collagenous band (arrowhead). b Collagenous band was stained by Azan (arrowhead). c Ulcerated area with perforation (arrow)\n\n\n\nPostoperative course was uneventful, and the patient was discharged on the 28th postoperative day. PPI-induced CC was suspected due to his past history; therefore, the PPI was subsequently changed from LPZ to RPZ. Following this change, he noted an improvement in diarrhea symptoms.\n\nDiscussion\nCC is a relatively uncommon, but increasingly diagnosed form of microscopic colitis. CC was described in 2 independent reports in 1976 from Canada and Sweden [7, 8]. Patients with CC typically complain of chronic, non-bloody, watery diarrhea. It is pathologically diagnosed by the presence of increased intraepithelial lymphocytes, mixed inflammatory cells in the lamina propria, and pathognomonic appearance of a thickened subepithelial collagen band [5]. CC is usually treated successfully with medication; therefore, the need for surgical intervention is rare [9]. However, emergent surgery is necessary if there is perforation of the bowel tract, which is accompanied by collagen deposition under the mucosal epithelium that reduces intestinal elasticity and extensibility [3]. A colonoscopy or barium enema sometimes can cause colonic perforations in collagenous colitis, and these iatrogenic perforations are thought to occur secondary to mechanical trauma or luminal insufflation causing linear mucosal tears that lead to rupture [10, 11].\n\nOnly 6 patients have been reported to have a spontaneous perforation in CC (Table 1) [9, 10, 12–15]. In all cases, including ours, there was a history of non-bloody diarrhea and no previous diagnosis of CC. CC occurs more frequently in females, and all previous reports described females, but our patient was male. All patients recovered following resection of the perforated segment. Of note, all CC perforations occurred in the left colon, in contrast to a perforation after endoscopic examination, which is commonly on the right side [16–18]. In recent years, reports of cases with characteristic longitudinal ulcers expressed as “mucosal tears” or “linear mucosal defect” are increasing [19–22]. This longitudinal ulcer is elongated and presents a mucosal split form and the boundary is clear, edema and redness of the ulcer margin are poor, and therefore different from a longitudinal ulcer seen in ischemic colitis or Crohn’s disease. A tortuous, longitudinal ulcer, characteristic of CC, was also observed in our case.Table 1 Reported cases of spontaneous perforation in collagenous colitis\n\n\tAuthor\tYear\tAge/sex\tMedications\tPerforation site\tSurgery\tOutcome\t\n1\tFreeman [6]\t2001\t37/F\tNone recorded\tSigmoid\tLaparotomy\tAlive\t\n2\tBohr [4]\t2005\t56/F\tClomipramine\tSplenic angle/descending colon\tSegmental resection\tAlive\t\n3\tBennett [7]\t2013\t67/F\tAspirin, loperamide\tSplenic angle\tPartial colectomy\tAlive\t\n4\tAkamoto [8]\t2014\t64/F\tNone\tDescending colon\tLeft colectomy\tAlive\t\n5\tCottreau [9]\t2016\t49/F\tDexilansoprazole, buproprion, clonazepam, ranitidine\tDescending colon\tLeft colectomy\tAlive\t\n6\tMitchell [5]\t2016\t80/F\tLoperamide, levothyroxine\tSplenic angle\tSegmental resection\tAlive\t\n7\tOur case\t2018\t77/M\tLansoprazole, aspirin, prednisolone, melphalan\tSplenic angle\tPartial colectomy\tAlive\t\nF female, M male\n\n\n\nAlthough the precise mechanism is unknown for the cause of CC, previous articles report that CC is caused by genetic factors [23, 24], intestinal factors due to malabsorption of bile acid [25, 26], and drugs [27]. In recent years, CC related to LPZ has attracted attention [28]. Oral administration rate of LPZ in patients with CC is as high as 53 to 83% in Japan [29, 30], while as low as 8% in European and American reports [31].\n\nProton pumps exist in colonic epithelial cells. Therefore, a proton pump inhibitor is presumed to change the composition and pH values of secretions from colonic mucosa and affect the immune response, which is a possible mechanism in developing CC [32]. LPZ is mainly metabolized by Cytochrome P450 2C19 (CYP2C19) and Cytochrome P450 3A4 (CYP3A4). A genetic polymorphism of CYP2C19 is reported in 18 to 23% of the Japanese population, compared with 1 to 6% in the Western population. This fact is considered as one of the reasons that LPZ-induced CC cases are more frequent in Japan [33]. Rabeprazole (RPZ), however, is not metabolized via CYP2C19 and CC induced by RPZ is rarer than LPZ. Therefore, it is suggested that the different PPI pharmacological action is involved in the pathogenesis of CC [30]. NSAIDs, antihypertensive drugs, and hyperlipidemic drugs are also metabolized by CYP3A4. When these drugs are used in combination with LPZ, CC may develop due to the high blood concentration of LPZ and drug interaction via CYP families [34]. In our case, the patient was taking LPZ because of the history of a gastric ulcer. After surgery, his PPI was subsequently changed from LPZ to RPZ with no changes in his other. After this change, he noted an improvement in his diarrhea symptoms. Therefore, we suggest that CC of this patient seemed to be caused by LPZ.\n\nConclusion\nIn summary, we report a case of CC triggered by a PPI. It is important to note that spontaneous perforation of CC is a possible complication of diagnosed acute abdomen disease.\n\nAbbreviations\nCCCollagenous colitis\n\nCRPC-reactive protein\n\nCTComputed tomography\n\nCYP2C19Cytochrome P450 2C19\n\nCYP3A4Cytochrome P450 3A4\n\nLPZLansoprazole\n\nNSAIDsNon-steroidal anti-inflammatory drugs\n\nPPIProton pump inhibitor\n\nRPZRabeprazole\n\nThis paper is not based on previous communications with a society or meeting.\n\nAcknowledgements\nWe thank Akiko Matsubara from the department of Pathological Diagnosis, Shiga University of Medical Science, for pathological guidance of this manuscript\n\nAuthors’ contributions\nHM is the first author of this manuscript and the corresponding author. SK, TM, and KT performed the surgery. TY, AO, and HI collected the clinical data. OI, KK, AA, TS, and MT revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe authors received no financial support for the preparation of this case report.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nOral informed consent was obtained from the patient for the publication of this case report and accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Tangri V Chande N Microscopic colitis an update J Clin Gastroenterol 2009 43 293 296 10.1097/MCG.0b013e31818f50ce 19169149 \n2. Tysk C Wickbom A Nyhlin N Eriksson S Bohr J Recent advances in diagnosis and treatment of microscopic colitis Ann Gastroenterol. 2011 24 4 253 262 24713787 \n3. Van Velden R Snieders I Quispel R Image of the month. Tearing of the colon in a patient with collagenous colitis during colonoscopy Clin Gastroenterol Hepatol. 2010 8 A28 10.1016/j.cgh.2010.06.002 \n4. Beaugerie L Pardi DS Review article: drug-induced microscopic colitis—proposal for a scoring system and review of the literature Aliment Pharmacol Ther. 2005 22 277 284 10.1111/j.1365-2036.2005.02561.x 16097993 \n5. Freeman HJ Collagenous mucosal inflammatory diseases of the gastrointestinal tract Gastroenterology. 2005 129 338 350 10.1053/j.gastro.2005.05.020 16012959 \n6. Pardi DS Kelly CP Microscopic colitis Gastroenterology. 2011 140 1155 1165 10.1053/j.gastro.2011.02.003 21303675 \n7. Freeman HJ Weinsteiys WM Shnitka TK Wensel RH Sartor VE Watery diarrhea syndrome associated with a lesion of the colonic basement membrane (CD) – lamina propia (LP) interfaxe Ann R Coll Phys Surg Can. 1976 9 45 \n8. Lindstrom CG Collagenous colitis with watery diarrhea – a new entity? Pathol Eur. 1976 11 87 89 934705 \n9. Bohr J Larsson LG Eriksson S Colonic perforation in collagenous colitis: an unusual complication Eur J Gastroenterol Hepatol. 2005 17 121 124 10.1097/00042737-200501000-00022 15647652 \n10. Mitchell A Dugas A Collagenous colitis presenting as spontaneous perforation in an 80-year-old woman: report of a case BMC Gastroenterology. 2016 16 124 10.1186/s12876-016-0533-1 27716080 \n11. Sherman A Ackert JJ Rajapaksa R West AB Oweity T Fractured colon: an endoscopically distinctive lesion associated with colonic perforation following colonoscopy in patients with collagenous colitis J Clin Gastroenterol. 2004 38 341 345 10.1097/00004836-200404000-00008 15087693 \n12. Freeman HJ James D Mahoney CJ Spontaneous peritonitis from perforation of the colon in collagenous colitis Can J Gastroenterol. 2001 15 265 267 10.1155/2001/194837 11331929 \n13. Bennett M Tompkins H Symour B O’Brien MJ Farraye FA Spontaneous colonic perforation in a patient with collagenous colitis Gastroenterol Hepatol. 2013 9 262 264 \n14. Akamoto S Fujiwara M Okano K Suzuki Y Spontaneous perforation in collagenous colitis Surgery. 2014 155 198 199 10.1016/j.surg.2012.10.008 23218876 \n15. Cottreau J Kelly R Topp T Costa A Filter ER Arnason T Spontaneous colonic perforation: a rare complication of collagenous colitis Clin J Gastroenterol. 2016 9 140 144 10.1007/s12328-016-0652-9 27178398 \n16. Cruz-Correa M Milligan F Giardiello FM Bayless TM Torbenson M Yardely JH Jackson FW Wlison Jackson F Collagenous colitis with mucosal tears on endoscopic insufflation: a unique presentation Gut 2002 51 600 10.1136/gut.51.4.600 12235088 \n17. Kakar S Pardi DS Burgart LJ Colonic ulcers accompanying collagenous colitis: implication of nonsteroidal anti-inflammatory drugs Am J Gastroenterol. 2003 98 1834 1837 10.1111/j.1572-0241.2003.07579.x 12907340 \n18. Wickbom A Lindqvist M Bohr J Ung KA Bergman J Eriksson S Tysk C Colonic mucosal tears in collagenous colitis Scand J Gastroenterol. 2006 41 726 729 10.1080/00365520500453473 16716973 \n19. Allende DS Taylor SL Bronner MP Colonic perforation as a complication of collagenous colitis in a series of 12 patients Am J Gastroenterol. 2008 103 2598 2604 10.1111/j.1572-0241.2008.01998.x 18702648 \n20. Smith RR Ragput A Mucosal tears on endoscopic insufflation resulting in perforation: an interesting presentation of collagenous colitis J Am Coll Surg 2007 205 725 10.1016/j.jamcollsurg.2007.02.082 17964451 \n21. Couto Gilberto Bispo Miguel Barreiro Pedro Monteiro Lucília Matos Leopoldo Unique endoscopy findings in collagenous colitis Gastrointestinal Endoscopy 2009 69 6 1186 1188 10.1016/j.gie.2008.06.010 19152884 \n22. Cuoco L Bertoncello V Salvagnini M Colonic perforation after colonoscopy in patients with collagenous colitis Am J Gastroenterol 2009 104 1846 1847 10.1038/ajg.2009.178 19436277 \n23. Jarnerot G Hertervig E Granno C Thorhallsson E Eriksson S Tysk C Hansson I Bjorknas H Bohr J Olesen M Willen R Kaqevi I Danielsson A Familial occurrence of microscopic colitis: a report on five families Scand J Gastroenterol 2001 36 959 962 10.1080/003655201750305486 11521987 \n24. van Tilburg AJ Lam HG Seldenrijk CA Stel HV Blok P Dekker W Meuwissen SG Familial occurrence of collagenous colitis: a report of two families J Clin Gastroenterol. 1990 12 279 285 10.1097/00004836-199006000-00009 2362097 \n25. Ung KA Gillberg R Kilander A Abarahamsson H Role of bile acids and bile acid binding agents in patients with collagenous colitis Gut. 2000 46 170 175 10.1136/gut.46.2.170 10644309 \n26. Fernandez-Banares F Esteve M Salas A Forné TM Espinos JC Martín-Comin J Viver JM Bile acid malabsorption in microscopic colitis and in previously unexplained functional chronic diarrhea Dig Dis Sci. 2001 46 2231 2238 10.1023/A:1011927302076 11680602 \n27. Beaugerie L Pardi DS Review article: drug-induced microscopic colitis―proposal for a scoring system and review of the literature Aliment Pharmacol Ther. 2005 22 277 284 10.1111/j.1365-2036.2005.02561.x 16097993 \n28. Umeno J Matsumoto T Nakamura S Yanai S Hirakawa K Yada S Jo Y Yamagata H Yoshimura R Watanabe T Gushima M Yao T Nakashima Y Iida M Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis Gastrointest Endosc 2008 67 1185 1191 10.1016/j.gie.2008.02.013 18513560 \n29. Umeno J Matsumoto T Nakamura S Iida M Diagnosis and management of collagenous colitis Gastroenterol Endosc 2010 52 1233 1242 \n30. Umeno J, Matsumoto T, Nakamura S, et al. Drug-induces collagenous colitis: special reference to the endoscopic features of lansoprazole-associated cases. Stomach Intestine. 2009;44:1973-1982.\n31. Fernandez-Banares F Esteve M Espinos JC Rosinach M Forne M Salas A Viver JM Drug consumption and the risk of microscopic colitis Am J Gastroenterol. 2007 102 324 330 10.1111/j.1572-0241.2006.00902.x 17100977 \n32. Fernandez-Banares F Salas A Esteve M Espinos J Forne M Viver JM Collagenous and lymphocytic colitis. Evaluation of clinical and histological features, response to treatment, and long-term follow-up Am J Gastroentterol. 2003 98 340 347 10.1111/j.1572-0241.2003.07225.x \n33. Ishizaki T Horai Y Review article: cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on Rabeprazole Aliment Pharmacol Ther. 1999 13 27 36 10.1046/j.1365-2036.1999.00022.x \n34. Yamazaki K Shimizu S Hanai Y Shinohara T Hotta K Kazuyoshi Y Nishiwaki S Fukutomi Y Ibuka T Araki H Shimizu M Mori Y Hitoshi I Kushima R Diagnosis and clinical features of drug-induced collagenous colitis Stomach Intestine. 2016 51 450 462\n\n", "fulltext_license": "CC BY", "issn_linking": "2198-7793", "issue": "5(1)", "journal": "Surgical case reports", "keywords": "Collagenous colitis; Colonic perforation; Spontaneous", "medline_ta": "Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101662125", "other_id": null, "pages": "90", "pmc": null, "pmid": "31152255", "pubdate": "2019-05-31", "publication_types": "D016428:Journal Article", "references": "10491726;10644309;11331929;11521987;11680602;12235088;12591052;12907340;15087693;15647652;16012959;16097993;16716973;17100977;17964451;18513560;18702648;19152884;19169149;19436277;20601144;21303675;23218876;2362097;24711775;24713787;27178398;27716080;934705", "title": "A case of spontaneous colonic perforation in collagenous colitis.", "title_normalized": "a case of spontaneous colonic perforation in collagenous colitis" }

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{ "abstract": "The Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) chemotherapy protocol has been one of the standard treatments for blood cancers, such as Mantle cell lymphoma (MCL), Burkitt's lymphoma (BL) and B-cell and T-cell acute lymphoblastic leukaemia (ALL). Due to high toxicity, it has been progressively replaced with new specific regimens with a better safety profile (GELA protocol for MCL, BURKIMAB for BL and PETHEMA for B-cell and T-cell ALL). The objective of this study is to analyse the toxicity and infectious complications of these therapeutic regimens, as well as the event free survival (EFS).\nThis is a retrospective and descriptive observational study of 81 patients, comparing 42 patients treated with H-CVAD/MTX-AraC (group A) versus 39 patients treated with GELA/BURKIMAB/PETHEMA (group B).\nAll patients in group A developed pancytopenia, but in group B 74.4% neutropenia, 51.3% thrombocytopenia and 69.2% anaemia. The total number of infections in group A was higher than in group B: 154 versus 48, 3.67 versus 1.23 per patient and 0.59 versus 0.25 per cycle. Likewise, febrile neutropenia happened: 106 versus 21 cases, 2.52 versus 0.52 per patient and 0.41 versus 0.11 per cycle. EVS is higher in group B: 33% versus 79% (2-year), and 24% versus 69% (5-year).\nCurrent therapeutic protocols have shown higher EFS due to better safety profile, with less haematological, neurological and haemorrhagic toxicity, as well as lower rates of infectious complications.", "affiliations": "Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Nephrology Department, Hospital Universitario Reina Sofía, Murcia, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Neurology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.;Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain.", "authors": "Marín-Sánchez|Alberto|A|;Martínez-Fernández|Gonzalo|G|;Gómez-Catalán|Irene|I|;Montoya-Morcillo|Mari Carmen|MC|;Algarra|Jesús Lorenzo|JL|;García|Ángela Ibañez|ÁI|;Hernández-Fernández|Francisco|F|;Romero-Macías|Juan Ramón|JR|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3332/ecancer.2021.1206", "fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605\nCancer Intelligence\n\n10.3332/ecancer.2021.1206\ncan-15-1206\nShort Communication\nComparison in safety of chemotherapy protocols for blood cancers: toxicity of H-CVAD versus GELA/BURKIMAB/PETHEMA LAL\nMarín-Sánchez Alberto 1\nMartínez-Fernández Gonzalo 2\nGómez-Catalán Irene 1\nMontoya-Morcillo Mari Carmen 1\nAlgarra Jesús Lorenzo 1\nGarcía Ángela Ibañez 1\nHernández-Fernández Francisco 3\nRomero-Macías Juan Ramón 1\n1 Haematology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain\n2 Nephrology Department, Hospital Universitario Reina Sofía, Murcia, Spain\n3 Neurology Department, Complejo Hospitalario Universitario de Albacete, Calle Hermanos Falcó 37, 02008 Albacete, Spain\nCorrespondence to: Alberto Marín-Sánchez [email protected]\n2021\n22 3 2021\n15 120627 8 2020\n© the authors; licensee ecancermedicalscience.\n2021\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground and objective\n\nThe Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) chemotherapy protocol has been one of the standard treatments for blood cancers, such as Mantle cell lymphoma (MCL), Burkitt’s lymphoma (BL) and B-cell and T-cell acute lymphoblastic leukaemia (ALL). Due to high toxicity, it has been progressively replaced with new specific regimens with a better safety profile (GELA protocol for MCL, BURKIMAB for BL and PETHEMA for B-cell and T-cell ALL). The objective of this study is to analyse the toxicity and infectious complications of these therapeutic regimens, as well as the event free survival (EFS).\n\nPatients and methods\n\nThis is a retrospective and descriptive observational study of 81 patients, comparing 42 patients treated with H-CVAD/MTX-AraC (group A) versus 39 patients treated with GELA/BURKIMAB/PETHEMA (group B).\n\nResults\n\nAll patients in group A developed pancytopenia, but in group B 74.4% neutropenia, 51.3% thrombocytopenia and 69.2% anaemia. The total number of infections in group A was higher than in group B: 154 versus 48, 3.67 versus 1.23 per patient and 0.59 versus 0.25 per cycle. Likewise, febrile neutropenia happened: 106 versus 21 cases, 2.52 versus 0.52 per patient and 0.41 versus 0.11 per cycle. EVS is higher in group B: 33% versus 79% (2-year), and 24% versus 69% (5-year).\n\nConclusions\n\nCurrent therapeutic protocols have shown higher EFS due to better safety profile, with less haematological, neurological and haemorrhagic toxicity, as well as lower rates of infectious complications.\n\nblood cancers\ntoxicity\ninfections\n==== Body\nIntroduction\n\nLymphomas and acute leukaemias are blood cancers with high morbidity and mortality rates. In order to cure them, intensive anticancer therapy is required [1] However, this can lead to significant toxicity and systemic complications. One of the most undesirable effects of the treatment regimens is haematological toxicity, specifically neutropenia, as it predisposes patients to the risk of infection by different germs [2].\n\nChemotherapy treatment targeting different types of haematological malignancies has evolved substantially in recent years [3]. Since 2000, the combined Hyper-CVAD/Methotrexate-Cytarabine (H-CVAD/MTX-AraC) protocol has been the treatment regimen of choice used in many centres for cancers such as Mantle cell lymphoma (MCL) [4], Burkitt’s lymphoma (BL) [5] and acute lymphoblastic leukaemia (ALL), type B (B-cell ALL) and type T (T-cell ALL) [6]. This protocol emerged from a study which obtained promising results carried out in the MD Anderson Cancer Center, Houston [7, 8]. Subsequently its use became widespread internationally due to its encouraging therapeutic success. In the last few years, this general treatment applied to the three disorders has fallen into disuse in favour of a more specific therapy for each type of disease [9–11]. In particular, the protocol of the French group GELA [12] began to be used for MCL, the BURKIMAB regimen (2008, 2013 and 2014 versions) [13] for BL and the recommendations of the Spanish group PETHEMA (2003, 2008 and 2011 versions) for ALL, depending on age and cytogenetic risk [14, 15].\n\nThe synergistic effect of the various drugs used in these regimens exerts an anticancer action on malignant cancer cells, but also in healthy haematopoietic cells, which leads to considerable haematological toxicity in the form of anaemia, thrombocytopenia and neutropenia [16]. Therefore, a decrease in the three haematopoietic cell series (pancytopenia) can occur at an early stage, while patients are progressing to the period of post-chemotherapy aplasia (nadir). This can expose patients to a situation of severe neutropenia for several days or weeks; increasing the risk of contracting infections caused by different microorganisms, and causing a considerable increase in morbidity and mortality rates [17]. These drug combinations also have significant non-haematological toxicity (hepatic, haemorrhagic, neurological, gastrointestinal and mucocutaneous) [18].\n\nThe only study to have analysed the outcomes of the H-CVAD/MTX-AraC regimen compared to a specific protocol for ALL similar to one of the current three (GELA, BURKIMAB, PETHEMA) is a comparative study in 2018 related to H-CVAD/MTX-AraC and the old PETHEMA-93, in which no significant differences were found [19]. However, the most updated versions of PETHEMA in 2008 and 2011 have shown better results in terms of efficacy and safety compared to the traditional PETHEMA-93 version, so hypothetically they could be also better than H-CVAD/MTX-AraC [20]. Nonetheless, comparative studies between H-CVAD/MTX-AraC and the most modern versions of the PETHEMA 2008 and 2011 protocols, together with the other current regimens GELA and BURKIMAB, so far do not exist.\n\nTaking into account these data, the aim of this study was to compare the safety results (haematological toxicity, non-haematological toxicity and infectious complications) for the only general protocol to those for the three recent specific regimens: H-CVAD/MTX-AraC versus GELA/BURKIMAB/PETHEMA, as well as the event free survival (EFS).\n\nMaterial and methods\n\nStudy design\n\nThis was a retrospective and descriptive observational study comparing two groups of patients: those who were treated with H-CVAD/MTX-AraC (group A); and those who were treated with GELA/BURKIMAB/PETHEMA (group B). Data from group A patients were collected retrospectively, using the information compiled in their medical histories, while data from group B were collected prospectively.\n\nPatients\n\nAll patients aged from 18 to 69 years old who were diagnosed with MCL, BL, B-cell ALL or T-cell ALL treated and evaluated at Complejo Hospitalario Universitario de Albacete (CHUA) from 1 January 2002 to 31 December 2018 were included in the study.\n\nOn the one hand, group A patients received a single type of general chemotherapy treatment according to the H-CVAD/MTX-AraC regimen for all disorders, from 1 January 2002 to 31 December 2010. They were followed up throughout that period of time and afterwards. On the other hand, group B patients were studied from 1 January 2011 to 31 December 2018. They received a specific kind of protocol for each disease: French group GELA regimen for patients with MCL; BURKIMAB for those with BL and PETHEMA for those with B-cell ALL or T-cell ALL. Therefore, all patients were monitored for 5 years (median). In addition, the presence of disease progression or death was registered during the follow-up.\n\nStudy variables and objectives\n\nThe following parameters were assessed in each study group:\n\nHaematological toxicity: anaemia, thrombocytopenia and neutropenia.\n\nNon-haematological toxicity: hepatic, haemorrhagic, neurological, gastrointestinal (diarrhoea) and mucocutaneous (mucositis).\n\nInfections and derived complications: number of patients affected by infection, infectious processes per group, episodes of febrile neutropenia, days of admission due to infection, delay of chemotherapy cycles due to infectious episode and death from sepsis/septic shock.\n\nEFS: 2-year and 5-year.\n\nBased on these parameters, the main objective was to compare the EFS between the two groups. The secondary objectives were to compare the rate of infections and their complications, and the incidence of haematological or other toxicity, in both groups.\n\nStatistical analysis\n\nTo analyse the quantitative variables, the arithmetic mean was used as the measure of central tendency and the standard deviation as the measure of dispersion. For qualitative variables, the absolute and relative frequency as a percentage was used for each of the variables, which were reflected in frequency tables and bar charts.\n\nThe quantitative variables were compared in groups using Student’s t test. Contingency tables with Fisher’s exact test were used to compare qualitative variables (appearance or not of a certain event in each group). In both cases, the level of statistical significance considered was 5% (p <0.05).\n\nStatistical calculations were performed with the SPSS 15.0 software package and Microsoft Excel 2010 for Windows.\n\nEthical considerations\n\nThis was an analysis that compared the current therapeutic regimens with an historical cohort of patients retrospectively, so it has not modified current treatment guidelines. The rules of the Declaration of Helsinki were followed and the confidentiality of the data was guaranteed.\n\nThe project and the informed consent forms for this study were submitted to and approved by the CHUA Independent Ethics Committee.\n\nResults\n\nComposition of the analysed sample\n\nThe study included a total of 81 patients diagnosed with haematological malignancies: 42 (51.9%) were treated with H-CVAD/MTX-AraC from 2002 to 2010 (group A) and 39 (48.1%) were treated with the specific treatment regimens for each disorder from 2011 to 2018 (group B). Group A patients received a total of 259 treatment cycles, while group B patients received 194 cycles (Table 1).\n\nIn group A, 13 patients (31.0%) with MCL, 8 (19.0%) with BL, 14 (33.3%) with B-cell ALL and 7 (16.7%) with T-cell ALL were included. In group B, 9 patients (23.1%) with MCL, 10 (25.6%) with BL, 15 (38.5%) with B-cell ALL and 5 (12.8%) with T-cell ALL were included. There were not differences in the distribution of patients between the two groups (p-value = 0.770), so these are balanced out in respect to their composition by disorder (Table 2).\n\nBaseline characteristics at diagnosis\n\nMCL (8 H-CVAD/MTX-AraC cycles versus 7 GELA cycles Þ AutoTPH):\n\nMedian age: 59 versus 56 years.\n\nState of the disease: 100% lymphadenopathy (same distribution: laterocervical 61.5% versus 66.7%), bone marrow (BM) infiltration – stage IV – t(11;14) (84.6% versus 88.9%) (Images 1 and 2), splenomegaly (53.8% versus 44.4%), B symptoms (23.1% versus 22.2%).\n\nBL (8 H-CVAD/MTX-AraC cycles versus 4-6 BURKIMAB cycles):\n\nMedian age: 37 versus 38 years.\n\nState of the disease: lymphadenopathy (37.5% versus 50% with the same distribution), ‘bulky’ mass (37.5% versus 30%), BM infiltration (50% versus 30%) (Images 3 and 4), stage IV (50% versus 50% due to infiltration of other organs), hypertransaminasemia due to hepatic infiltration (50% versus 40%), splenomegaly (25% versus 20%), B symptoms (37.5% versus 30%), human immunodeficiency virus (0% versus 30%).\n\nLAL-B (8 H-CVAD/MTX-AraC cycles versus 4 PETHEMA LAL-B cycles):\n\nMedian age: 36 versus 33 years.\n\nState of the disease: 100% BM infiltration (obvious stage IV), B symptoms (78.6% versus 60%), high risk patients – complex karyotype (35.7% versus 60%).\n\nLAL-T (8 H-CVAD cycles versus 4 PETHEMA LAL-T cycles) :\n\nMedian age: 27 versus 26 years.\n\nState of the disease: 100% BM infiltration (obvious stage IV), high risk patients – hyperleukocytosis and/or complex karyotype (71.5% versus 80%).\n\nHaematological toxicity\n\nIn group A, 100% of the patients had involvement of the three haematopoietic cell lines (anaemia, thrombocytopenia and neutropenia) (Table 3). Neutropenia was mostly severe (76.2% grade IV) and 23.8% grade III. Thrombocytopenia was also severe (47.6% grade IV and 52.4% grade III). In group B, the incidence of neutropenia was 74.4% (41.0% grade IV, 33.3% grade III). Half of patients (51.3%) had thrombocytopenia and 69.2% had anaemia. Differences between both groups regarding haematological toxicity were significant (p < 0.01) (Table 3).\n\nNon-haematological toxicity\n\nHepatic toxicity was higher in group B than group A (46.2% versus 21.4%, respectively, p = 0.033), and mostly grade II (72.2% of hepatic toxicities in 33.3% of all patients in group B) (Table 4). The incidence of haemorrhagic toxicity was significantly higher in group A (23.8% versus 5.1%, p = 0.027), with major bleeding 7.2% versus 0%, and minor bleeding 16.6% versus 5.1%. Neurological toxicity exclusively affected group A patients (14.3% versus 0%, p = 0.026). Conversely, diarrhoea only occurred in group B patients, although with low frequency (10.3% versus 0%, p = 0.049). Mucositis was very uncommon in the two groups (7.1% versus 5.1%, respectively, not significant) (Table 4).\n\nInfections\n\nThe incidence of any infectious adverse event was similar in patients from both groups (81% versus 74.4%, respectively, p = 0.6) (Table 5). However, the total number of infections was higher in group A: 154 total events, 3.67 processes per patient and 0.59 episodes per cycle; compared to 48 events, 1.23 processes per patient and 0.25 episodes per cycle, in group B (p <0.01 for the three events). With regard to febrile neutropenia, in group A there were 106 cases, 2.52 per patient and 0.41 per cycle; while in group B, there were 21 cases, 0.54 per patient and 0.11 per cycle (p < 0.01) (Figure 1).\n\nThese infectious complications caused delay in the next chemotherapy cycle: 23 events, 0.55 per patient and 0.09 per cycle, in group A; compared to 11 events, 0.28 per patient and 0.06 per cycle, in group B (p <0.01); in addition to an average of 23 days of hospital admission per patient in group A versus 9 days in group B (p <0.01). Lastly, there were a total of five deaths caused by septic shock in group A patients versus one in group B (p = 0.2).\n\nBacteraemia was higher in group A: 30 (71.4%) versus 22 (56.4%) patients. In addition, the microbiological isolates in blood cultures were similar: Coagulase negative staphylococcus (38% versus 27%), E. coli (19% versus 20%), E. coli blee (10% versus 6.7%), Klebsiella pneumoniae (10% in group A) and Campylobacter jejuni (10% in group B).\n\nEFS : 2-year and 5-year\n\nEFS 2-year and 5-year was higher in group B (Table 6 and Figure 2). In group A, 2-year EFS is 33% compared to 79% in group B (p <0.001). 5-year EFS is 24% versus 69%, respectively (p <0.001).\n\nDiscussion\n\nThe treatment of haematological malignancies can lead to multiple complications due to its toxicity. Taking into account the aim of minimising its harmful effects, a number of progressively more specific therapeutic regimens have emerged for each type of disorder over the years [21]. The purpose of this study was, therefore, to analyse the differences in the safety profile between the different chemotherapy protocols, which yielded interesting results.\n\nFirstly, haematological toxicity was significantly higher in patients treated with the general regimen (group A), occurring in all cases, and also in a more severe fashion. Due to the important implications in terms of infections, which will be discussed later, now we will focus on neutropenia [22]. All patients in this group developed neutropenia, most reaching grade IV. However, although most of the patients treated with the specific regimens (group B) also developed neutropenia, less than half of them had such a severe form. Approximately half of the patients in group B developed thrombocytopenia, but only a quarter of them grade IV, while in group A almost half of the patients manifested the most severe form. It was also found that a considerably smaller proportion of patients in group B developed anaemia compared to group A. Therefore, the specific therapeutic regimens showed less haematological toxicity and in less severe forms.\n\nIt was also interesting to compare non-haematological toxicity between the two groups. Hepatic toxicity was the most common form, especially in group B, occurring in almost half of the patients, although it was mild in most cases. This could be due to the administration of more hepatotoxic drugs, such as L-asparaginase [23], present in the current PETHEMA protocol but not in the H-CVAD/MTX-AraC one. To control this harmful effect, the corresponding drug dose adjustments are made according to the patient’s liver function, and it is monitored by changes in transaminase levels, without major incidents or clinical repercussions [24]. Another important aspect to highlight is haemorrhagic toxicity, which affected almost a quarter of group A. This alarming complication is probably favoured by the fact that around half of the group A patients had moderate/severe thrombocytopenia, leading to a risk of bleeding which can potentially be life-threatening, especially if it affects certain vital organs. It is also important to stress the complete lack of neurological toxicity of the specific regimens in our patients, compared to some cases in the general protocol group A which, although it was isolated, nevertheless it involved harmful complications and sequelae. In contrast, there was none related to gastrointestinal toxicity (diarrhoea) in group A patients, compared to isolated cases in group B, although almost all of them were self-limiting. The final aspect to mention is the anecdotal incidence of mucositis in both groups, without any clinical significance.\n\nWith this in mind, we would like to focus on the analysis of infections and their consequences which, as stated earlier, is the main objective of this study [25]. It is obvious that infectious complications continue to be the main cause of morbidity and mortality in these patients [26], as the vast majority manifested at least one episode during the course of their treatment, without differences between the two groups. However, this was the source of some of the most interesting questions we were able to explore. On the one hand, in group A there were three times more infectious processes in general, and per patient, compared to group B, with group B having half the number for each chemotherapy cycle versus group A. In addition, there were five times more cases of febrile neutropenia, in total and per patient, in group A (H-CVAD/MTX-AraC), compared to group B (specific regimens), with group B also having four-fold fewer cases per cycle. These data can probably be explained by the lower haematological toxicity found in the current protocols, especially in terms of neutropenia, which means that patients have a lower risk of contracting infections [27]. On the other hand, in group A, twice as many infectious events were the cause of delay in the next chemotherapy cycle compared to group B. This may be explained by a higher frequency and severity of febrile neutropenia that was previously found in group A, which leads to a slower and more difficult recovery from the infectious episode, complicating the ability to administer the next cycle. All the above factors may also have contributed to the higher number of days of hospital admission for infection required by patients in group A; in total almost three times the number, and per patient more than double, compared to group B. This means that these patients are hospitalised, away from their home environment, for longer periods of time, which may affect both their quality of life and their psychosocial well-being [28]. Moreover, these long hospital stays can increase the risk of contracting nosocomial infections and, in turn, could have economic consequences due to the increased occupation of hospital beds [29]. Finally, it was striking that no differences were found between groups in septic shock mortality rates, despite the fact that there were five times more deaths in patients treated with H-CVAD/MTX-AraC. However, one possible explanation for this apparent discrepancy could be the low number of deaths from septic shock in both cases, which makes the sample small in terms of achieving significant differences.\n\nFinally, differences in 2-year and 5-year EFS between the two groups will be discussed. In group A, a third of the patients did not suffer from any event at 2 years into follow-up, in contrast, in group B more than three-quarters of patients did not exhibit any event. These results were corroborated at 5 years, a quarter of the former and almost three-quarters of the latter are free from any event, respectively. Seemingly, the combinations of drugs used in modern regimens have added some benefit to the treatment of these disorders specifically through their synergistic effect which was not present in the single regimen established for all chemotherapeutic cycles in general. Finally, new toxicity prevention strategies could play a very important role in this notable improvement of results [26, 27].\n\nConclusion\n\nIn conclusion, lower haematological, neurological and haemorrhagic toxicity is found with the specific protocols. It is especially important to highlight the lower infection rate and milder profile with the current therapeutic regimens, which clearly benefit patients in many aspects of their daily life. In addition, they have longer EFS, which is an obvious long-term benefit. Therefore, this study has demonstrated a better safety profile of the newer regimens compared to H-CVAD and has now become the treatment of choice for many of our patients, confirming the great therapeutic advances in blood cancers in recent years [30]. Nevertheless, larger studies are necessary to confirm these results.\n\nFunding\n\nThe authors declare that they received no funding to carry out this study.\n\nConflicts of interest\n\nThe authors declare that they have no conflict of interest.\n\nAcknowledgments\n\nThe authors would like to thank Cristina Marín-Sánchez and Dr Jav Ahmad for the English version of the paper. For the Haematology Department of the Albacete University Hospital Complex, patients, relatives and all those who helped me with their support in this study.\n\nFigure 1. Comparison of febrile neutropenia between treatment groups.\n\nFigure 2. Comparison of EFS between treatment groups.\n\nImage 1. Bone marrow infiltration HE in MCL.\n\nImage 2. Bone marrow infiltration CD20(+) in MCL.\n\nImage 3. Bone marrow infiltration HE in BL.\n\nImage 4. Bone marrow infiltration PAX-5(+) in BL.\n\nTable 1. Patients and cycles received according to disorder and treatment regimen.\n\nDisorder\tTotal\tGroup A\nH-CVAD/MTX-AraC\n2002–10\tGroup B\nspecific regimens\n2011–18\t\nLCM\t22\npatients\t137\ncycles\t13\npatients\t75\ncycles\t9\npatients\t62\ncycles\t\nLB\t18\npatients\t89\ncycles\t8\npatients\t42\ncycles\t10\npatients\t47\ncycles\t\nLAL-B\t29\npatients\t143\ncycles\t14\npatients\t86\ncycles\t15\npatients\t57\ncycles\t\nLAL-T\t12\npatients\t84\ncycles\t7\npatients\t56\ncycles\t5\npatients\t28\ncycles\t\nTotal\t81\npatients\t453\ncycles\t42\npatients\t259\ncycles\t39\npatients\t194\ncycles\t\n\nTable 2. Patients groups according to disorder.\n\nDisorder\tGroup A\tGroup B\t\t\nN\t%\tN\t%\tp-value\t\n42\t100%\t39\t100%\t0.770\t\nLCM\t13\t31%\t9\t23.1%\t\t\nLB\t8\t19%\t10\t25.6%\t\t\nLAL-B\t14\t33.3%\t15\t35.8%\t\t\nLAL-T\t7\t16.7%\t2\t12.8%\t\t\n\nTable 3. Differences in haematological toxicity between the two treatment groups.\n\n\tGroup A\tGroup B\t\t\n\tN\t%\tN\t%\tp-value\t\nPatients\t42\t\t39\t\t\t\nNeutropenia\t42\t100.0%\t29\t74.4%\t<0.001\t\n- Grade III\t10\t23.8%\t13\t33.3%\t\n- Grade IV\t32\t76.2%\t16\t41.0%\t\nThrombocytopenia\t42\t100.0%\t20\t51.3%\t<0.001\t\n- Grade III\t22\t52.4%\t10\t25.6%\t\n- Grade IV\t20\t47.6%\t10\t25.6%\t\nAnaemia\t42\t100.0%\t27\t69.2%\t<0.001\t\n\nTable 4. Differences in non-haematological toxicity between the two treatment groups.\n\n\tGroup A\tGroup B\t\t\n\tN\t%\tN\t%\tp-value\t\nPatients\t42\t\t39\t\t\t\nHepatic toxicity\t9\t21.4%\t18\t46.2%\t0.033\t\n- Grade I\t1\t2.4%\t1\t2.6%\t\n- Grade II\t6\t14.3%\t13\t33.3%\t\n- Grade III\t1\t2.4%\t3\t7.7%\t\n- Grade IV\t1\t2.4%\t1\t2.6%\t\nHaemorrhagic toxicity\t10\t23.8%\t2\t5.1%\t0.027\t\n- Major bleeding\t3\t7.2%\t2\t0%\t\n- Minor bleeding\t7\t16.6%\t0\t5.1%\t\nNeurological toxicity\t6\t14.3%\t0\t0.0%\t0.026\t\n- Resting tremor Þ Vincristine suspension\t1\t2.4%\t0\t0.0%\t\n- Mild paresthesias (hands and feet)\t3\t7.2%\t0\t0.0%\t\n- Severe sensory motor neuropathy Þ Death\t2\t4.8%\t0\t0.0%\t\nDiarrhoea\t0\t0.0%\t4\t10.3%\t0.049\t\nMucositis\t3\t7.1%\t2\t5.1%\t0.999\t\n\nTable 5. Mean number of infectious processes and associated characteristics.\n\nInfections\tGroup A\tGroup B\t\t\n\tN\t%\tN\t%\tp-value\t\nPatients with some infectious process\t34\t81.0%\t29\t74.4%\t0.595\t\nTotal of infectious process\t154\t100%\t48\t100%\t<0.01\t\n- Mean per patient\t3.67\t\t1.23\t\t\n- Mean per cycle of treatment\t0.59\t\t0.25\t\t\nFebrile neutropenia\t106\t68.8%\t21\t43.7%\t<0.01\t\n- Mean per patient\t2.52\t\t0.54\t\t\n- Mean per cycle of treatment\t0.41\t\t0.11\t\t\nInfectious events Þ delay CT cycle\t23\t\t11\t\t<0.01\t\n- Mean per patient\t0.55\t\t0.28\t\t\n- Media per cycle of treatment\t0.09\t\t0.06\t\t\nTotal of days of admission due to infection\t968\t100%\t352\t100%\t<0.01\t\n- Mean per patient\t23\t\t9.0\t\t\n- Mean per cycle of treatment\t3.7\t\t1.8\t\t\nDeath from septic shock\t5\t11.9%\t1\t2.6%\t0.2\t\n\nTable 6. EFS between treatment groups.\n\n\tGroup A\tGroup B\t\t\nEst.\t95% CI\tEst.\t95% CI\tp-value\t\nEFS\t\n- At 2 years\t33%\t21%-48%\t79%\t64%-89%\t<0.001\t\n- At 5 years\t24%\t13%-39%\t69%\t54%-81%\t<0.001\n==== Refs\nReferences\n\n1. Sanz M Carreras E Rovira M Manual Práctico de Hematología Clínica 2019 6th Barcelona Ediciones Escofet Zamora SL\n2. Chu E Devita VT Physician´s cancer chemotherapy drug manual 2019\n3. Mathisen MS Kantarjian HM Jabbour EJ Emerging drugs for acute lymphocytic leukemia Expert Opin Emerg Drugs 2014 19 1 37 50 10.1517/14728214.2014.872629 24354521\n4. Romaguera JE Fayad LE Feng L Ten-year follow-up after intense chemoimmunotherapy with rituximab-HyperCVAD alternating with rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma Br J Haematol 2010 150 2 200 208 20528872\n5. Thomas DA Kantarjian HM Faderl S Hyper-CVAD and rituximab for de novo Burkitt lymphoma/leukemia Blood 2011 118 21 2698 10.1182/blood.V118.21.2698.2698\n6. Thomas DA O’Brien S Faderl S Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia J Clin Oncol 2010 28 24 3880 3889 10.1200/JCO.2009.26.9456 20660823\n7. Kantarjian HM O’Brien S Smith TL Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia J Clin Oncol 2000 18 3 547 561 10.1200/JCO.2000.18.3.547 10653870\n8. Fayad L Thomas D Romaguera J Update of the M. D. Anderson cancer center experience with hyper-CVAD and rituximab for the treatment of mantle cell and Burkitt-type lymphomas Clin Lymphoma Myeloma 2007 8 Suppl. 2 57 62 10.3816/CLM.2007.s.034\n9. De Guibert S Jaccard A Bernard M Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma Haematologica 2006 91 3 425 426 16531272\n10. Oriol A Ribera JM Berqua J High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients Cancer 2008 113 1 117 125 10.1002/cncr.23522 18457327\n11. Litzow MR Pharmacotherapeutic advances in the treatment of acute lymphoblastic leukaemia in adults Drugs 2011 71 415 442 21395356\n12. Delarue R Haioun C Ribrag V CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte Blood 2013 121 1 48 53 10.1182/blood-2011-09-370320 22718839\n13. Ribera JM García O Grande C Dose-intensive chemotherapy including rituximab in Burkitt’s leukemia or lymphoma regardless of human immunodeficiency virus infection status: final results of a phase 2 study (Burkimab) Cancer 2013 119 9 1660 1668 10.1002/cncr.27918 23361927\n14. Ribera JM Oriol A Morgades M Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial J Clin Oncol 2014 32 15 1595 1604 10.1200/JCO.2013.52.2425 24752047\n15. Ribera JM Morgades M Ciudad J Post-remission treatment with chemotherapy or allogeneic hematopoietic stem cell transplantation (alloHSCT) of high-risk (HR) Philadelphia chromosome-negative (Ph-neg) adult acute lymphoblastic leukemia (ALL) according to minimal residual disease (MRD) preliminary results of the pethema ALL-HR-11 trial Blood 2015 126 1333 10.1182/blood.V126.23.1333.1333\n16. Gill S Lane SW Crawford J Prolonged haematological toxicity from the hyper-CVAD regimen: manifestations, frequency, and natural history in a cohort of 125 consecutive patients Ann Hematol 2008 87 9 727 734 10.1007/s00277-008-0488-6 18401583\n17. García Rodríguez JA Gobernado M Gomis M Guía clínica para la evaluación y el tratamiento del paciente neutropénico con fiebre Rev Esp Quimoter 2001 14 1 75 83\n18. Díaz-Pedroche C Salavert M Aguado JM Evaluación individualizada del riesgo de infecciones en el paciente oncohematológico Rev Esp Quimioter 2006 19 2 117 129 16964329\n19. Erkut N Akidan O Selim Batur D Comparison between Hyper-CVAD and PETHEMA ALL-93 in adult acute lymphoblastic leukemia: a single-center study Chemotherapy 2018 63 4 207 213 10.1159/000492531 30304722\n20. Ribera JM Oriol A Bethencourt C Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial Haematologica 2005 90 10 1346 1356 16219571\n21. Ribera JM Montesinos P Subirá M Pautas de quimioterapia en hemopatías malignas 2017 7th Barcelona Ambos Marketing Services SL\n22. Kuderer N Dale DC Crawford J Impact of primary prophylaxis with granulocyte colony stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review J Clin Oncol 2007 25 21 3158 3167 10.1200/JCO.2006.08.8823 17634496\n23. Gokbuget N Baumann A Beck J PEG-asparaginase intensification in adult acute lymphoblastic leukemia (ALL): significant improvement of outcome with moderate increase of liver toxicity in the German Multicenter Study Group for Adult ALL (GMALL) Study 07/2003 Blood 2010 116 21 494 10.1182/blood.V116.21.494.494\n24. Earl M Incidence and management of asparaginase–associated adverse events in patients with acute lymphoblastic leukemia Clin Adv Hematol Oncol 2009 7 9 600 606 20020672\n25. Nesher L Rolston KV The current spectrum of infection in cancer patients with chemotherapy related neutropenia Infection 2014 42 1 5 13 10.1007/s15010-013-0525-9 23975584\n26. Crawford J Dale DC Lyman GH Chemotherapy induced neutropenia: risks, consequences, and new directions for its management Cancer 2004 100 2 228 237 10.1002/cncr.11882 14716755\n27. De Naurois J Novitzky-Basso I Gill MJ Management of febrile neutropenia: ESMO clinical practice guidelines Ann Oncol 2010 27 Suppl 5 252 256 10.1093/annonc/mdq196\n28. Terol M López S Rodríguez J Diferencias en la calidad de vida: un estudio longitudinal de pacientes de cáncer recibiendo tratamiento de quimioterapia Anales de Psicología 2000 16 2 111 122\n29. Kuderer NM Dale DC Crawford J Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients Cancer 2006 106 10 2258 2266 10.1002/cncr.21847 16575919\n\n", "fulltext_license": "CC BY", "issn_linking": "1754-6605", "issue": "15()", "journal": "Ecancermedicalscience", "keywords": "blood cancers; infections; toxicity", "medline_ta": "Ecancermedicalscience", "mesh_terms": null, "nlm_unique_id": "101392236", "other_id": null, "pages": "1206", "pmc": null, "pmid": "33912231", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "24752047;30304722;11376354;20020672;14716755;22718839;18284717;20528872;16531272;21395356;16219571;18457327;17634496;23361927;23975584;24354521;20555092;10653870;16964329;16575919;20660823;18401583", "title": "Comparison in safety of chemotherapy protocols for blood cancers: toxicity of H-CVAD versus GELA/BURKIMAB/PETHEMA LAL.", "title_normalized": "comparison in safety of chemotherapy protocols for blood cancers toxicity of h cvad versus gela burkimab pethema lal" }

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], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARIN?SANCHEZ, A.. COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. ECANCERMEDICALSCIENCE. 2021?15:10.3332/ECANCER.2021.1206", "literaturereference_normalized": "comparison in safety of chemotherapy protocols for blood cancers toxicity of h cvad versus gela burkimab pethema lal", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210625", "receivedate": "20210625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19463265, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" }, { "companynumb": "ES-PFIZER INC-2021488323", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHOTREXATE 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"DOXORUBICIN HCL" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "MARIN?SANCHEZ, A.. COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. 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SODIUM" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHOTREXATE SODIUM." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN HCL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOLOGICAL MALIGNANCY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, 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"patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Septic shock", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MARIN?SANCHEZ, A.. COMPARISON IN SAFETY OF CHEMOTHERAPY PROTOCOLS FOR BLOOD CANCERS: TOXICITY OF H?CVAD VERSUS GELA/BURKIMAB/PETHEMA LAL. ECANCERMEDICALSCIENCE. 2021?15:10.3332/ECANCER.2021.1206", "literaturereference_normalized": "comparison in safety of chemotherapy protocols for blood cancers toxicity of h cvad versus gela burkimab pethema lal", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20210625", "receivedate": "20210625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19463263, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "Histoplasma capsulatum is an environmental fungus commonly found in the Ohio and Mississippi River valleys, Central and South America, and Asia. The most affected areas in Argentina are the Paraná and de La Plata river basins. Patients with histoplasmosis can have a wide range of clinical presentations. Most of them are asymptomatic, while those with compromised cellular immunity are at increased risk for the disseminated form. We present the case of a patient undergoing treatment with methotrexate for seronegative arthritis who developed the disseminated form of the disease, and who represented a diagnostic challenge due to the difficulty in identifying the etiologic agent.", "affiliations": "Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina. E-mail: [email protected].;Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Servicio de Infectología, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Departamento de Patología, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.;Departamento de Medicina, VI Cátedra de Medicina Interna, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Argentina.", "authors": "Vega|Patricia|P|;Aguilar|Andrea|A|;Barahona Rojas|Janeth|J|;Sierra|Mariela|M|;Von Stecher|Florencia|F|;Pisarevsky|Ana Andrea|AA|", "chemical_list": "D008727:Methotrexate", "country": "Argentina", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0025-7680", "issue": "81(4)", "journal": "Medicina", "keywords": "disseminated histoplasmosis; methotrexate", "medline_ta": "Medicina (B Aires)", "mesh_terms": "D001118:Argentina; D001168:Arthritis; D005260:Female; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D008727:Methotrexate", "nlm_unique_id": "0204271", "other_id": null, "pages": "641-644", "pmc": null, "pmid": "34453808", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": null, "title": "Disseminated histoplasmosis in a woman with seronegative arthritis.", "title_normalized": "disseminated histoplasmosis in a woman with seronegative arthritis" }

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{ "abstract": "We present a case of endobronchial fusariosis following bilateral sequential lung transplantation for idiopathic pulmonary arterial hypertension in a 13 years old boy who was treated successfully with posaconazole and nebulized amphotericin B. We discuss the role of nebulized amphotericin B in treating invasive pulmonary fungal disease in children. To our knowledge, this is the first pediatric case of endobronchial fusariosis reported in the literature.", "affiliations": "Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Infectious Diseases Department, Alfred Health and Monash University, Melbourne, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.;Lung Transplant Service, Alfred Hospital, Melbourne, Australia.;Discipline of Child and Adolescent Health, The University of Sydney, Australia.;Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australia.", "authors": "Al Yazidi|Laila S|LS|;Huynh|Julie|J|;Britton|Philip N|PN|;Morrissey|C Orla|CO|;Lai|Tony|T|;Westall|Glen P|GP|;Selvadurai|Hiran|H|;Kesson|Alison|A|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.mmcr.2019.01.002", "fulltext": "\n==== Front\nMed Mycol Case RepMed Mycol Case RepMedical Mycology Case Reports2211-7539Elsevier S2211-7539(18)30132-510.1016/j.mmcr.2019.01.002Case ReportEndobronchial fusariosis in a child following bilateral lung transplant Al Yazidi Laila S. [email protected]⁎Huynh Julie [email protected] Philip N. [email protected] C. Orla [email protected] Tony [email protected] Glen P. [email protected] Hiran [email protected] Alison adea Infectious Diseases and Microbiology, The Children's Hospital at Westmead, Sydney, Australiab The School of Women's and Children's Health, University of New South Wales, New South Wales, Australiac Sultan Qaboos University, College of Medicine, Muscat, Omand Discipline of Child and Adolescent Health, The University of Sydney, Australiae Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Australiaf Infectious Diseases Department, Alfred Health and Monash University, Melbourne, Australiag Lung Transplant Service, Alfred Hospital, Melbourne, Australiah Department of Respiratory Medicine, The Children's Hospital at Westmead, Sydney, Australia⁎ Corrosponding author. [email protected] 1 2019 3 2019 14 1 2019 23 77 80 7 11 2018 8 1 2019 11 1 2019 © 2019 Published by Elsevier B.V. on behalf of International Society for Human and Animal Mycology.2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present a case of endobronchial fusariosis following bilateral sequential lung transplantation for idiopathic pulmonary arterial hypertension in a 13 years old boy who was treated successfully with posaconazole and nebulized amphotericin B. We discuss the role of nebulized amphotericin B in treating invasive pulmonary fungal disease in children. To our knowledge, this is the first pediatric case of endobronchial fusariosis reported in the literature.\n\nKeywords\nEndobronchialFusariosisLung transplantationNebulized amphotericinPediatric\n==== Body\n1 Introduction\nInvasive fungal disease (IFD) causes significant morbidity and mortality in the lung transplant population; however, the epidemiologic data in children have been sparse with a variable prevalence reported as ranging from 0% to 20%. Aspergillus and Candida infections are the most common infections in children following lung transplantation. Endobronchial fuseriosis is very rare. To our knowledge, this is the first pediatric case of endobronchial fusariosis reported in the literature.\n\n2 Case\nA 13 year old boy underwent bilateral sequential lung transplantation in July 2016 for idiopathic pulmonary arterial hypertension diagnosed 2 years earlier. At routine surveillance bronchoscopy few weeks post-transplantation, Aspergillus species was grown from a bronchoalveolar lavage (BAL) sample. There was no evidence of radiological or endobronchial changes and treatment with posaconazole modified release tablet was started as a prophylaxis (100 mg daily). Routine post-transplant immunosuppression regimen included tacrolimus (2 mg daily), mycophenolate mofetil (MMF) (250 mg twice daily) and prednisolone (0.3 mg/kg daily). Post-transplantation course was also complicated by steroid-induced diabetes mellitus (DM), stenosis of left main bronchial anastomosis and drug-induced neutropenia likely related to trimethoprim-sulphamethoxazole, and valganciclovir administered for Pneumocystis jirovecii and cytomegalovirus (CMV) prophylaxis, respectively. CMV reactivation eight-month post-transplantation (while on valaciclovir) was treated with two weeks of intravenous ganciclovir (5 mg/kg bd) and then valganciclovir (450 mg daily) as maintenance therapy.\n\nA surveillance bronchoscopy one month later (nine months post-lung transplantation) revealed white plaques at the left main bronchus anastomotic site and this was defined as day 0. (Fig. 1) Broncho-alveolar lavage (BAL) washings revealed fungal elements on cytology and Fusarium species grew on Sabouraud agar. Clinically, the patient was asymptomatic but severely neutropenic (count of 0.0 × 109/L). His trough posaconazole level was 0.91 mg/L. Given the risk of anastomotic breakdown and consequent disseminated fusariosis in a severely neutropenic patient, we increased the posaconazole dose to 300 mg daily whilst awaiting antifungal susceptibility results. We aimed for a trough level of posaconazole of > 2 mg/L. The patient was also commenced on daily granulocyte-colony stimulating factor (G-CSF) and trimethoprim-sulphamethoxazole was changed to atovaquone/proguanil to reverse the neutropenia. Histopathology revealed changes suggestive of early rejection (A1B1), so we were unable to reduce the immunosuppression any further. The isolate was later identified as Fusarium mundagurra using DNA sequencing (Plant Pathology Unit, Royal Botanic Gardens Sydney). Drug susceptibility testing was performed using Sensititre™ YeastOne™ (CLSI-compatible) at the Mycology Reference Laboratory at the Royal North Shore Hospital, New South Wales, Australia and showed minimum inhibitory concentrations of 1 mg/L for amphotericin B, posaconazole and voriconazole, ≥ 8 mg/L for the echinocandin class.Fig. 1 Photo of the endo-bronchial white plaque seen at the lower left lobe anastomotic site during a surveillance bronchoscopy.\n\nFig. 1\n\nFive weeks later, the patient remained asymptomatic, had stable lung function, was mildly neutropenic (0.8 × 109/L) and his posaconazole trough level was 2.3 mg/L. His chest computed tomography (CT) demonstrated progressive focal stenosis of the distal left main-stem bronchial anastomotic site. There were no features suggestive of lung parenchymal fungal disease and blood cultures remained sterile. Follow-up bronchoscopy demonstrated persistent white plaques at the anastomotic site; but now there was also evidence of bleeding from the friable endobronchial surface and displacement of the staple/suture suggestive of some anastomotic dehiscence. A trans-bronchial biopsy yielded inadequate tissue to assess for fungal invasion. Fusarium mundagurra grew again from BAL sample and the antifungal susceptibility testing showed increased MICs; 8 mg/L to amphotericin B and 2 mg/L to both posaconazole and voriconazole. Given the progression of endobronchial disease, posaconazole dosing was increased to 500 mg daily to achieve a target area under the concentration-time curve over MIC (AUC/MIC) ratio of > 100 (trough level > 3.8 mg/L) and nebulized liposomal amphotericin B (Ambisome) 25 mg thrice weekly was added. The patient initially developed cough and bronchospasm with nebulized liposomal amphotericin B; however, this was successfully managed with salbutamol pre-treatment. Whilst Fusarium mundagurra was grown again from a BAL sample taken two months post-commencement of dual antifungal therapy; subsequent BAL samples were culture negative at the 5 and 8 month mark. Eight months from commencing nebulized amphotericin B and increased posaconazole dose the surveillance bronchoscopy showed no evidence of white plaques and the anastomotic site looked healthy. In addition, his neutrophil count had recovered to > 1.0 × 109/L three months post commencement of G-CSF and so the dose was reduced to thrice weekly. Seventh month post commencement of G-CSF the patient was able to maintain a neutrophil count above 2 × 109/L, and so the GCSF ceased. He is being monitored closely for potential recrudescence and is continuing on the same antifungal regimen indefinitely. His progress is summarised in Fig. 2.Fig. 2 Summary of the patient BAL cultures and the antifungal agents used for treatment during the course of his disease. LTx: lung transplantation; D: day, L-AMP B: liposomal amphotericin B; Plus. Sign (+): Growth in BAL culture; Minus sign (-): no growth. D0: 1st day when the fusarium grew from the BAL.\n\nFig. 2\n\n3 Discussion\nInvasive fungal disease (IFD) causes significant morbidity and mortality in the lung transplant population; however, the epidemiologic data in children have been sparse with a variable prevalence reported as ranging from 0% to 20% [1]. Aspergillus and Candida species are the most common causes of IFD in this setting; however, endobronchial fusariosis following lung transplantation has rarely been reported [1], [2]. There are only 10 cases of endobronchial fusarosis reported in the adult lung transplant population with a 70% mortality rate [2], [3]. Here, we present the first pediatric case of endobronchial fusariosis that was successfully eradicated. Disseminated fusariosis usually occurs in immunocompromised patients with severe and persistent neutropenia; however, one third (3/10) of the reported adult cases of endobronchial fusariosis post lung-transplantation developed disseminated fusariosis in the setting of normal neutrophil counts [2]. Overall, outcome of fusariosis in immunocompromised patients appears proportional to the ongoing level of immunosuppression [4]. Factors that have been associated with increased mortality include disseminated infection, persistent neutropenia and corticosteroid use [2], [4].\n\nFusarium mundagarra is one of six novel species of Fusarium isolated from natural ecosystems in Australia in the last few years. Carnarvon Gorge is the geographic origin of the first recognized isolate in central Queensland, Australia. It is considered as a part of the Fusarium redolens species complex [5]. There are no clinical antifungal breakpoints or epidemiological cut-off values to guide therapy for this species [6].\n\nManagement of fusariosis in immunocompromised patients can be challenging given the intrinsic resistance of Fusarium species to most antifungal agents [4]. In vitro susceptibility testing has shown intrinsic resistance to fluconazole, itraconazole and the echinocandin class, while susceptibility to amphotericin B, voriconazole and posaconazole is unpredictable [4]. Despite the early diagnosis, invasive fusariosis is associated with high morbidity and up to 70% mortality [4]. There are no comparative studies to compare clinical efficacy with the in vitro susceptibility of different antifungal agents for treatment of Fusarium species. The current recommendations in lung transplant recipients are voriconazole or liposomal amphotericin B as first-line therapy and posaconazole for refractory disease [2], [4]. Antifungal combination for fusariosis has not been evaluated either in animal models or in humans [4]. From first principles, antifungal therapy should be combined with surgical resection where possible and reduction of immunosuppression when possible [4]. Antifungal choice should take into account the known characteristics of the fungal isolate, in vitro susceptibility results and host-specific factors [4]. Our patient was on posaconazole for Aspergillus colonization and he was tolerating it very well. We optimized the dose of posaconazole according to the AUC/MIC ratio to maximize time dependent killing. In vitro and In vivo modelling studies have indicated that that the AUC/MIC is the pharmacokinetic/dynamic target for posaconazole treatment response; however studies looking at this relationship is limited to Aspergillus and Mucorales infections where the target is defined as > 100 [7], [8]. Nebulized liposomal amphotericin B (Ambisome) was added when the patient didn’t show any signs of improvement. His tacrolimus dose was reduced when possible, and G-CSF was given to reverse the severe neutropenia.\n\nThere is convincing evidence for using nebulized amphotericin B for IFD prophylaxis in adult lung transplant recipients but very little evidence for its use for IFD treatment [1], [9], [10]. A 10 year observational study showed significant reduction of Aspergillus species colonization and infection among lung-transplant recipients receiving prophylactic nebulized liposomal amphotericin B [9]. Several comparative studies showed no significant differences between deoxycholate and lipid formulation of amphotericin in reducing the incidence of IA, when used as single agents [10], [11]. Although it has been a widely studied agent for antifungal prophylaxis, the optimal dosages, formulations, and duration of therapy remains undetermined [10]. Studies using daily administration of amphotericin B products for short durations (up to 2 weeks) followed weekly or fortnightly for 1–3 months have generally proved to be successful as prophylaxis [10]. Studies showed that inhaled deoxycholate (conventional) amphotericin B achieves high concentrations in the lower airway of transplanted lungs, but concentration at the anastomotic sites and in the native lung are lower [10]. The concentration of inhaled amphotericin B (in BAL aliquots) and amphotericin B lipid complex (measured in epithelial lining fluid) remained above the generally reported MIC of Aspergillus for at least 7 days which enables once-weekly administration [10], [12].\n\nThe limitation of this route of administration is that it does not protect against extra-pulmonary infections, especially early post-operative pleural space infection with Candida species. In addition, emerging species with reduced amphotericin susceptibility in lung transplant recipients on lifetime nebulized amphotericin B prophylaxis has been reported [9]. Systemic absorption of nebulized amphotericin B is minimal and quite safe compared with systemic antifungal therapy; however, it can cause cough, dyspnea, bronchospasm, wheezing and nausea in a small proportion which may affect compliance [10], [12]. A recent retrospective study comparing adverse events of the inhaled deoxylate with lipid formulations of amphotericin B observed no difference in the rates of adverse events concluding that both the nebulized deoxycholate and lipid (Abelcet) amphotericin B can be safely used [13].\n\nAlthough there has been increased use of nebulized amphotericin B (both deoxycholate and lipid formulations) in children for IFD prophylaxis in the lung-transplantation setting, there are still limited data on its efficacy and safety in children. An international multicenter survey of antifungal prophylaxis in pediatric lung transplantation reported that most centers use either voriconazole or nebulized amphotericin B as a mono-therapy for IFD prophylaxis [14]; however, the updated international guidelines [1] could not give any recommendations for effective, safe anti-fungal prophylaxis in children and no specific recommendations were made regarding nAmB given the absence of published data.\n\nIn regards to using nebulized amphotericin B for treatment of IFD in lung transplant recipients, the updated guidelines from the International Society for Heart and Lung Transplantation for management of fungal infections recommend azole therapy, with therapeutic drug monitoring to ensure maximal efficacy, as a primary monotherapy for Aspergillus endobronchial fungal infections but did not give any specific recommendations for the addition of nebulized amphotericin B to the standard azole regimens for treatment of pulmonary fungal infections [1]. Evidence for an additive benefit of nebulized amphotericin B in the treatment of invasive aspergillosis is limited however; nebulized amphotericin B could be used in combination with systemic anti-fungal drugs, depending on the severity of IFD, or possibly in situations in which large cavitary lesions might render the penetration of systemic agents difficult [1]. There is a single case report of a complex airway infection involving an endobronchial prosthesis that was treated with a combination of systemic voriconazole and nebulized amphotericin [1]. There are not enough published data to give any specific recommendations for using nebulized amphotericin B in the treatment of IFD in children following lung transplantation [1].\n\nAlthough our patient showed clinical improvement after adding nebulized liposomal amphotericin, we are not certain that adjunctive nebulized amphotericin contributed to bronchoscopic and microbiological cure above the optimal posaconazole therapy and reduced immunosuppression. It is also possible that fusarium mundagarra is a less virulent species compared to the more well-known fusarium solani. There is, however, an argument in our case that given the high rates of dissemination following endobronchial fusariosis in lung transplant recipients, nebulized amphotericin in addition to a systemic anti-fungal agent was at least able to contain the infection until some level of immune reconstitution could be achieved. This case suggests that adjunctive nebulized amphotericin should be considered in similar cases where there is slow response to or progress on systemic antifungal therapy.\n\nIn conclusion, Fusarium species are an important but uncommon pathogen post-lung transplantation with a potentially high mortality rate. Treatment is difficult because of high levels of intrinsic resistance of Fusarium species to many antifungal agents and reduction of immunosuppression is essential for achieving a good outcome. Multicenter, observational studies and randomized trials are needed to ascertain the optimal prophylactic and therapeutic strategies for fungal infections in pediatric lung transplant recipients [10].\n\nAcknowledgements\nThe Mycology Reference Laboratory at the Royal North Shore Hospital who helped with identification of the clinical isolates and with the anti-fungal susceptibility.\n\nConflict of interest\nNone to declare.\n\nFunding source\nNone.\n==== Refs\nReferences\n1 Husain S. Sole A. Alexander B.D. Aslam S. Avery R. Benden C. The 2015 International Society for heart and lung transplantation guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: executive summary J. Heart Lung Transplant. 35 3 2016 261 282 26970469 \n2 Carneiro H.A. Coleman J.J. Restrepo A. Mylonakis E. Fusarium infection in lung transplant patients: report of 6 cases and review of the literature Medicine 90 1 2011 69 80 21200188 \n3 Terasaki J. Shah S. Schnadig V. Valentine V. Airway complication contributing to disseminated fuseriosis after lung transplantation Transpl. Infect. Dis. 16 2014 621 624 24890670 \n4 Al-Hatmi A.M.S. Bonifaz A. Ranque S. Sybren de Hoog G. Verweij P.E. Meis J.F. Current antifungal treatment of fusariosis Int. J. Antimicrob. Agents 51 3 2018 326 332 28705676 \n5 Laurence M. Walsh J. Shuttleworth L. Robinson D. Johansen R. Petrovic T. Six novel species of Fusarium from natural ecosystems in Australia Fungal Divers. 77 2016 349 366 \n6 Espinel-Ingroff A. Colombo A. Cordoba S. Dufresne P. Fuller J. Ghannoum M. Evaluation of MIC distributions and epidemiological Cutoff value (ECV) Definitions for Fusarium species identified by Molecular methods for the CLSI Broth Microdilution method Antimicrob. Agents Chemother. 60 2 2015 1079 1084 26643334 \n7 Dekkers B.G.J.B.M. van der Elst K.C.M. Sturkenboom M.G.G. Veringa A. Span L.F.R. Therapeutic drug monitoring of Posaconazole: an update Curr. Fungal Infect. Rep. 10 2 2016 51 61 27358662 \n8 Lewis R.E.A.N. Kontoyiannis D.P. Comparative pharmacodynamics of posaconazole in neutropenic murine models of invasive pulmonary aspergillosis and mucormycosis Antimicrob. Agents Chemother. 58 11 2014 6767 6772 25182639 \n9 Peghin M. Monforte V. Martin‐Gomez M.T. Ruiz‐Camps I. Berastegui C. Saez B. 10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation Transplant. Int. 29 2016 51 62 \n10 Patel T.S. Eschenauer G.A. Stuckey L.J. Carver P.L. Antifungal prophylaxis in lung transplant recipients Transplantation 100 9 2016 1815 1826 26950711 \n11 Drew R. Dodds A. Benjamin D. Duane D. Palmer S. Perfect J. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients Transplantation 77 2 2004 232 237 14742987 \n12 Husain S. Capitano B. Corcoran T. Studer S.M. Crespo M. Johnson B. Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients Transplantation 90 11 2010 1215 1219 20881664 \n13 Lowry C. Marty F. Vargas S. Lee J. Fiumara K. Deykin A. Safety of aerosolized liposomal versus deoxycholate amphotericin B formulations for prevention of invasive fungal infections following lung transplantation: a retrospective study Transpl. Infect. Dis. 9 2 2007 121 125 17461997 \n14 Mead L. Danziger-Isakov L. Michaels M. Goldfarb S. Glanville A. Benden C. Antifungal prophylaxis in pediatric lung transplantation: an international multicenter survey Pediatr. Transplant. 18 4 2014 393 397 24802346\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-7539", "issue": "23()", "journal": "Medical mycology case reports", "keywords": "Endobronchial; Fusariosis; Lung transplantation; Nebulized amphotericin; Pediatric", "medline_ta": "Med Mycol Case Rep", "mesh_terms": null, "nlm_unique_id": "101598259", "other_id": null, "pages": "77-80", "pmc": null, "pmid": "30723665", "pubdate": "2019-03", "publication_types": "D002363:Case Reports", "references": "14742987;17461997;20881664;21200188;24802346;24890670;25182639;26339864;26643334;26950711;26970469;27358662;28705676", "title": "Endobronchial fusariosis in a child following bilateral lung transplant.", "title_normalized": "endobronchial fusariosis in a child following bilateral lung transplant" }

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ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. MEDICAL MYCOLOGY CASE REPORTS. 2019?23:77-80", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190205", "receivedate": "20190205", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15921114, "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": "PHHY2019AU030609", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "017469", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MG/KG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. MEDICAL MYCOLOGY CASE REPORTS. 2019?23:77-80", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190211", "receivedate": "20190211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15948077, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "AU-APOTEX-2019AP007606", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM SULFAMETHOXAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "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": "VALGANCICLOVIR." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "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": "VALACICLOVIR" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "090419", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MG, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS AGAINST TRANSPLANT REJECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MG/KG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspergillus test positive", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bronchitis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP, SELVADURAI H, KESSON A. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. DOI: 10.1016/J.MMCR.2019.01.002. MEDICAL MYCOLOGY CASE REPORTS. 2019?23:77-80", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190213", "receivedate": "20190213", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15955230, "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": "AU-ACCORD-107622", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "4", "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": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "065416", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "FILM-COATED TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLIC ACID." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MG/KG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR/VALGANCICLOVIR HYDROCHLORIDE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "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": "SULFAMETHOXAZOLE/TRIMETHOPRIM" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bronchostenosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. MEDICAL MYCOLOGY CASE REPORTS. 2019?23:77-80", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190219", "receivedate": "20190219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15979870, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "AU-BAUSCH-BL-2019-004194", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75250", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "DOSE REDUCED", "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": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE, TRIMETHOPRIM" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "75250", "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": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "MODIFIED-RELEASE TABLET", "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, 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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "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": "VALGANCICLOVIR." } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "AL YAZIDI L, HUYNH J, BRITTON P, MORRISSEY C, LAI T, WESTALL G. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. MEDICAL MYCOLOGY CASE REPORTS. 2019?23:77-80.", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "1", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190214", "receivedate": "20190214", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15963365, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20190417" }, { "companynumb": "PHHY2019AU030553", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", 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"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": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIVIRAL PROPHYLAXIS", 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null, "drugseparatedosagenumb": "1", "drugstartdate": "2016", "drugstartdateformat": "602", "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "65461", "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": "4", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "MODIFIED RELEASE TABLET", "drugdosagetext": "100 MG, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Bronchial anastomosis complication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Steroid diabetes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2017" } }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. 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"drugauthorizationnumb": "090596", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "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": "0.3 MILLIGRAM/KILOGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMPHOTERICIN B" }, "drugadditional": "3", "drugadministrationroute": "055", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "THRICE WEEKLY", "drugenddate": null, "drugenddateformat": null, "drugindication": "FUSARIUM 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"drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "AS MAINTENANCE THERAPY.", "drugenddate": null, "drugenddateformat": null, "drugindication": "CYTOMEGALOVIRUS INFECTION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ATOVAQUONE\\PROGUANIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEUTROPENIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ATOVAQUONE/PROGUANIL" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Bronchospasm", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Steroid diabetes", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspergillus infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cough", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP, ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT. MED-MYCOL-CASE-REPORTS 2019?23:77-80.", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190225", "receivedate": "20190225", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16002433, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "AU-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-200114", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", "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": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "76588", "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": "VALACYCLOVIR" }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "300 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "300", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "250 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": "805", "drugintervaldosageunitnumb": "12", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "250", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TRIMETHOPRIM-SULPHAMETHOXAZOLE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALGANCICLOVIR" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "450 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "450", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VALGANCICLOVIR." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.3 MILLIGRAM/KILOGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": ".3", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." }, { "actiondrug": "3", "activesubstance": { "activesubstancename": "POSACONAZOLE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "100 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PROPHYLAXIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "100", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "POSACONAZOLE" } ], "patientagegroup": null, "patientonsetage": "13", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diabetes mellitus", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Fusarium infection", "reactionmeddraversionpt": "21.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AL YAZIDI LS, HUYNH J, BRITTON PN, MORRISSEY CO, LAI T, WESTALL GP, ET AL. ENDOBRONCHIAL FUSARIOSIS IN A CHILD FOLLOWING BILATERAL LUNG TRANSPLANT.. MED MYCOL CASE REPORTS. 2019?JAN 23 (9):77-80", "literaturereference_normalized": "endobronchial fusariosis in a child following bilateral lung transplant", "qualification": "3", "reportercountry": "AU" }, "primarysourcecountry": "AU", "receiptdate": "20190228", "receivedate": "20190228", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16016123, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" } ]

{ "abstract": "Crizotinib is an oral small-molecule inhibitor of anaplastic lymphoma kinase (ALK) tyrosine-kinase that has been approved for treating patients with advanced echinoderm microtubule associated protein like 4-ALK rearranged non-small-cell lung cancer (NSCLC). Toxic epidermal necrolysis (TEN) is a rare adverse event associated with crizotinib. The present study reported a case of a 75-year-old Chinese male patient with advanced NSCLC with ALK fusion, who developed TEN after 56 days of crizotinib treatment and demised due to this dermatological adverse event. The occurrence of severe cutaneous necrolysis that predominantly involves the skin and mucous membranes during crizotinib treatment should alert clinicians to be aware of TEN and take prompt actions.", "affiliations": "Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Dermatology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Dermatology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.;Department of Medical Oncology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China.", "authors": "Yang|Shaoyu|S|;Wu|Liming|L|;Li|Xin|X|;Huang|Jie|J|;Zhong|Jianbo|J|;Chen|Xueqin|X|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2018.1553", "fulltext": null, "fulltext_license": null, "issn_linking": "2049-9450", "issue": "8(3)", "journal": "Molecular and clinical oncology", "keywords": "crizotinib; epidermal; necrolysis; non-small-cell lung cancer; toxic", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "457-459", "pmc": null, "pmid": "29456853", "pubdate": "2018-03", "publication_types": "D016428:Journal Article", "references": "28000240;24108082;28190531;28202399;15057820;23169500;17509004;23724913;25994067;27212422;23891512;27040849", "title": "Crizotinib-associated toxic epidermal necrolysis in an ALK-positive advanced NSCLC patient.", "title_normalized": "crizotinib associated toxic epidermal necrolysis in an alk positive advanced nsclc patient" }

[ { "companynumb": "CN-PFIZER INC-2017471842", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CRIZOTINIB" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202570", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "20160511", "drugstartdateformat": "102", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CRIZOTINIB" } ], "patientagegroup": null, "patientonsetage": "75", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Hepatic failure", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Oedema peripheral", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 2016" } }, "primarysource": { "literaturereference": "YANG, S.. CRIZOTINIB-ASSOCIATED TOXIC EPIDERMAL NECROLYSIS IN AN ALK-POSITIVE ADVANCED NSCLC PATIENT. MOLECULAR AND CLINICAL ONCOLOGY. 2018?8(3):457-459", "literaturereference_normalized": "crizotinib associated toxic epidermal necrolysis in an alk positive advanced nsclc patient", "qualification": "1", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20180208", "receivedate": "20171107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14165046, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20180508" } ]

{ "abstract": "We present a case of common challenges in assessment and treatment of substance use disorders in patients with advanced heart failure requiring left ventricular assist device (LVAD). Top experts in the field of consultation-liaison psychiatry, cardiology, and cardiac surgery provide guidance for this commonly encountered clinical case based on their experience and review of the available literature. Key teaching topics include the role of LVAD in heart failure management, the impact of substance use disorder on heart failure and LVAD patient outcomes, and recommendations for assessment and management of substance use disorder in a patient with LVAD. Specifically, we highlight the challenges of assessing for substance use disorder in LVAD candidates and the limited literature available to guide treatment in this challenging patient population.", "affiliations": "Division of Collaborative Care and Wellness, Department of Psychiatry, University of Rochester Medical Center, Rochester, NY. Electronic address: [email protected].;Division of Cardiology, Department of Medicine, University of Rochester Medical Center, Rochester, NY.;Division of Cardiac Surgery, Department of Surgery, University of Rochester Medical Center, Rochester, NY.;Department of Psychiatry, Yale University, New Haven, CT.;Division of Collaborative Care and Wellness, Department of Psychiatry, University of Rochester Medical Center, Rochester, NY.", "authors": "Choi|Joy|J|;Alexis|Jeffrey|J|;Gosev|Igor|I|;Zimbrean|Paula|P|;Nickels|Mark|M|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.jaclp.2021.07.015", "fulltext": null, "fulltext_license": null, "issn_linking": "2667-2960", "issue": "62(6)", "journal": "Journal of the Academy of Consultation-Liaison Psychiatry", "keywords": "heart failure; left ventricular assist device; substance use disorder; transplant", "medline_ta": "J Acad Consult Liaison Psychiatry", "mesh_terms": null, "nlm_unique_id": "101775059", "other_id": null, "pages": "568-576", "pmc": null, "pmid": "34391977", "pubdate": "2021", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device.", "title_normalized": "management of substance use disorders in a patient with left ventricular assist device" }

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Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac failure", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug dependence", "reactionmeddraversionpt": "24.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Body mass index increased", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Euphoric mood", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anxiety disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Insomnia", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Joy Choi, Jeffrey Alexis, Igor Gosev, Paula Zimbrean and Mark Nickels.. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device.. Journal of the Academy of Consultation-liaison Psychiatry.. 2021;62:568-576", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220324", "receivedate": "20220324", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20632248, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-MACLEODS PHARMACEUTICALS US LTD-MAC2022034975", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "203359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "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": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "203359", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, 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null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. Journal of the Academy of Consultation-Liaison Psychiatry. 2021;62(6):568-76", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220329", "receivedate": "20220329", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20646959, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220424" }, { "companynumb": "US-drreddys-SPO/USA/22/0147884", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077380", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077380", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "077380", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "205299", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. J Acad Consult Liaison Psychiatry. 2021;62(6):568-76. doi:10.1016/j.jaclp.2021.07.015", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220328", "receivedate": "20220322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20621049, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-MYLANLABS-2022M1044776", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "090323", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "090323", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Euphoric mood", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANNABIS SATIVA SUBSP. INDICA TOP" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROMORPHONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Psychotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Psychotherapy", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. J-Acad-Consult-Liaison-Psychiatry 2021;62(6):568-576.", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220615", "receivedate": "20220615", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20961852, "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" }, { "companynumb": "US-MLMSERVICE-20220310-3425696-1", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": "4", "drugadministrationroute": null, "drugauthorizationnumb": "202152", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "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": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device. Journal of the Academy of Consultation-Liaison Psychiatry. 2021;62(6):568-76.", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220323", "receivedate": "20220323", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20625045, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220423" }, { "companynumb": "US-MLMSERVICE-20220310-3425696-1", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "QUETIAPINE" }, 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"drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE\\NALOXONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": 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"drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": "34", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device power source issue", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Device malfunction", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M.. Management of Substance Use Disorders in a Patient With Left Ventricular Assist Device.. Journal of the Academy of Consultation-Liaison Psychiatry.. 2021;62(6)::568-576", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220623", "receivedate": "20220328", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20641325, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" }, { "companynumb": "US-MLMSERVICE-20220310-3425696-1", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201109", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Insomnia", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE FUMARATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201109", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Euphoric mood", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "QUETIAPINE FUMARATE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "CANNABIS SATIVA SUBSP. INDICA TOP" }, "drugadditional": "4", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CANNABIS SATIVA SUBSP. INDICA TOP" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROMORPHONE" }, "drugadditional": "4", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROMORPHONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHAMPHETAMINE" }, "drugadditional": "4", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHAMPHETAMINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUPRENORPHINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Substance use disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUPRENORPHINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BUSPIRONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BUSPIRONE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "Generalised anxiety disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ESCITALOPRAM OXALATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "Attention deficit hyperactivity disorder", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ESCITALOPRAM" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sedation", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "25.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "Choi J, Alexis J, Gosev I, Zimbrean P, Nickels M. Management of substance use disorders in a patient with left ventricular assist device. Journal of the Academy of Consultation-Liaison Psychiatry. 2021;62(6):568-576", "literaturereference_normalized": "management of substance use disorders in a patient with left ventricular assist device", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220617", "receivedate": "20220408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20688711, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": 2, "seriousnessdeath": 2, "seriousnessdisabling": 2, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 2, "seriousnessother": 1, "transmissiondate": "20220721" } ]

{ "abstract": "A 71-year-old man presented with ulcerating yellow-red plaques of the back, chest, face, and extremities (Figure 1). He had a 10-year history of these lesions. The initial plaque appeared on the back followed by rapid progression of multiple similar lesions involving the face, chest, abdomen, and extremities. The plaques on his face were predominately in the periorbital and eyelid regions. Skin biopsy revealed an ulcerated epidermis. Dense sheets of foamy histiocytes were present in the dermis and contained foci of necrobiosis. Numerous Touton giant cells were present and cholesterol clefts were prominent. Special stains for organisms were negative. On further laboratory evaluation, serum protein electrophoresis revealed a monoclonal spike of 0.5 g/dL IgG lambda. Results from bone marrow biopsy were negative. Other significant laboratory findings included an elevated sedimentation rate and low serum complement. Clinical findings, histopathology, and laboratory evaluations were consistent with the diagnosis of necrobiotic xanthogranuloma (NXG).", "affiliations": "University of Nebraska Medical Center, 2212 South 64th Plaza #401, Omaha, NE 68106, USA. [email protected]", "authors": "Sutton|Leigh|L|;Sutton|Stephanie|S|;Sutton|Margaret|M|", "chemical_list": "D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D007146:Immunoglobulin lambda-Chains; D017338:Cladribine", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1540-9740", "issue": "11(2)", "journal": "Skinmed", "keywords": null, "medline_ta": "Skinmed", "mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001706:Biopsy; D001797:Blood Protein Electrophoresis; D017338:Cladribine; D018450:Disease Progression; D006801:Humans; D007074:Immunoglobulin G; D007146:Immunoglobulin lambda-Chains; D008297:Male; D058252:Necrobiotic Xanthogranuloma; D016896:Treatment Outcome", "nlm_unique_id": "101168327", "other_id": null, "pages": "121-3", "pmc": null, "pmid": "23745232", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Treatment of necrobiotic xanthogranuloma with 2-chlorodeoxyadenosine.", "title_normalized": "treatment of necrobiotic xanthogranuloma with 2 chlorodeoxyadenosine" }

[ { "companynumb": "US-JNJFOC-20130712043", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DAYS 1, 2, 3, 4 AND 5 OF A 28 DAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "NECROBIOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "020229", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": "DAYS 1, 2, 3, 4 AND 5 OF A 28 DAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "XANTHOGRANULOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "2", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CLADRIBINE." } ], "patientagegroup": "6", "patientonsetage": "71", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "18.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SUTTON L, SUTTON S, SUTTON M. TREATMENT OF NECROBIOTIC XANTHOGRANULOMA WITH 2-CHLORODEOXYADENOSINE. SKINMED 2013;11 (2):121-123.", "literaturereference_normalized": "treatment of necrobiotic xanthogranuloma with 2 chlorodeoxyadenosine", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150717", "receivedate": "20150717", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11280214, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Androgen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer. Studies addressing the efficacy of different depot formulations of long acting luteinizing hormone releasing hormone agonists in the Brazilian population are lacking. We aimed to compare the efficacy of three schedules of leuprolide acetate in lowering PSA in a real world population.\n\n\n\nWe reviewed the medical records of patients with prostate cancer seen at our institution between January 2007 and July 2018. We analyzed patients treated with long-acting leuprolide acetate and grouped these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the serum prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels at baseline and at 6 and 12 months within each treatment stratum. We considered two-sided P values < 0.05 as statistically significant. We analyzed toxicity descriptively.\n\n\n\nWe analyzed a total of 932 patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Nearly half of the patients had locally advanced disease. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (P < 0.001 in all cases). Sexual impotence and hot flashes were the most frequently reported toxicities.\n\n\n\nTo our knowledge, this is the largest assessment of real-world data on alternative schedules of leuprolide in a Brazilian population. Our study suggests that PSA levels can be effectively be reduced in most patients treated with monthly, quarterly, or semiannual injections of long-acting leuprolide acetate.", "affiliations": "Hospital do Câncer de Muriaé, MG, Brasil.;Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil.", "authors": "de Freitas|Carla S M|CSM|;Soares|Aleida N|AN|", "chemical_list": "D000085:Acetates; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C493311:luprolide acetate gel depot; D017430:Prostate-Specific Antigen; D016729:Leuprolide", "country": "Brazil", "delete": false, "doi": "10.1590/S1677-5538.IBJU.2019.0212", "fulltext": "\n==== Front\nInt Braz J Urol\nInt Braz J Urol\nibju\nInternational Brazilian Journal of Urology : official journal of the Brazilian Society of Urology\n1677-5538 1677-6119 Sociedade Brasileira de Urologia \n\n32167701\nS1677-5538.IBJU.2019.0212\n10.1590/S1677-5538.IBJU.2019.0212\nOriginal Article\nEfficacy of Leuprorelide acetate (Eligard®) in daily practice in Brazil: a retrospective study with depot formulations in patients with prostate cancer\nhttp://orcid.org/0000-0002-9397-9777de Freitas Carla S. M. 1 Soares Aleida N. 2 \n1 \nHospital do Câncer de Muriaé\nMG\nBrasil\nHospital do Câncer de Muriaé, MG, Brasil\n\n\n2 \nInstituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte\nBelo HorizonteMG\nBrasil\nInstituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil\n\nCorrespondence address: Carla Simone Moreira de Freitas, MD, MSc Hospital do Câncer de Muriaé Av. Cristiano Ferreira Varella, 555, Universitário Muriaé, Minas Gerais, 36.880-000, Brasil. Fax: +55 32 3729-7000, E-mail: [email protected] OF INTEREST\n\nNone declared.\n\n\n20 2 2020 \nMay-Jun 2020 \n46 3 383 389\n29 3 2019 01 11 2019 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.ABSTRACT\nIntroduction:\nAndrogen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer. Studies addressing the efficacy of different depot formulations of long acting luteinizing hormone releasing hormone agonists in the Brazilian population are lacking. We aimed to compare the efficacy of three schedules of leuprolide acetate in lowering PSA in a real world population.\n\nMaterials and Methods:\nWe reviewed the medical records of patients with prostate cancer seen at our institution between January 2007 and July 2018. We analyzed patients treated with long-acting leuprolide acetate and grouped these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the serum prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels at baseline and at 6 and 12 months within each treatment stratum. We considered two-sided P values <0.05 as statistically significant. We analyzed toxicity descriptively.\n\nResults:\nWe analyzed a total of 932 patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Nearly half of the patients had locally advanced disease. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (P <0.001 in all cases). Sexual impotence and hot flashes were the most frequently reported toxicities.\n\nConclusion:\nTo our knowledge, this is the largest assessment of real-world data on alternative schedules of leuprolide in a Brazilian population. Our study suggests that PSA levels can be effectively be reduced in most patients treated with monthly, quarterly, or semiannual injections of long-acting leuprolide acetate.\n\nKeywords:\nProstatic Neoplasmsagonists [Subheading]Prostate-Specific Antigen\n==== Body\nINTRODUCTION\nAccording to GLOBOCAN, it is estimated that 1.276.106 men were diagnosed with prostate cancer worldwide in 2018, with an expect 6.3% increase in incidence for the year of 2020 (1-3). By the year 2030, the burden from prostate cancer in Central and South America is expected to nearly double as a result of population growth and aging, moreover, increased early detection and public awareness are likely to lead to further increase in incidence in this world region (4). In Brazil, prostate cancer is the most frequent non--cutaneous tumor and the second leading cause of death from cancer in men (5).\n\nGiven the androgen dependence that characterizes prostate cancer, androgen deprivation therapy plays a key role in distinct phases of the disease. Among patients with advanced disease, androgen deprivation is the mainstay of therapy for both hormone-sensitive and castration-resistant prostate cancer (6), with long-acting luteinizing-hormone-releasing hormone (LHRH) agonists being currently the main form of achieving androgen deprivation (7). Most patients treated with a LHRH agonist achieve castrate testosterone levels similar to those found after bilateral orchiectomy (8). As a result of testosterone suppression, disease control can be achieved in the majority of patients as indicated, for example, by decreased levels of prostate specific antigen (PSA). Clinical trials of different LHRH agonists have demonstrated the efficacy of these agents in different settings. In particular, the efficacy and safety of Eligard® (a depot formulation of leuprolide acetate for subcutaneous injection every 1, 3 or 6 months) have been assessed and confirmed in clinical trials (9, 10). However, such studies are often limited by strict selection criteria, and a need remains for “real-world” data collected in observational studies (9-14).\n\nOBJECTIVES\nIn the current study, we sought to investigate the efficacy of Eligard® used monthly, quarterly and semiannually, in a heterogeneous population of patients from routine clinical practice at the Muriaé Cancer Hospital, state of Minas Gerais, Brazil.\n\nMATERIALS AND METHODS\nStudy design and patient eligibility\nThe study protocol was reviewed and approved by the Institutional Ethics Committee, and written informed consent was waived due to the observational nature of the investigation. In this retrospective study, we reviewed the medical records of 932 patients with prostate cancer seen at our institution between January 2007 and July 2018. Given the observational nature of the study, diagnostic and treatment decisions, including the choice of androgen deprivation therapy, formulation and schedule, as well as use of concomitant medication, were at the discretion of the attending physicians.\n\nEligible patients were men with prostate cancer, aged ≥18 years old, and treated with Eligard® (henceforward referred to as androgen de-privation) at some point during the study period. We included in this study all the patients who had baseline serum PSA results. We grouped patients into three separate strata according to the administration of androgen deprivation therapy every 1, 3 or 6 months.\n\nData collection, outcomes of interest, and statistical analysis\nWe collected data on demographic patient characteristics, features of prostate cancer, dates and clinical events related to treatment, serum PSA results, and toxicity. The primary outcome measure was the serum PSA levels at 6 months and 12 months after treatment initiation. After using the Kolmogorov-Smirnov test to demonstrate that PSA levels did not have normal distribution, we used Friedman test to compare, within each treatment stratum (monthly, quarterly, or semiannually), the distribution of PSA levels at baseline and at 6 and 12 months. Moreover, we used Wilcoxon's rank sum test to make pairwise comparisons between adjacent time points within strata. We made no comparisons between strata. We considered two-sided P values <0.05 as statistically significant and performed the analyses with SPSS, version 22.0.\n\nRESULTS\nPatient characteristics\nA total of 932 patients fulfilled the selection criteria and were analyzed, with their key characteristics being displayed in Table-1. The median age was 72 years (interquartile range, 65 to 78 years). Comorbidities were reported in 43.8% of the study population, most of which cardiovascular (85.0%). The median time since diagnosis of prostate cancer was 8.5 months, with 598 (64.2%) patients being diagnosed ≤12 months and 158 (17.0%) >4 years. The Gleason score was distributed relatively evenly between, low (Gleason ≤6), intermediate (Gleason 7) and high (Gleason ≥8) grade, and nearly three quarters of patients had non-metastatic disease. Bone metastases were reported in 161 (74%) of the patients in stage IV, while 5 patients (2.3%) had metastases at other distant sites and 12 (5.5%) had lymph node metastases. Radiotherapy and radical prostatectomy were the most frequent treatment modalities, in the beginning of the use of Eligard®.\n\nTable 1 Patient characteristics (n=932).\nCharacteristic\tValue\t\nAge, years\t\n\tMedian (interquartile range)\t72 (65 to 78)\t\nTime since diagnosis of prostate cancer in months\t\n\tMedian (interquartile range)\t8.5 (5 to 26)\t\nEthnicity\t\n\tWhite\t307 (32.9%)\t\n\tBlack\t619 (66.5%)\t\n\tNot available\t6 (0.6%)\t\nGleason score\t\n\tLow\t320 (34.3%)\t\n\tIntermediate\t318 (34.1%)\t\n\tHigh\t274 (29.4%)\t\n\tNot available\t20 (2.1%)\t\nProstate cancer stage at diagnosis\t\n\tI\t35 (3.8%)\t\n\tII\t369 (39.6%)\t\n\tIII\t269 (28.9%)\t\n\tIV\t218 (23.4%)\t\n\tNot available\t41 (4.4%)\t\nTreatment\t\n\tRadical prostatectomy\t163 (17.5%)\t\n\tTransurethral resection of the\t72 (7.7%)\t\n\tprostate\t\n\tRadiotherapy\t588 (63.1%)\t\n\t\tRT locally advanced\t235 (39.9%)\t\n\t\tRT rescue\t104 (17.7%)\t\n\t\tRT adjuvant\t122 (20.7%)\t\n\t\tRT palliative\t127 (21.7%)\t\nChemotherapy\t52 (5.6%)\t\nNot available\t57 (6.1%)\t\nIndication for androgen deprivation\nAndrogen deprivation therapy was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Overall across strata, 711 (76.3%) of the patients were treated concomitantly with other modalities, and 129 (13.8%) patients had received previous hormone therapy for the underlying disease. Nearly half of the patients were considered to have locally advanced prostate cancer, and this was the main indication for androgen deprivation. There was biochemical recurrence after prostatectomy in 104 of the 235 (44.3%) patients who underwent prostatectomy and in 122 (20.7%) of the 588 treated with radiotherapy. RT locally advanced (235, 39.9%), rescue radiotherapy 104 (17.7%), adjuvant radiation therapy 122 (20.7%), palliative radiotherapy 127 (21.7%).\n\nAmong the 932 patients, 803 (86.2%) were treated with the LHRH agonist alone, while 129 (13.8%) of the patients received it in combination with an antiandrogen (bicalutamide [8.4%], flutamide [4.8%], or cyproterone acetate [0.6%]).\n\nPSA levels\n\nTable-2 presents summary results for the serum PSA levels in each stratum at the three time points of interest. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (arrows in Figure-1). As shown in Figure-1, all pairwise comparison between adjacent time points within strata were statistically significant, with the exception of the comparison between 6 and 12 months for the monthly administration.\n\nTable 2 Serum prostate specific antigen (PSA) levels versus leuprolide schedule.\nStratum\tMedian PSA (interquartile range), ng/mL\tP value\t\n\tBaseline\t6 months\t12 months\t\t\nMonthly\tn=115\tn=108\tn=104\t<0.001\t\n\t25.6 (13.7 to 86.0)\t0.18 (0.05 to 1.6)\t0.08 (0.1 to 0.7)\t\t\nQuarterly\tn=637\tn=588\tn=512\t<0.001\t\n\t28.8 (13.0 to 87.0)\t0.54 (0.05 to 3.59)\t0.09 (0.01 to 1.0)\t\t\nSemiannualy\tn=180\tn=151\tn=103\t<0.001\t\n\t23.2 (9.4 to 70.5)\t0.39 (0.04 to 2.08)\t0.04 (0.01 to 0.37)\t\t\nFigure 1 Median levels of serum prostate specific antigen (PSA) in each stratum over time.\nSafety and tolerability\nA total of 72 (7.7%) patients reportedly had treatment-associated toxicity registered in the medical records. Among these cases, sexual impotence and hot flashes were the most frequent and were reported in 58 (6.2%) and 23 (2.5%) patients, respectively. More severe toxicity that was possibly associated with treatment was reported in only 9 (0.9%) of patients: there were two cases of hemorrhagic stroke, and one case each of heart failure secondary to coronary insufficiency, peripheral vascular insufficiency, angina, pulmonary embolism, and acute myocardial infarction. Despite this potential association with treatment, all these cases had comorbidity whose causal link with the toxicity could not be ruled out by chart review. In many cases, treatment for the comorbidity was reportedly used irregularly by the affected patients. No patient reportedly discontinued treatment prematurely due to toxicity.\n\nDISCUSSION\nTo our knowledge, the current study is the largest reported assessment of real-world data on patients with prostate cancer in Brazil. The study confirms the effectiveness and safety of this depot formulation of leuprolide acetate in clinical practice. Effectiveness was assessed on the basis of serum PSA declines during the first year of treatment, and safety was ascertained on the basis of toxicity reported in the medical records. Although the reliability and state of completion of medical records are well-known limitations of retrospective studies, the toxicity profile disclosed by our study overlaps with the profile of adverse events reported in clinical trials. On the other hand, the PSA data are objective and were available for the vast majority of time points. As a result, we believe our results add to the current literature by confirming the effectiveness of this LHRH agonist and the validity of a flexible approach, in terms of the choice of administration schedule, which may suit individual patients and clinicians according to their priorities.\n\nThree other observational studies have been conducted with the objective of evaluating the effectiveness, tolerability and/or impact on the quality of life of this depot formulation of leuprolide acetate in daily clinical practice among patients with prostate cancer. In the ELIRE study, conducted in France, the formulation used was for administration every 3 or every 6 months (11). Among 1.853 registered patients, the mean age was 75 years, and the mean time to diagnosis was 7 months. Interestingly, the criteria for choosing between the quarterly or semiannual administration were different, with patients using the latter schedule being more likely to be older and less autonomous than those using the former. The authors concluded that semiannual administration provides more flexibility in the management and follow-up of patients with locally advanced or metastatic prostate cancer. The results suggest that the semiannual use of the LHRH agonist is as effective as the other regimens, resulting in a difference in treatment cost between groups, impacting positively on Brazilian public health. The MANTA study, conducted in Belgium, assessed both a monthly and a quarterly schedule in 243 patients and confirmed that both depot formulations of leuprolide acetate are well tolerated and reliably lowered serum PSA and testosterone levels in routine clinical practice (13). Finally, a study in Germany assessed the administration of leuprolide acetate every 6 months in 1.273 patients (12). At 12 months, there was a median reduction of 96% (to 0.5ng/mL) in serum PSA levels. Interestingly, further PSA and serum testosterone decreases were observed in a subpopulation of patients treated initially with other LHRH analogues and who switched to 6-monthly leuprolide acetate. Similar to the present study, toxicity was reported in the German study in 9% of patients, and the majority were not considered serious. Of note, this LHRH agonist was found to be the most frequently used form of medical castration in another study from Germany, in this case based on a claims database (15).\n\nClinical trials usually demonstrate the efficacy and tolerability of therapeutic agents in relatively homogeneous populations of patients meeting strict selection criteria. Real-world studies are important because they have broader criteria and may include far more patients in populations that are likely to be observed in routine clinical practice. Compared with patients enrolled in clinical trials (9, 10), patients in observational studies usually display larger variability in tumor staging, Gleason scores, indications for androgen deprivation, and comorbidity. Many of the patients analyzed in observational studies, including ours, would have been excluded from clinical trials (11-13). Reassuringly, however, the results of clinical trials and observational studies with this LHRH analogue overlap to show that PSA levels can be effectively reduced in most patients treated with monthly, quarterly, and semiannual injections.\n\nOur study did not aim at formally to compare the effectiveness or tolerability of the three schedules of administration of this LHRH analogue. Nevertheless, the results show that median serum PSA levels were reduced by at least 99.7% across the three strata, with no notable differences among them. Moreover, these results were seen in spite of the fact that most patients received the LHRH analogue alone, unlike in some studies, in which variable proportions of patients were treated with combinations containing an anti-androgen, a bisphosphonate, or chemotherapy. In such a heterogeneous population as ours, and considering the ease of use and local tolerability of this depot formulation, we believe that the choice among the different schedules has to be individualized based on preference and health-care system convenience. Arguably, semiannual injections can provide benefits in terms of patient visits and use of resources, but this hypothesis remains to be tested formally in our specific health-care scenario. In Japan, for example, the 6-month formulation was found to reduce medical costs, loss of productivity, and intangible costs in comparison with the 3-month formulation (16). Likewise, in a cost-minimization analysis conducted in Europe, the 6-month formulation was found to offer the greatest cost savings, and the authors considered that it should be the treatment of choice in eligible European patients (17). In the Brazilian health-care system, which aims at providing universal coverage for all citizens (18), it is conceivable that a reduced number of patient visits, especially for the elderly and for those living far from the treatment center, may bring efficiencies and allow for the opening of vacancies for other patients in need.\n\nCONCLUSIONS\nOur study confirms that serum PSA levels can be effectively reduced in most of the patients with prostate cancer treated with monthly, quarterly, or semiannual injections of this LHRH agonist. This therapeutic goal is achieved at the expense of a relatively favorable toxicity profile, and it is hoped that schedules of administration every 6 months will bring the added benefit of convenience and cost savings in clinical practice in Brazil and elsewhere.\n==== Refs\nREFERENCES\n1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 2015 136 E359 E386 25220842 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-86.\n2 Taitt HE Global Trends and Prostate Cancer: A Review of Incidence, Detection, and Mortality as Influenced by Race, Ethnicity, and Geographic Location Am J Mens Health 2018 12 1807 1823 30203706 2. Taitt HE. 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Year 8, nr. 2 Jul-Dec 2017 Monitoramento das ações de controle do câncer de prostata Available at. <http://www.saude.df.gov.br/wp-conteudo/uploads/2018/03/Informativo-C%C3%A2ncer-de-Pr%C3%B3stata-2017.pdf > Accessed 21 December 2018 5. Brasil. Ministério da Saúde. Instituto Nacional de Câncer. Informativo Detecção Precoce. Year 8, nr. 2, July/December 2017. Monitoramento das ações de controle do câncer de prostata. Available at. <http://www.saude.df.gov.br/wp-conteudo/uploads/2018/03/Informativo-C%C3%A2ncer-de-Pr%C3%B3stata-2017.pdf> (Accessed 21 December 2018).\n6 Merseburger AS Alcaraz A von Klot CA Androgen deprivation therapy as backbone therapy in the management of prostate cancer Onco Targets Ther 2016 9 7263 7274 27942220 6. Merseburger AS, Alcaraz A, von Klot CA. Androgen deprivation therapy as backbone therapy in the management of prostate cancer. Onco Targets Ther. 2016;9:7263-74.\n7 Mottet N Van den Bergh RCN Briers E European Association of Urology Prostate Cancer Guidelines Available at. <https://uroweb.org/guideline/prostate-cancer/ > Accessed 22 December 2018 7. Mottet N, Van den Bergh RCN, Briers E, et al. European Association of Urology. Prostate Cancer Guidelines. Available at. <https://uroweb.org/guideline/prostate-cancer/> (Accessed 22 December 2018).\n8 Grant JB Ahmed SR Shalet SM Costello CB Howell A Blacklock NJ Testosterone and gonadotrophin profiles in patients on daily or monthly LHRH analogue ICI 118630 (Zoladex) compared with orchiectomy Br J Urol 1986 58 539 544 2946356 8. Grant JB, Ahmed SR, Shalet SM, Costello CB, Howell A, Blacklock NJ. Testosterone and gonadotrophin profiles in patients on daily or monthly LHRH analogue ICI 118630 (Zoladex) compared with orchiectomy. Br J Urol. 1986;58:539-44.\n9 Chu FM Jayson M Dineen MK Perez R Harkaway R Tyler RC A clinical study of 22.5mg. La-2550: A new subcutaneous depot delivery system for leuprolide acetate for the treatment of prostate cancer J Urol 2002 168 1199 1203 12187267 9. Chu FM, Jayson M, Dineen MK, Perez R, Harkaway R, Tyler RC. A clinical study of 22.5mg. La-2550: A new subcutaneous depot delivery system for leuprolide acetate for the treatment of prostate cancer. J Urol. 2002;168:1199-203.\n10 Crawford ED Sartor O Chu F Perez R Karlin G Garrett JS A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer J Urol 2006 175 533 536 16406989 10. Crawford ED, Sartor O, Chu F, Perez R, Karlin G, Garrett JS. A 12-month clinical study of LA-2585 (45.0 mg): a new 6-month subcutaneous delivery system for leuprolide acetate for the treatment of prostate cancer. J Urol. 2006;175:533-6.\n11 Ouzaid I Rouprêt M The role of a 6-month depot form of hormone therapy in the treatment of advanced hormone-dependent prostate cancer: Results from the ‘ELIRE’ observational study Prog Urol 2011 21 866 874 22035913 11. Ouzaid I, Rouprêt M. [The role of a 6-month depot form of hormone therapy in the treatment of advanced hormone-dependent prostate cancer: Results from the ‘ELIRE’ observational study]. Prog Urol. 2011;21:866-74.\n12 Tunn UW A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1273 patients BMC Urol 2011 11 15 15 21801354 12. Tunn UW. A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1273 patients. BMC Urol. 2011;11:15.\n13 Braeckman J Michielsen D Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard(®)/ Depo-Eligard(®)) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study Arch Med Sci 2014 10 477 483 25097577 13. Braeckman J, Michielsen D. Efficacy and tolerability of 1- and 3-month leuprorelin acetate depot formulations (Eligard(®)/ Depo-Eligard(®)) for advanced prostate cancer in daily practice: a Belgian prospective non-interventional study. Arch Med Sci. 2014;10:477-83.\n14 Ohlmann CH Gross-Langenhoff M Efficacy and Tolerability of Leuprorelin Acetate (Eligard®) in Daily Practice in Germany: Pooled Data from 2 Prospective, Non-Interventional Studies with 3- or 6-Month Depot Formulations in Patients with Advanced Prostate Cancer Urol Int 2018 100 66 71 29197875 14. Ohlmann CH, Gross-Langenhoff M. Efficacy and Tolerability of Leuprorelin Acetate (Eligard®) in Daily Practice in Germany: Pooled Data from 2 Prospective, Non-Interventional Studies with 3- or 6-Month Depot Formulations in Patients with Advanced Prostate Cancer. Urol Int. 2018;100:66-71.\n15 Hupe MC Hammerer P Ketz M Kossack N Colling C Merseburger AS Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes Front Oncol 2018 8 543 543 30538951 15. Hupe MC, Hammerer P Ketz M, Kossack N, Colling C, Merseburger AS. Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes. Front Oncol. 2018;8:543.\n16 Goto R Uda A Hiroi S Iwasaki K Takashima K Oya M Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations J Med Econ 2017 20 1155 1162 28758810 16. Goto R, Uda A, Hiroi S, Iwasaki K, Takashima K, Oya M. Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations. J Med Econ. 2017;20:1155-62.\n17 Wex J Sidhu M Odeyemi I Abou-Setta AM Retsa P Tombal B Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation Clinicoecon Outcomes Res 2013 5 257 269 23836996 17. Wex J, Sidhu M, Odeyemi I, Abou-Setta AM, Retsa P, Tombal B. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation. Clinicoecon Outcomes Res. 2013;5:257-69.\n18 Lopes LC Barberato-Filho S Costa AC Osorio-de-Castro CG. Rational use of anticancer drugs and patient lawsuits in the state of São Paulo, Southeastern Brazil Rev Saude Publica 2010 44 620 628 20676553 18. Lopes LC, Barberato-Filho S, Costa AC, Osorio-de-Castro CG. Rational use of anticancer drugs and patient lawsuits in the state of São Paulo, Southeastern Brazil. Rev Saude Publica. 2010;44:620-8.\n\n", "fulltext_license": "CC BY", "issn_linking": "1677-5538", "issue": "46(3)", "journal": "International braz j urol : official journal of the Brazilian Society of Urology", "keywords": "Prostate-Specific Antigen; Prostatic Neoplasms; agonists [Subheading]", "medline_ta": "Int Braz J Urol", "mesh_terms": "D000085:Acetates; D000368:Aged; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D001938:Brazil; D006801:Humans; D016729:Leuprolide; D008297:Male; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms; D012189:Retrospective Studies", "nlm_unique_id": "101158091", "other_id": null, "pages": "383-389", "pmc": null, "pmid": "32167701", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "21801354;23836996;20676553;30203706;27942220;22424666;2946356;25097577;12187267;30538951;25220842;22035913;16406989;28758810;29197875;27678315", "title": "Efficacy of Leuprorelide acetate (Eligard®) in daily practice in Brazil: a retrospective study with depot formulations in patients with prostate cancer.", "title_normalized": "efficacy of leuprorelide acetate eligard in daily practice in brazil a retrospective study with depot formulations in patients with prostate cancer" }

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EFFICACY OF LEUPRORELIDE ACETATE (ELIGARD?) IN DAILY PRACTICE IN BRAZIL: A RETROSPECTIVE STUDY WITH DEPOT FORMULATIONS IN PATIENTS WITH PROSTATE CANCER. INTERNATIONAL BRAZ J UROL : OFFICIAL JOURNAL OF THE BRAZILIAN SOCIETY OF UROLOGY. 2020?46:3:383-389", "literaturereference_normalized": "efficacy of leuprorelide acetate eligard in daily practice in brazil a retrospective study with depot formulations in patients with prostate cancer", "qualification": "1", "reportercountry": "BR" }, "primarysourcecountry": "BR", "receiptdate": "20200408", "receivedate": "20200408", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17644055, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200713" } ]

{ "abstract": "BACKGROUND\nPatients with relapsed diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Gemcitabine, methylprednisolone, cisplatin +/- rituximab (GEM-P+/-R) is a salvage regimen with limited overlap in toxicity with first-line therapy and short duration of inpatient delivery.\n\n\nMETHODS\nWe assessed the efficacy and safety of GEM-P+/-R in a retrospective single-centre analysis including patients meeting criteria of ≥ 18 yr of age, histologically proven DLBCL, treated between 2001 and 2011 in second-line with gemcitabine 1000 mg/m(2) day 1, 8 and 15, methylprednisolone 1000 mg day 1-5, cisplatin 100 mg/m(2) day 15 (replaced with carboplatin AUC5 if contraindication/toxicity) +/- rituximab 375 mg/m(2) day 1 and 15, every 28 d.\n\n\nRESULTS\nForty-five patients aged 25-74 received a median of three cycles of GEM-P+/-R; 64% received rituximab. In 44 evaluable patients receiving GEM-P+/-R, overall response rate (ORR) was 48%; in 28 evaluable patients treated with rituximab + GEM-P (R-GEM-P), ORR was 61%. With median follow-up of 50.5 months (95% CI: 28.3-72.7), 3-yr overall survival (OS) from start of GEM-P+/-R was 31.4% (95% CI: 16.5-46.3); in patients treated with R-GEM-P, 3-yr OS was 49.1% (95% CI: 28.7-69.5). Predominant grade ≥ 3 toxicities were haematological; thrombocytopenia 69%, neutropenia 60% and febrile neutropenia 7%.\n\n\nCONCLUSIONS\nR-GEM-P is a deliverable regimen with useful activity in second-line treatment of DLBCL. Our data suggest that rituximab should be given concurrently.", "affiliations": "The Royal Marsden NHS Foundation Trust, London, Surrey, UK.", "authors": "Barton|Sarah|S|;Hawkes|Eliza A|EA|;Cunningham|David|D|;Peckitt|Clare|C|;Chua|Sue|S|;Wotherspoon|Andrew|A|;Attygalle|Ayoma|A|;Horwich|Alan|A|;Potter|Mike|M|;Ethell|Mark|M|;Dearden|Claire|C|;Gleeson|Mary|M|;Chau|Ian|I|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D003841:Deoxycytidine; D000069283:Rituximab; C056507:gemcitabine; D016190:Carboplatin; D002945:Cisplatin; D008775:Methylprednisolone", "country": "England", "delete": false, "doi": "10.1111/ejh.12416", "fulltext": null, "fulltext_license": null, "issn_linking": "0902-4441", "issue": "94(3)", "journal": "European journal of haematology", "keywords": "cisplatin; diffuse; gemcitabine; large B-cell; lymphoma; relapse; rituximab", "medline_ta": "Eur J Haematol", "mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D003841:Deoxycytidine; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D009503:Neutropenia; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D016879:Salvage Therapy; D016019:Survival Analysis; D013921:Thrombocytopenia; D016896:Treatment Outcome", "nlm_unique_id": "8703985", "other_id": null, "pages": "219-26", "pmc": null, "pmid": "25039915", "pubdate": "2015-03", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Rituximab, Gemcitabine, Cisplatin and Methylprednisolone (R-GEM-P) is an effective regimen in relapsed diffuse large B-cell lymphoma.", "title_normalized": "rituximab gemcitabine cisplatin and methylprednisolone r gem p is an effective regimen in relapsed diffuse large b cell lymphoma" }

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RITUXIMAB, GEMCITABINE, CISPLATIN AND METHYLPREDNISOLONE (R-GEM-P) IS AN EFFECTIVE REGIMEN IN RELAPSED DIFFUSE LARGE B-CELL LYMPHOMA. EUR-J-HAEMATOL 2015? 94(3):219-226.", "literaturereference_normalized": "rituximab gemcitabine cisplatin and methylprednisolone r gem p is an effective regimen in relapsed diffuse large b cell lymphoma", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20151211", "receivedate": "20151211", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11828395, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160305" } ]

{ "abstract": "BACKGROUND\nHemophagocytic lymphohistiocytosis is a disease process characterized by unregulated hyperactivation of the immune system associated with multiorgan involvement and high mortality rates. Early recognition is crucial and a recently validated diagnostic schema, the H-Score, may facilitate diagnosis particularly in secondary hemophagocytic lymphohistiocytosis cases. We present a patient with secondary hemophagocytic lymphohistiocytosis in association with metastatic renal cell carcinoma in whom high-dose steroid therapy induced a remarkable response.\n\n\nMETHODS\nA 35-year-old Vietnamese man with quiescent systemic lupus erythematosus was diagnosed 5 months prior to admission with left-sided renal cell carcinoma metastatic to the pancreas and spine. Ten days prior to admission, a febrile illness (temperatures to 39 °C) associated with flu-like symptoms unresponsive to levofloxacin developed. He took only two doses of pazopanib prior to admission. High fevers unresponsive to antimicrobial therapy, cytopenias, disseminated intravascular coagulation, and progressive multiorgan failure led to intubation and intensive care unit stay. Extensive infectious disease workup showed only negative results, but elevation of interleukin-2 receptor, exceedingly high ferritin levels and other features earned an H-Score of 302, consistent with >99% diagnostic probability for secondary hemophagocytic lymphohistiocytosis. High-dose steroid therapy produced a rapid clinical and biochemical response.\n\n\nCONCLUSIONS\nHemophagocytic lymphohistiocytosis is a life-threatening disorder which is likely to be under-recognized. Increased awareness of this disease entity and its diagnosis is crucial toward early recognition and treatment. To our knowledge, our patient is only the second reported with secondary hemophagocytic lymphohistiocytosis occurring in the setting of renal cell carcinoma.", "affiliations": "Department of Internal Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA, 92868, USA.;Department of Internal Medicine, Arrowhead Regional Medical Center, 400 N Pepper Avenue, Colton, CA, 92324, USA.;Department of Pathology and Laboratory Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA, 92868, USA. [email protected].", "authors": "El-Masry|Monica|M|;Eisenbud|Lauren|L|;Tran|Minh-Ha|MH|http://orcid.org/0000-0002-9974-5277", "chemical_list": "D005938:Glucocorticoids; D015375:Receptors, Interleukin-2; D003907:Dexamethasone; D005293:Ferritins", "country": "England", "delete": false, "doi": "10.1186/s13256-016-1196-9", "fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 119610.1186/s13256-016-1196-9Case ReportSecondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report El-Masry Monica [email protected] 1Eisenbud Lauren [email protected] 2http://orcid.org/0000-0002-9974-5277Tran Minh-Ha [email protected] 31 0000 0000 9632 6718grid.19006.3eDepartment of Internal Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA 92868 USA 2 0000 0004 0383 4879grid.413942.9Department of Internal Medicine, Arrowhead Regional Medical Center, 400 N Pepper Avenue, Colton, CA 92324 USA 3 0000 0000 9632 6718grid.19006.3eDepartment of Pathology and Laboratory Medicine, UC Irvine Health School of Medicine, 101 The City Drive S, Orange, CA 92868 USA 2 3 2017 2 3 2017 2017 11 5614 7 2016 29 12 2016 © The Author(s). 2017\nOpen 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\nHemophagocytic lymphohistiocytosis is a disease process characterized by unregulated hyperactivation of the immune system associated with multiorgan involvement and high mortality rates. Early recognition is crucial and a recently validated diagnostic schema, the H-Score, may facilitate diagnosis particularly in secondary hemophagocytic lymphohistiocytosis cases. We present a patient with secondary hemophagocytic lymphohistiocytosis in association with metastatic renal cell carcinoma in whom high-dose steroid therapy induced a remarkable response.\n\nCase presentation\nA 35-year-old Vietnamese man with quiescent systemic lupus erythematosus was diagnosed 5 months prior to admission with left-sided renal cell carcinoma metastatic to the pancreas and spine. Ten days prior to admission, a febrile illness (temperatures to 39 °C) associated with flu-like symptoms unresponsive to levofloxacin developed. He took only two doses of pazopanib prior to admission. High fevers unresponsive to antimicrobial therapy, cytopenias, disseminated intravascular coagulation, and progressive multiorgan failure led to intubation and intensive care unit stay. Extensive infectious disease workup showed only negative results, but elevation of interleukin-2 receptor, exceedingly high ferritin levels and other features earned an H-Score of 302, consistent with >99% diagnostic probability for secondary hemophagocytic lymphohistiocytosis. High-dose steroid therapy produced a rapid clinical and biochemical response.\n\nConclusions\nHemophagocytic lymphohistiocytosis is a life-threatening disorder which is likely to be under-recognized. Increased awareness of this disease entity and its diagnosis is crucial toward early recognition and treatment. To our knowledge, our patient is only the second reported with secondary hemophagocytic lymphohistiocytosis occurring in the setting of renal cell carcinoma.\n\nKeywords\nHemophagocytic lymphohistiocytosisDisseminated intravascular coagulationFeverFever of unknown originAltered mental statusissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nHemophagocytic lymphohistiocytosis (HLH) is a disease process characterized by unregulated hyperactivation of the immune system resulting in variable combinations of fever, multiorgan involvement (particularly transaminase elevation), and peripheral blood cytopenias [1]. Presentations are generally divided into primary and secondary forms, the former typically occurring in infants or young children and often incorporating either autosomal recessive mutations in any of several recognized familial hemophagocytic lymphohistocytosis (FHL) genes, or as a feature of other, non-FHL immunodeficiency syndromes (see Table 1) [2, 3]. Primary HLH, which has an incidence of 1.2 per million children per year [4], is diagnosed based upon criteria set forth by the Histiocyte Society [5] (see Table 1).Table 1 Hemophagocytic lymphohistiocytosis (HLH) 2004 diagnostic criteria (Adapted with permission from John Wiley and Sons Ltd. from Brisse et al. [3] and Henter et al. [5]). Diagnostic criteria 1–5 represent the original 1991 diagnostic criteria; the HLH 2004 revision adds criteria 6–8. The diagnosis of primary HLH can be made either on a molecular or clinical basis\n\nHLH Molecular diagnosis\tAt least 5 of the following 8 diagnostic criteria\t\nFHL genes\t\nPRF1, UNC13D, STX11, STXBP2\n\t1. Fever\t2. Splenomegaly\t\n3. Cytopenias (≥2/3 lineages)a\n\t4. High triglyceride/low fibrinogen levelsb\n\t\nNon-FHL genes\t\nRAB27A, LYST, AP3B1, SH2D1A, XIAP\n\t5. Hemophagocytosis\t6. Low/absent NK-cell activity\t\n7. Ferritin ≥500 ng/mL\t8. Soluble IL-2 receptor ≥2400 U/mL\t\n\nFHL Familial hemophagocytic lymphohistocytosis, NK Natural Killer, and IL Interleukin. non-FHL gene mutations occur in Gricselli syndrome, Chediak-Higashi syndrome, Hermansky-Pudlak syndrome type 2, and X-linked lymphoproliferative disease\n\n\naHb <9 g/dL, platelets <100 K/mcL, neutrophils <1.0 K/mcL. bTriglycerides ≥265 mg/dL, fibrinogen ≤150 mg/dL\n\n\n\n\nSecondary HLH occurs typically in adolescents or adults and in the setting of infectious, rheumatologic (i.e., juvenile idiopathic inflammatory arthritis), or malignant conditions (i.e., lymphoma) [6]. The HLH-2004 criteria may have reduced sensitivity and specificity in secondary HLH - where sufficient criteria may not be met at disease onset but develop later in the course and associated malignancy and inflammatory conditions may predispose to higher baseline ferritin values [3]. It has, therefore, been suggested that this disorder is likely under-recognized in modern practice [7]. Treatment is largely based upon the original HLH-94 protocol [8] incorporating an initial 8-week induction regimen using corticosteroids in most patients and chemotherapy (etoposide) in selected patients (i.e., when Epstein-Barr virus (EBV)-driven disease is present). Despite treatment, the mortality of secondary HLH ranges from 32.4% to as high as 87.5% [9, 10].\n\nWe recently encountered a 35-year-old male patient with a history of systemic lupus erythematosus (SLE) and metastatic renal cell carcinoma, who presented with a flu-like illness. Fevers, multiorgan failure, altered mental status, cytopenias, and disseminated intravascular coagulation (DIC) findings progressed rapidly in the face of empiric antimicrobial and antiviral therapy. Diagnosis of secondary HLH and immediate institution of corticosteroid therapy was associated with a dramatic clinical response.\n\nCase presentation\nA 35-year-old Vietnamese man with underlying SLE who was taking hydroxychloroquine, azathioprine, and prednisone was diagnosed 5 months prior to admission with metastatic renal cell carcinoma with a 6.6 × 6.0 × 7.2-cm left renal mass with disruption of fat planes, suggestive of involvement of the tail of the pancreas, as well as a 4.1 × 3.2 × 2.6-cm mass at the T8 spinal vertebra. On hospital day (HD) -43, he underwent hemivertebrectomy with fusion of adjacent vertebral levels; pathologic examination of the T8-mass demonstrated renal cell carcinoma. He was first evaluated at our institution for a second opinion for his malignancy on HD −21. Plans were put forth to obtain outside records and undertake multidisciplinary treatment planning during tumor board.\n\nHowever, on approximately HD −10, he developed a febrile illness (temperatures to 38.9 °C measured at home) with flu-like symptoms comprised of shortness of breath, frontal headaches, sore throat with neck pain, nausea, vomiting, diarrhea, and generalized weakness. He took pazopanib 800 mg daily, which had been prescribed prior to onset of illness, on HDs −3 and −2. Despite an outpatient course of levofloxacin, progression of symptoms led ultimately to presentation on HD 0.\n\nPresenting vital signs in the emergency department included fever of 39.2 °C, tachycardia of 101 beats per minute (bpm), and relative hypotension at 106/66 mmHg. Initial laboratory studies demonstrated multiorgan involvement with pancytopenia, acute kidney injury, hyponatremia, abnormal liver function tests, and elevations in lactic acid, procalcitonin, and lipase levels. Clinically, he was judged to be euvolemic. Further studies noted that serum osmolality was low at 267 mOsm/kg, spot urine sodium 24 mmol/L, and urine osmolality 776 mOsm/kg. A plain film of the chest was normal, save for spinal hardware, and cranial computed tomography showed no acute intracranial process. His SLE was clinically judged to be quiescent, corroborated by an anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody screen and an extensive infectious disease workup both of which showed only negative results (see Table 2).Table 2 Results of infectious disease workup\n\nSource\tTest result\t\nBlood\tCultures: no growth (bacterial/fungal)\tNegative for HIV 1/2 and HIV p24 Ag\tNonreactive for Lyme antibody and Treponema pallidum immunoassay\tNegative for Coccidioides IgM and IgG. Negative for Histoplasma Ag\tViral hepatitis panel (A, B, C) significant only for hepatitis B core Ab\tEBV serology consistent with seropositive statusa\n\tCMV serology consistent with seronegative status\t\nUrine\tUrinalysis significant only for trace proteinuria\tNegative for Legionella Ag\tNegative for Streptococcus pneumoniae Ag\t\t\nNasopharyngeal swab\tNegative for Group A Streptococcus (direct antigen test)\tNegative for influenza A, B, RSV (rt-PCR)\tNegative for MSSA and MRSA\t\t\t\t\t\nCerebrospinal fluid (CSF)\tCSF showed 14 nucleated cells/mm3 (normal 0–5/mm3) consisting of 84% polymorphonuclear leukocytes, 9% lymphocytes, and 7% monocytes; 44 mg/dL glucose (normal 41–70 mg/dL); 70 mg/dL protein (normal 15–45 mg/dL)\t\nCryptococcus neoformans Ag and C. gattii Ag\tNonreactive for West Nile virus IgG/IgM\tNegative for HSV 1, 2 and enterovirus (PCR)\tNegative for acid fast bacilli, no growth occurred during fungal and mycobacterial culture\t\nStool\tNegative for Clostridium difficile toxin B (PCR)\t\t\t\t\t\t\t\nOther\tPPD skin test 0-mm induration\tQuantiferon Gold tuberculosis test indeterminate\t\t\t\t\t\t\n\nAb antibody, Ag antigen, CMV cytomegalovirus, EBV Epstein-Barr virus, HSV herpes simplex virus, Ig immunoglobulin, MSSA methicillin-sensitive Staphylococcus aureus, MRSA methicillin-resistant Staphylococcus aureus, PCR polymerase chain reaction, PPD purified protein derivative, RSV respiratory syncytial virus\n\n\naEBV viral capsid, nuclear, and early diffuse IgG Abs reactive, viral capsid IgM nonreactive; EBV PCR not performed\n\n\n\n\nHe was started on broad-spectrum antibiotics (vancomycin and piperacillin-tazobactam) and admitted to the internal medicine service. On HD 2, given a declining mental status and concern for meningitis, piperacillin-tazobactam was discontinued, and ceftriaxone, acyclovir, and ampicillin were added to the vancomycin. Ultimately, the patient required intubation for airway protection and was transferred to the medical intensive care unit (ICU). Lumbar puncture was performed and the results are presented in Table 2.\n\nOn HD 2 he developed urinary retention with a 600-ml output following straight catheterization prompting placement of a Foley catheter. Also on HD 2, loose stools developed along with increased abdominal rigidity and a rise in lactic acid levels from an admission value of 1.8 mmol/L (normal 0.5–2.2) to 4.9 mmol/L. Stool polymerase chain reaction (PCR) was negative for Clostridium difficile toxin B. His mental status deteriorated and he became agitated and required intubation on HD 2 for airway protection and was transferred to the medical ICU.\n\nLaboratory values on HD 2 included elevated aspartate aminotransferase (AST, normal range 13-39 U/L)/alanine aminotransferase (ALT, normal range 7-52 U/L) of 547 and 118 U/L, respectively; declining albumin from 2.7 to 1.7 mg/dL; and elevated LDH of 2833 U/L (normal 140-271 U/L), lipase of 501 U/L (normal 11–82 U/L), and triglycerides of 500 mg/dL (normal <150 mg/dL). Iron studies revealed a low transferrin of 99.3 mg/dL (normal 203–362 mg/dL) and TIBC of 139 mcg/dL (284–507 mcg/dL), low-normal serum iron of 50 mcg/dL (normal 49–181 mcg/dL), and normal saturation of 36% (normal 20–55%). Ferritin was substantially elevated at >7500 ng/mL (normal 23–233 ng/mL) and later peaked at >15,000 ng/mL.\n\nThe Quantiferon Gold tuberculosis (TB) test resulted as indeterminate due to a high degree of nonspecific reactivity produced by the patient’s specimen (i.e., NIL (negative control tube) >10 IU/mL). This was in concert with a very high C-reactive protein (CRP) result of 25.9 mg/dL (normal range 0.0–1.0 mg/dL) and an elevated soluble interleukin (IL)-2 receptor result of 1112 pg/mL (normal ≤1033 pg/mL). A purified protein derivative (PPD) skin test yielded 0-mm induration.\n\nDespite broad-spectrum antibiotics, the patient remained persistently febrile, with daily fevers exceeding 38.4 °C (maximal temperature was on HD 2 at 38.9 °C). He developed rigors and a subsequent mild rhabdomyolysis with creatinine kinase values increasing to a maximum of 7546 U/L (normal 30–223 U/L) on HD 2. Aggressive cooling measures were required, including acetaminophen and a cooling blanket. Continuous rigors with abdominal rigidity precluded accurate physical examination for hepatosplenomegaly. A kidneys-ureters-bladder (KUB) plain film taken on HD 2, however, had findings consistent with possible hepatosplenomegaly.\n\nA coagulopathy developed with maximal values on HD 5 of Prothrombin Time (PT) 29.7 s (normal 11.5–14.1 s), International Normalized Ratio (INR) of 2.91 (0.87–1.13), Partial Thromboplastin Time (PTT) 63.5 s (normal 24.7–37.0 s), and nadir fibrinogen level of 76 mg/dL (211–410 mg/dL). The latter prompted cryoprecipitate transfusions on HD 4 and HD 6. Progression of coagulopathy occurred in parallel with progression of thrombocytopenia, with nadir platelet count by HD 9 of 25 K/mcL (normal 150–400 K/mcL). Nadir hemoglobin also occurred on HD 9 at 7 g/dL. Schistocytosis was absent and neither red blood cell nor platelet transfusions were required throughout the hospital stay.\n\nThe combination of fever (maximal recorded 39.2 °C) in the setting of an infectious disease workup which showed only negative results, with trilineage cytopenias, elevated AST and ALT, hypofibrinogenemia (nadir of 76 mg/dL), significant hyperferritinemia (peak >15,000 ng/mL), triglycerides of 500 mg/dL, as well as suggestion on KUB imaging for hepatosplenomegaly, was compatible with a secondary HLH diagnosis. Involvement of the central nervous system (CNS) was evident given his mental status changes and agitation. Additionally, natural killer (NK)-cell function was reduced with a Lytic Unit 30 value of 5 lytic sets (normal LU30 = 7–125 lytic sets) and soluble IL-2 receptor level modestly elevated at 1112 pg/mL (normal ≤1033).\n\nHigh-dose steroids were, therefore, initiated. Dexamethasone, preferred because it can cross the blood-brain barrier, was initiated at 10 mg/m2 daily for weeks 1 and 2, followed by 5 mg/m2 daily for weeks 3 and 4, then 2.5 mg/m2 daily for weeks 5 and 6, then 1.25 mg/m2 daily for week 7 with tapering to zero during week 8. Clinical response was immediately noted with resolution of fevers and rigors and rapidly improving mental status. Laboratory abnormalities also improved; their trends following initiation of dexamethasone are further detailed in Fig. 1. Our patient was subsequently extubated on HD 5 and discharged in ambulatory condition with full cognitive ability on HD 20.Fig. 1 Timeline. Improvement in laboratory values with initiation of dexamethasone. PLT platelet count (normal 150–400 K/mcL), AST aspartate aminotransferase (normal 13–39 U/L), CK creatinine kinase (normal 30–223 U/L)\n\n\n\n\nDiscussion\nOur 35-year-old patient developed secondary HLH in the setting of preexisting immunosuppression due to underlying SLE and metastatic renal cell carcinoma. To our knowledge, this is the first case of HLH reported in the setting of pazopanib therapy and only the second case reported in association with renal cell carcinoma (RCC) [11].\n\nBased upon a validated cohort of secondary HLH patients [12], Fardet et al. developed a diagnostic H-Score [13] to predict the likelihood of secondary HLH. Points are assigned based upon presence of:Three clinical features○ Known immunosuppression – no: 0/yes: 18; high temperature <38.4 °C: 0, 38.4 to 39.4 °C: 33, >39.4 °C: 49; neither hepatomegaly nor splenomegaly: 0, either: 23, or both: 38\n\n\n\n\nFive biologic features○ Triglycerides mg/dL <132.9: 0, 132.9 to 354.3: 44, >354.3: 64; ferritin ng/mL <2000: 0, 2000–6000: 35, >6000: 50; AST U/L <30: 0, ≥30: 19; fibrinogen mg/dL >250: 0, ≤250: 30; number of cytopenic lineages – 1: 0, 2: 24, 3: 34\n\n\n\n\nOne cytologic feature○ Hemophagocytosis – no: 0, yes: 35\n\n\n\n\n\n\n\nIn regards to the validation cohort, the median (IQR) H-Score in the group with and without secondary HLH was 230 (203–257) and 125 (91–150), respectively. At H-Scores of 90, 150, 190, 200, 220, 230, 240, and 250, the probability for secondary HLH was <1%, 25%, 80%, 88%, 96%, 98%, 99%, and >99%, respectively [13]. Performance of the H-Score was compared against that of the adapted HLH-2004 criteria in a validation study by Debaugnies et al. [14]. In their comparison, the HLH-2004 criteria were shortened to exclude low NK-cell activity and soluble IL-2 receptor levels, thereby having six total criteria instead of the original eight. Among adult patients at initial presentation, the H-Score outperformed the modified HLH-2004 criteria at disease recognition: an H-Score of >138 offered 90% sensitivity, 79% specificity, and 86% diagnostic accuracy compared to the scenario in which five out of six HLH-2004 criteria are met, where respective values were: 55%, 100%, and 80%. For established disease, and using maximal score values, the two diagnostic criteria (using an H-Score >185) performed similarly.\n\nIn addition to meeting at least five out of the eight criteria in the original HLH-2004 diagnostic guidelines [5], our patient also had a diagnostic H-Score. Qualifying elements included: known immunosuppression (SLE on hydroxychloroquine, azathioprine, and steroids), a maximum temperature of 39.6 °C, hepatosplenomegaly, triglycerides of 500 mg/dL, AST >30 U/L, ferritin >6000 ng/mL, fibrinogen nadir <250 mg/dL, and trilineage cytopenias, earning an H-Score of 302, consistent with a diagnostic probability of >99%. The dramatic improvement on all fronts that ensued following initiation of steroid therapy lends further confidence to accuracy of our diagnosis.\n\nOther features consistent with secondary HLH in our patient include the presence of a euvolemic, hypo-osmolar hyponatremia with spot urine sodium of 24 mmol/L, consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) [1]. Additionally, our patient manifested CNS involvement with encephalopathy and agitation requiring intubation for airway protection.\n\nThe most common viral drivers for secondary HLH are EBV, HIV, herpes viruses, cytomegalovirus (CMV), viral hepatitis, and influenza [1]. In our patient, viral-testing was negative for these entities. Bacterial, fungal, and mycobacterial cultures also tested negative. SLE is also a recognized driver [1], but our patient did not appear to have signs of active disease, suggesting that the HLH was secondary to metastatic renal cell carcinoma.\n\nConclusions\nHLH is a life-threatening disorder resulting from immunologic hyperactivation that can progress to multiorgan failure. Early recognition is critical so that progression may be interrupted. However, this disease entity is likely under-recognized which is of concern given its high mortality rate. In pediatric cases, diagnosis is based upon the HLH-2004 criteria; which, for adult cases, may be insensitive for diagnosis earlier in the disease course. The H-Score is a validated diagnostic tool more appropriate for use among secondary HLH cases. For pediatric or EBV/lymphomatous cases, chemotherapeutic agents are often added. For adult cases, a high-dose dexamethasone regimen based upon the HLH-94 protocol may be used.\n\nAcknowledgements\nWe wish to acknowledge our respective mentors, who have guided us throughout our careers.\n\nFunding\nNo external funding was utilized to support publication of this manuscript.\n\nAvailability of data and materials\nNot applicable.\n\nAuthors’ contributions\nMEM and LE performed relevant data extraction and analysis. MT drafted the manuscript. MEM and LE participated at all stages in editing and revision of the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nEthics approval and consent to participate\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n==== Refs\nReferences\n1. Ramos-Casals M Brito-Zeron P Lopez-Guillermo A Khamashta MA Bosch X Adult haemophagocytic syndrome Lancet 2014 383 1503 1516 10.1016/S0140-6736(13)61048-X 24290661 \n2. Online Mendelian Inheritance in Man, OMIM®. Baltimore: Johns Hopkins University. MIM Number: {267700}: {05/21/2015}. World Wide Web URL: https://omim.org/.\n3. Brisse E Matthys P Wouters CH Understanding the spectrum of haemophagocytic lymphohistiocytosis: update on diagnostic challenges and therapeutic options Br J Haematol 2016 174 175 87 10.1111/bjh.14144 27292929 \n4. Henter JI Elinder G Söder O Ost A Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis Acta Paediatr Scand 1991 80 4 428 35 10.1111/j.1651-2227.1991.tb11878.x 2058392 \n5. Henter JI Horne A Arico M Egeler RM Filipovich AH Imashuku S HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Pediatr Blood Cancer 2007 48 124 131 10.1002/pbc.21039 16937360 \n6. Emmenegger U Schaer D Larroche C Neftel K Haemophagocytic syndromes in adults: current concepts and challenges ahead Swiss Med Wkly 2005 135 289 314 \n7. Raschke RA Garcia-Orr R Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults Chest 2011 140 4 933 938 10.1378/chest.11-0619 21737492 \n8. Henter JI Arico M Egeler RM Elinder G Favara BE Filipovich AH HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis Med Pediatr Oncol 1997 28 342 347 10.1002/(SICI)1096-911X(199705)28:5<342::AID-MPO3>3.0.CO;2-H 9121398 \n9. Oto M Yoshitsugu K Uneda S Nagamine M Yoshida M Prognostic factors and outcomes of adult-onset hemophagocytic lymphohistiocytosis: a retrospective analysis of 34 cases Hematol Rep 2015 7 5841 10.4081/hr.2015.5841 26331000 \n10. Hayden A Park S Giustini D Lee AYY Chen LYC Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review Blood Rev 2016 30 6 411 420 10.1016/j.blre.2016.05.001 27238576 \n11. Chao CT Cao CC Lee SY Ho SJ Jhuang YJ Li LH Kao TW Renal cell carcinoma with secondary hemophagocytic syndrome: a case report Can Urol Assoc J 2012 6 2 e64 e66 10.5489/cuaj.10188 22511436 \n12. Riviere S Galicier L Coppo P Marzac C Aumont C Lambotte O Fardet L Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients Am J Med 2014 127 1118 1125 10.1016/j.amjmed.2014.04.034 24835040 \n13. Fardet I Galicier L Lambotte O Marzac C Aumont C Chahwan D Development and validation of the H-Score, a score for the diagnosis of reactive hemophagocytic syndrome Arthritis Rheumatol 2014 66 9 2613 20 10.1002/art.38690 24782338 \n14. Debaugnies F Mahadeb B Ferster A Meuleman N Rozen L Demulder A Corazza F Performances of the H-Score for diagnosis of hemophagocytic lymphohistiocytosis in adult and pediatric patients Am J Clin Pathol 2016 145 6 862 870 10.1093/ajcp/aqw076 27298397\n\n", "fulltext_license": "CC BY", "issn_linking": "1752-1947", "issue": "11(1)", "journal": "Journal of medical case reports", "keywords": "Altered mental status; Disseminated intravascular coagulation; Fever; Fever of unknown origin; Hemophagocytic lymphohistiocytosis", "medline_ta": "J Med Case Rep", "mesh_terms": "D000328:Adult; D002292:Carcinoma, Renal Cell; D003907:Dexamethasone; D004211:Disseminated Intravascular Coagulation; D005293:Ferritins; D005938:Glucocorticoids; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D009102:Multiple Organ Failure; D010198:Pancytopenia; D015375:Receptors, Interleukin-2; D016896:Treatment Outcome", "nlm_unique_id": "101293382", "other_id": null, "pages": "56", "pmc": null, "pmid": "28249615", "pubdate": "2017-03-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "24835040;21737492;16937360;2058392;27292929;26331000;24290661;27298397;24782338;22511436;27238576;16034684;9121398", "title": "Secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report.", "title_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report" }

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"reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Influenza like illness", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Urinary retention", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transferrin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Interleukin-2 receptor increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Coagulopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Procalcitonin increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood osmolarity decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Lipase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Abdominal rigidity", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "C-reactive protein increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hepatosplenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Activated partial thromboplastin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Platelet count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Iron binding capacity total decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Serum ferritin increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M, EISENBUD L, TRAN M-H. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT. J-MED-CASE-REP 2017;11NO. 1.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170525", "receivedate": "20170525", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13581477, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-HORIZON-PRE-0203-2017", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "202020", "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": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": null, "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": "HYDROXYCHLOROQUINE" } ], "patientagegroup": "5", "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histiocytosis haematophagic", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M, EISENBUD L, TRAN MH. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT. J MED CASE REP. 2017;11(1):56.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170522", "receivedate": "20170522", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13566587, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "US-MYLANLABS-2017M1028449", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "040274", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTATIC RENAL CELL CARCINOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PAZOPANIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Histiocytosis haematophagic", "reactionmeddraversionpt": "20.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M, EISENBUD L, TRAN M-H. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT. J-MED-CASE-REP 2017;11:NO. 1.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170516", "receivedate": "20170516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13550301, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20170830" }, { "companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201703-001825", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": "3", "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": "AZATHIOPRINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LEVOFLOXACIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "INFLUENZA LIKE ILLNESS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVOFLOXACIN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROXYCHLOROQUINE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "009768", "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": "HYDROXYCHLOROQUINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PAZOPANIB" }, "drugadditional": "3", "drugadministrationroute": null, "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": "PAZOPANIB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": "3", "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": "PREDNISONE." } ], "patientagegroup": null, "patientonsetage": "35", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Transferrin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neck pain", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Tachycardia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Mental status changes", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalopathy", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Disseminated intravascular coagulation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dyspnoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "C-reactive protein increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood osmolarity decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood triglycerides increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyponatraemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Prothrombin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "International normalised ratio increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Histiocytosis haematophagic", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood lactate dehydrogenase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood albumin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Inappropriate antidiuretic hormone secretion", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Oropharyngeal pain", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatosplenomegaly", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Iron binding capacity total decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Haemoglobin decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aspartate aminotransferase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Chills", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Activated partial thromboplastin time prolonged", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Interleukin-2 receptor increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Blood lactic acid increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lipase increased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hypofibrinogenaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Influenza like illness", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hyperferritinaemia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Procalcitonin", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Natural killer cell count decreased", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "20.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "EL-MASRY M,EISENBUD L,TRAN M. SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA: A CASE REPORT.. JOURNAL OF MEDICAL CASE REPORTS 2017 MAR 02;11:56:.", "literaturereference_normalized": "secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170406", "receivedate": "20170322", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13358263, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20170830" } ]

{ "abstract": "BACKGROUND\nIn Turkey, pharmacovigilance began in 1985. A fully structured adverse drug reaction (ADR)-reporting system was established with the publication of the first pharmacovigilance regulation in 2005. Subsequent regulation published in 2014 brought further improvements to the system.\n\n\nOBJECTIVE\nIn this study, we aimed to analyse the ADR-reporting pattern in the context of the first pharmacovigilance legislation in Turkey.\n\n\nMETHODS\nWe analysed ADR reports submitted to the Turkish Pharmacovigilance Center (TUFAM) from 2005 to 2014 with respect to reporting rate (RR), patient characteristics, type of the ADRs, suspected drugs, source of the report and the profession of the reporter.\n\n\nRESULTS\nThe annual RR increased gradually over the study period. RRs for females were greater than those for males. RRs were highly correlated with age. Most commonly reported ADRs were skin and subcutaneous tissue disorders. Most commonly suspected drugs were antineoplastic and immunomodulating agents. There was no remarkable change in reporting pattern of ADRs, patient characteristics or classes of suspected drugs over the years. The most common source of reports was spontaneous reporting. Contribution of the reports from studies increased gradually. Most of the reports were reported by physicians. RRs by pharmacists increased substantially over the years.\n\n\nCONCLUSIONS\nThis study showed that the annual RR increased gradually over the 9-year study period. This increase was neither due to an increased reporting of a specific group of ADRs or drugs, nor to an increased reporting in a specific group of patients. There was a general increase in RR in parallel to pharmacovigilance activities.", "affiliations": "Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey.;Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520, Ankara, Turkey. [email protected].", "authors": "Ozcan|Gulnihal|G|;Aykac|Emel|E|;Kasap|Yelda|Y|;Nemutlu|Nergiz T|NT|;Sen|Ebru|E|;Aydinkarahaliloglu|N Demet|ND|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1007/s40801-015-0054-1", "fulltext": "\n==== Front\nDrugs Real World OutcomesDrugs Real World OutcomesDrugs - Real World Outcomes2199-11542198-9788Springer International Publishing Cham 270737555410.1007/s40801-015-0054-1Original Research ArticleAdverse Drug Reaction Reporting Pattern in Turkey: Analysis of the National Database in the Context of the First Pharmacovigilance Legislation Ozcan Gulnihal Aykac Emel Kasap Yelda Nemutlu Nergiz T. Sen Ebru Aydinkarahaliloglu N. Demet [email protected] Department of Risk Management, Turkish Pharmacovigilance Center (TUFAM), Turkish Medicines and Medical Devices Agency, 06520 Ankara, Turkey 8 1 2016 8 1 2016 3 2016 3 1 33 43 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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.Introduction\nIn Turkey, pharmacovigilance began in 1985. A fully structured adverse drug reaction (ADR)-reporting system was established with the publication of the first pharmacovigilance regulation in 2005. Subsequent regulation published in 2014 brought further improvements to the system.\n\nObjective\nIn this study, we aimed to analyse the ADR-reporting pattern in the context of the first pharmacovigilance legislation in Turkey.\n\nMethods\nWe analysed ADR reports submitted to the Turkish Pharmacovigilance Center (TUFAM) from 2005 to 2014 with respect to reporting rate (RR), patient characteristics, type of the ADRs, suspected drugs, source of the report and the profession of the reporter.\n\nResults\nThe annual RR increased gradually over the study period. RRs for females were greater than those for males. RRs were highly correlated with age. Most commonly reported ADRs were skin and subcutaneous tissue disorders. Most commonly suspected drugs were antineoplastic and immunomodulating agents. There was no remarkable change in reporting pattern of ADRs, patient characteristics or classes of suspected drugs over the years. The most common source of reports was spontaneous reporting. Contribution of the reports from studies increased gradually. Most of the reports were reported by physicians. RRs by pharmacists increased substantially over the years.\n\nConclusion\nThis study showed that the annual RR increased gradually over the 9-year study period. This increase was neither due to an increased reporting of a specific group of ADRs or drugs, nor to an increased reporting in a specific group of patients. There was a general increase in RR in parallel to pharmacovigilance activities.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s40801-015-0054-1) contains supplementary material, which is available to authorized users.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\nReporting rate of adverse drug reactions increased gradually over the years in Turkey in parallel to awareness activities on drug safety.\t\nIn Turkey, the reporting rate of adverse drug reactions was higher in females and elderly patients.\t\nThe number of ADRs reported per million boxes of drug consumption was highest for antineoplastic and immunomodulating agents.\t\n\n\nIntroduction\nAdverse drug reactions (ADRs) are common causes of mortality and morbidity all around the world [1, 2]. They represent an important economic burden for health systems [3, 4]. ADRs that occur in real-world medical practice cannot always be predicted by pre-marketing data since a limited number of selected patients are enrolled in clinical trials for specific indications and monitored for a limited period of time. Therefore, post-marketing surveillance is the most important tool for pharmacovigilance systems for early detection of unexpected and serious ADRs [5].\n\nWorld data on ADRs are collected at the Uppsala Monitoring Center (UMC) constituted under the auspices of the World Health Organization’s (WHO) Programme for International Drug Monitoring [5, 6]. All member countries send national ADR reports to the UMCs individual case safety reports (ICSR) database system, VigiBase [7, 8]. UMC continuously monitors the VigiBase for possible signals and alerts. Alerts from UMC constitute an important reference for decision-making processes of national pharmacovigilance authorities. However, ADR profiles vary from country to country owing to differences in genetics, diet and traditions of populations, and medical practices [5, 6, 9]. Additionally, pharmacovigilance legislations and the structure of the pharmacovigilance systems vary among WHO member countries [10, 11]. Because of these factors, information derived from the cumulative data may not always be relevant or applicable to individual populations. To be able to detect local signals and take accurate actions for minimization of the risk, it is important for countries to monitor and analyse their own national ADR databases continually. Such analysis can also guide actions to stimulate ADR reporting, and help to assess the effectivity of national legislations and pharmacovigilance activities.\n\nIn Turkey, pharmacovigilance activities started in 1985 with the establishment of the “Turkish Adverse Drug Reaction Monitoring and Evaluation Center” (TADMER) under the General Directorate of Pharmaceuticals and Pharmacy. In 1987, TADMER joined the WHO Programme as an official member. In 2005, first pharmacovigilance regulation, “Regulation on the Monitoring and Assessment of the Safety of Medicinal Products for Human Use”, became effective [12]. With this regulation, TADMER started to conduct pharmacovigilance activities under the name “Turkish Pharmacovigilance Center” (TUFAM), in order to stress the term “Pharmacovigilance”. In the regulation, major responsibilities of TUFAM were defined as: monitoring national ADR reports and drug safety alerts worldwide, communicating drug safety alerts to healthcare professionals, educating physicians and pharmacists on pharmacovigilance, conducting risk minimization methods, and assessing conformity of risk management plans and periodic safety update reports. Taking this first regulation as reference, responsibilities of Authorization Holders, Pharmacovigilance Inspections and Structure of Risk Management Systems were addressed in detail in the guidelines published in 2005, 2009 and 2011, respectively. In 2012, the General Directorate of Pharmaceuticals and Pharmacy became an agency called the Turkish Medicines and Medical Devices Agency. With this structural change, a Risk Management Unit was formed to take over risk minimization activities. Since then, TUFAM has been concentrating on monitoring and assessing national ADR reports.\n\nNational ADR reports reach TUFAM from two major sources: healthcare professionals and marketing authorization holders (MAHs). Healthcare professionals can notify spontaneous reports to the TUFAM either directly or by means of the pharmacovigilance contact points (PvCPs) within the health organization that they are employed in. PvCPs are physicians or pharmacists who are responsible for encouraging the notification of ADRs, collecting and communicating information to TUFAM, and carrying out training and awareness activities at hospitals they work in. According to regulation, a PvCP should be assigned to work at university hospitals, training and research hospitals, and private hospitals with a bed capacity of 50 or more. This regulation was later expanded to cover all hospitals. This method is different from many countries, and has the intention of communicating information faster between TUFAM and health-care professionals.\n\nMAHs are responsible for keeping the records of all suspected ADRs and notifying serious ADRs occurring in Turkey to the TUFAM within 15 days. They collect both spontaneous reports and solicited reports from patient support programmes where they receive and collect information relating to the use of their medicinal products. In Turkey, MAHs are also responsible for screening national and international literature for ADRs regarding the local population and forwarding a copy to TUFAM.\n\nSpontaneous and solicited ADR reports reaching TUFAM from healthcare professionals and MAHs are sent to the VigiBase as ICSRs. In this way TUFAM contributes to the integration of world data on ADRs as intended by the WHO programme. In 2014, national pharmacovigilance regulation was revised in the context of harmonization with EU directives [13]. With these new regulations, patient reports also started to be accepted and sent to the VigiBase by TUFAM. Additionally national ADRs mentioned in the literature started to be sent to the Vigibase if they complied with the requirements of an ICSR.\n\nIn this study, we aimed to analyse the national ADR reports submitted to VigiBase in the period for which the first pharmacovigilance legislation was effective and present the ADR reporting pattern in Turkey. This is the first detailed study on the National ADR Database of Turkey.\n\nMethods\nData\nThis study included national ADR reports for all the marketed drugs that were submitted to VigiBase by TUFAM between 1 July 2005 and 31 December 2013. In the study period all of the spontaneous and solicited reports that reach TUFAM and satisfy the minimum criteria of reporting were submitted to Vigibase. Minimum criteria of reporting were defined in the regulation as: (a) an identifiable reporter, (b) an identifiable patient, (c) at least one suspected drug, and (d) at least one ADR. The reports for which missing information could not be completed were not submitted to the VigiBase, since they did not comply with a valid ICSR.\n\nFor each report, information about the type of the report, qualification of the reporter, age and sex of the patient, suspected medications, ADRs and seriousness of the ADRs was extracted from the VigiBase. Number of reports in individual categories was counted for each study-year. Data were presented as report count, percentage of reports and/or RR for individual groups. RR was used as a measure of annual frequency of reporting in each category and estimated by adjusting the number of reports in the individual category in a year by the number of individuals residing in the corresponding category for that year. Different from other years, data for 2005 were given only for the second half of the year since the first pharmacovigilance regulation became effective on 30 June 2005.\n\nRRs for specific age or sex groups were estimated to observe the differences in RRs within age or sex groups. The Turkish Statistical Institute’s population by sex and age groups data were used for estimation [14]. Additionally, RRs per million patient visits and million inpatients were estimated as a measure of frequency of reporting for a million visits and a million hospitalizations. RRs for a million boxes of drug consumption and a thousand individuals in health profession groups were estimated to investigate the pattern of reporting for different drug and reporter groups, respectively. The Turkish Ministry of Health’s data on number of hospital visits by years, number of inpatients by years, consumption of drugs by years and number of healthcare professionals by years were used for estimation [15]. Estimation was done only for the years in which Ministry of Health’s data are available.\n\nClassification of Reports\nIn Vigibase there are two categories for defining the type of report: spontaneous reports and reports from studies. The terminology for spontaneous reports in our database and Vigibase is the same but solicited reports from patient support programmes in our database were coded as reports from studies during entry into the Vigibase.\n\nReporters were classified according to six groups: physicians, pharmacists, other health professionals, consumers, lawyers and unknown.\n\nFor age grouping 5-year interval age groups were used. Accordingly, patients were divided into the following age groups: 0–4, 5–9, 10–14, 15–19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74 and +75 years. In order to calculate age-specific RRs, the number of ADR reports within each 5-year interval age group was adjusted by the number of individuals in the age group for the corresponding year [14].\n\nADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) [16]. Seriousness of ADRs was classified according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E2A criteria used in VigiBase [17].\n\nSuspected drugs were classified according to the Anatomical Therapeutic Chemical (ATC) Classification system at level 2 at most, which provides information about pharmacological/therapeutic subgroup [18].\n\nStatistics\nStudent’s t test was used for analysing the significance of difference between RRs for a million inhabitants and a million inpatients per year, and the difference between RRs in sex groups. Pearson’s correlation coefficient (r) was calculated for correlation analysis.\n\nResults\nWe examined spontaneous and solicited reports that were submitted to TUFAM for all the marketed drugs in the period from June 2005 to the end of 2013. During the study period, a total of 8065 reports satisfied the minimum criteria for reporting and were thus included in the study.\n\nAdverse Drug Reaction (ADR) Reporting Rates\nThe number of ADR reports submitted in a year increased gradually over the study period (Fig. 1).Fig. 1 Annual number of adverse drug reaction (ADR) reports submitted to Vigibase by the Turkish Pharmacovigilance Centre (TUFAM) between 2005 and 2013. Asterisk data was given for the second half of the year\n\n\n\nAn increase in population, hospital visits or drug consumption may cause bias in favour of an increase in reporting of ADRs over years. To address these possibilities we adjusted the number of reports with the number of inhabitants (in millions), patient visits (in millions) and boxes of drug consumed (in millions) in a year, and estimated annual RRs (Table 1). We observed that the annual RR for a million inhabitants increased from 1.5 in 2005 to 32.1 in 2013 in parallel with the annual number of reports. The greatest increase in RR was observed in 2012 with a 10.7 increase. The annual RR for a million patient visits and a million boxes of drug consumption also increased over the years, and were highly correlated with the increase in RR for a million inhabitants (r = 0.99). Additionally, we observed that the annual RRs for a million inhabitants were significantly higher than those for a million patient visits (p < 0.05).Table 1 Annual reporting rate of adverse drug reactions per million inhabitants, million patient visits and million boxes of drug consumption in Turkey between 2005 and 2013\n\nYear\t2005a\n\t2006\t2007\t2008\t2009\t2010\t2011\t2012\t2013\t\nRRb (#/mill. inhab./year)\t1.5\t4.3\t5.0\t5.4\t7.1\t13.5\t14.6\t25.3\t32.1\t\nRate of increase in RR b\n\t\t2.8\t0.7\t0.4\t1.7\t6.4\t1.1\t10.7\t6.8\t\nRRc (#/mill. visits/year)\t\t\t\t\t1.8\t3.3\t3.2\t5.4\t6.5\t\nRRd (#/mill. boxes /year)\t\t\t0.3\t0.3\t0.4\t0.7\t0.7\t1.1\t1.6\t\n\nRR reporting rate\n\n\naData was given for the second half of the year only\n\n\nbNumber of reports/million inhabitants/year\n\n\ncNumber of reports/million patient visits/year\n\n\ndNumber of reports/million boxes of drug consumption/year\n\n\n\nType of Reports\nThe most common type of reporting was spontaneous reports in all years investigated (Table 2). Contribution of reports from studies increased gradually starting from 2010. The greatest increase in reporting from studies was observed in 2012.Table 2 Percentage distribution of adverse drug reaction reports by type in Turkey between 2005 and 2013\n\nYear\t2005a\n\t2006\t2007\t2008\t2009\t2010\t2011\t2012\t2013\t\nSpontaneous\t100.0\t99.0\t100.0\t99.5\t99.6\t92.3\t81.8\t71.1\t74.5\t\nReport from study\t0.0\t1.0\t0.0\t0.5\t0.4\t7.7\t18.2\t28.9\t25.5\t\nTotal\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t100.0\t\n\naData were given for the second half of the year\n\n\n\nADRs by Sex\nOverall, 56.5 % of reports were reported for females. The percentage of reports for females was greater than that for males for all years (data not shown). When the number of reports for sex groups was standardized for the corresponding population in millions, annual RRs for females were still significantly greater than those for males (p < 0.05) (Table 3).Table 3 Annual reporting rate of adverse drug reactions for females and males in Turkey between 2005 and 2013\n\nYear\t2005a\n\t2006\t2007\t2008\t2009\t2010\t2011\t2012\t2013\t\nReporting rateb\n\t\n Female\t2.2\t4.8\t5.5\t6.1\t8.0\t15.2\t17.6\t28.5\t35.7\t\n Male\t0.8\t3.7\t4.3\t4.7\t6.0\t11.5\t11.2\t20.7\t26.7\t\n\naData were given for the second half of the year\n\n\nbNumber of reports/million individuals in the sex group/year\n\n\n\nADRs by Age\nWe calculated the RRs per million inhabitants in 5-year age group intervals to observe the pattern of reporting with respect to age groups (Fig. 2). The 9-year averages of RRs were highest in age groups 65–69, 70–74, 60–64 and +75 years, and tended to decrease with the decrease in age of the patients. Despite the high positive correlation between RRs and age (r = 0.93), we observed a higher RR in 0–4 years age group compared to adjacent age groups. When this age group was removed from the correlation analysis, strength of correlation increased further (r = 0.97).Fig. 2 Reporting rate (RR) of adverse drug reactions by 5-year interval age groups in Turkey between 2005 and 2013 (9-year average)\n\n\n\nType of Reporter\nIn general, most of the ADR reports were reported by physicians (59.8 %), followed by other health professionals (28.7 %) and pharmacists (9.1 %). A small percentage of reports was reported by consumers (2.3 %) (data not shown).\n\nIn Table 4, RRs are given that were calculated by adjusting the number of reports with the number of actively working professionals (in thousands) in the corresponding year. In general, RRs of physicians were greater than those of pharmacists. However, RRs of pharmacists increased substantially over the years and even exceeded the RRs for physicians in the year 2013. RRs of other health professionals could not be calculated since the definition of “other health professionals” used in the Health Statistics in Turkey is more comprehensive, and included: surgery technician, biologist, environmental health technician, child development specialist, dental technician, dietitian, physical therapy technician, physiotherapist, first aid and emergency care repairman, heart-lung pump operation technician, laboratory repairman, laboratory technician, audiologist, audiometric repairman, audiometric technician, orthopaedic technician, pathological anatomy technician, perfusion pump technician, prosthetics technician, psychologist, radiographer, health physicist, war health officer, health technician, health repairman, cytopathologist, social worker, medical secretary, medical technologist and public health technician in addition to nurse, anaesthesia technician, and emergency and first aid technician included in national pharmacovigilance system.Table 4 Annual reporting rate of adverse drug reactions by physicians and pharmacists in Turkey between 2009 and 2013\n\nHealth professional\t2009\t2010\t2011\t2012\t2013\t\nPhysician\t3.6\t6.2\t5.5\t6.7\t8.0\t\nPharmacist\t1.9\t2.9\t4.3\t6.6\t10.3\t\nNumber of reports/thousand professionals actively working in Turkey/year\n\n\n\nADRs According to Seriousness\nIn the study period a total of 16,248 ADRs were reported in 8065 reports. The average number of ADRs per report showed a slight increase from 1.8 in 2005 to 2.3 in 2013 with a 9-year average of 2.0 (data not shown).\n\nAmong all the reports, 70.5 % included a serious ADR. The most commonly specified seriousness criterion was medically important conditions (44.8 %), which was followed by hospitalization or prolongation of existing hospitalization (36.6 %), life-threatening conditions (14.3 %), death (8.6 %), persistent or significant disability/incapacity (2.7 %) and congenital anomalies (0.2 %) (data not shown).\n\nWe wanted to estimate the frequency of reporting of ADRs as a cause of hospitalization or prolongation of existing hospitalization among hospitalized patients. We observed a gradual increase in RR over years with a 32.5 increase per million inpatients from 2009 to 2013 (Fig. 3).Fig. 3 Annual reporting rate (RR) of adverse drug reactions as a cause of hospitalization or prolongation of hospitalization between 2009 and 2013. Asterisk number of reports in which hospitalization or prolongation of hospitalization was reported as the seriousness criterion /number of inpatients in Turkey/year\n\n\n\nDuring the study period, seriousness criterion was reported as congenital anomaly in 14 reports. Suspected drugs and ADR terms for these reports are listed in Table 5.Table 5 Suspected drugs and adverse drug reaction (ADR) terms in the reports where congenital anomaly was reported as the seriousness criterion in Turkey between 2005 and 2013\n\nCase\tSuspected drug\tADR terms\t\n1\tAdalimumab\tMaternal exposure during pregnancy; abortion\t\n2\tAdefovir dipivoxil\tCongenital anomaly, third finger first phalanx deficiency\t\n3\tButamirate citrate\tDysmorphism; alopecia areata; hypotonia; mental retardation; failure to thrive; brain malformation; congenital deafness; congenital blindness\t\n4\tDasatinib\tFlatulence; maternal exposure during pregnancy\t\n5\tDrospirenone/ethinylestradiol\tTherapeutic abortion due to anomaly\t\n6\tEntecavir\tCongenital musculoskeletal anomaly\t\n7\tEscitalopram, mirtazapine, hyoscine n-butylbromide, medazepam\tMaternal exposure during pregnancy; congenital anomaly not otherwise specified, abnormality of right forearm reduction of the fetus\t\n8\tInsulin aspart\tCongenital anomaly (5-alfa reductase enzyme deficiency dependent ambiguous genitalia, left coronary artery variation anomaly and horse-shoe kidney)\t\n9\tInsulin regular/insulin isophane\tMaternal exposure during pregnancy; congenital hand malformation; limb malformation\t\n10\tInsulin regular/insulin isophane\tPremature baby; breech presentation; fetal exposure during pregnancy\t\n11\tIsotretinoin\tCongenital hydrocephalus; eyelid ptosis; cleft palate; ear malformation\t\n12\tOlanzapine\tMaternal exposure during pregnancy; hypotonia neonatal; cyanosis neonatal; talipes\t\n13\tRanibizumab\tVentricular septal defect\t\n14\tTenofovir disoproxil fumarate\tPremature baby; fetal death; placental disorder\t\n\n\nADRs by System Organ Classification (SOC)\nThe percentage distribution of most frequently reported ADRs by SOC is given in Fig. 4. These 14 SOCs listed in the figure covered 90.2 % of all ADRs in the database.Fig. 4 Percentage distribution of adverse drug reactions by most frequently reported system organ classes in Turkey between 2005 and 2013\n\n\n\nSkin and subcutaneous tissue disorders, general disorders and administration site conditions, gastrointestinal disorders and nervous system disorders were the most frequently reported ADR SOCs, constituting together approximately 50 % of ADR SOCs in the database (Fig. 4). There was no remarkable change in reporting pattern of ADRs by SOCs over time. These four SOCs were in the top five of most frequently reported ADR SOCs in all years investigated (data not shown).\n\nADRs by Therapeutic Groups\nIn the study period a total of 9394 drugs were reported in 8065 reports. In 88.8 % of the reports only one drug was reported as the suspected drug. In the rest of the reports mostly two drugs (6.8 %) or three drugs (3.9 %) were suspected to cause the ADR. The average number of drugs per report was around 1.2 for all years.\n\nMost commonly reported drugs belong to the ATC classes antineoplastic and immunomodulating agents (26.5 %), anti-infectives for systemic use (24.5 %) and nervous system drugs (14.3 %) (Fig. 5). These three ATC classes were the most frequently reported drug groups in all years investigated (data not shown) and covered 65.5 % of all the suspected drugs reported in the 9-year period.Fig. 5 Percentage distribution of adverse drug reaction reports by Anatomical Therapeutic Chemical (ATC) class (first level) of suspected drugs in Turkey between 2005 and 2013\n\n\n\nReporting rate with respect to million boxes of drug consumption slightly increased over the study period (Table 1). RR for antineoplastic and immunomodulating agents was significantly high compared to overall RR (p < 0.01) (Supplementary Table 1). With the second-level ATC subgroups, most commonly reported drug groups were antibacterials for systemic use, immunosuppressants and antineoplastic agents (Supplementary Table 2). Most commonly reported active substances and percentage of serious ADRs reported for these drugs were listed in Table 6.Table 6 Report counts and Anatomical Therapeutic Chemical (ATC) codes for most commonly reported active substances in Turkey between 2005 and 2013 and percentage of serious adverse drug reactions (ADRs) for each substance\n\n\tSuspected drug\tReport count\tPercent of serious ADRs\tATC code\t\n1\tAdalimumab\t457\t98\tL04\t\n2\tInterferon beta-1b\t289\t74\tL03\t\n3\tEtanercept\t230\t59\tL04\t\n4\tCeftriaxone sodium\t214\t32\tJ01\t\n5\tPeginterferon alfa\t210\t96\tL03\t\n6\tRibavirin\t209\t98\tJ05\t\n7\tTelaprevir\t196\t100\tJ05\t\n8\tInfliximab\t147\t61\tL04\t\n9\tMoxifloxacin\t138\t63\tJ01\t\n10\tCefazolin sodium\t106\t26\tJ01\t\n\n\nADR reports related to vaccines constitute a very small percentage of the database (1.46 %, 118 reports) since safety of vaccines has being monitored by immunization programmes in Turkey. Most commonly reported vaccines in our database were pneumococcal conjugate vaccine (40 reports), rotavirus vaccine (19 reports) and influenza vaccines (19 reports) in the 9-year study period.\n\nDiscussion\nADR Reporting Rates and Report Types\nThis is the first study to analyse general ADR reporting patterns in the national pharmacovigilance database of Turkey. Our analyses showed that ADR RRs for a million inhabitants in Turkey increased remarkably over the last 9 years (Table 1). Most remarkable increases were observed in 2010, 2012 and 2013. There were salient advances in these years likely to contribute to the increased RR. In 2010, patient support programmes became effective and contribution of these programmes to the ADR database increased after that (Table 2). With the structural change in our National Pharmacovigilance Center in 2012, TUFAM started to concentrate mostly on monitoring and assessment of national ADR reports and was given the opportunity to dedicate more resources on the activities to raise awareness on pharmacovigilance and encourage ADR reporting nationwide. In 2012, a remarkable increase was observed in the rate of reporting from both patient support programmes and spontaneous sources. This observation can be evaluated as a translation of the effectivity of the structural change. In 2013, TUFAM started to accept patient notifications in the context of a pilot project via an electronic system developed by UMC. The system was incorporated into the Turkish Medicines and Medical Devices Agency’s website. In the first year of the project, a remarkable number of reports were submitted by consumers and contributed to the increasing trend in annual RR (data not shown).\n\nIn the study, we observed a significantly higher annual RR for million inhabitants than that for million patient visits. This observation suggests a considerable frequency of ADRs related to self-medication. Self-medication is a public health problem all over the world and studies have shown that self-medication-related ADRs should not be ignored [19, 20]. This point should also be addressed in Turkey by future studies.\n\nADRs by Sex and Age\nIn the study period RR for female patients was significantly high than that for males (Table 3). This is consistent with other studies [21–23]. There can be different factors contributing to the higher rate of reporting in females: the incidence of ADRs may be higher in females, hospital visits may more frequently involve female patients or female patients may more frequently consult a healthcare professional concerning an ADR. However, it is not possible to discern the individual contribution of these factors to the existing data.\n\nIn accordance with the results of previous studies [21, 23, 24], RRs were higher in the elderly where drug consumption is high (Fig. 2). Interestingly, RRs for the 0–4 years age group was remarkably high compared to those of adjacent age groups. In the study period, a patient support programme regarding use of palivizumab was active. Since palivizumab is used mostly in neonates, a large number of reports that reached TUFAM from the palivizumab patient support programme in the study period could be an explanation for the relatively high RR in the 0–4 year age group.\n\nADRs by Type of Reporter\nReports from physicians constituted the greatest percentage of reports, followed by reports from other health professionals and pharmacists. However, these data does not reflect reporting behaviors of profession groups since number of individuals in each profession group vary greatly. Therefore, number of reports was adjusted with the number of individuals in each profession group for the years between 2009 and 2013 in which corresponding data are available. It was observed that RR of physicians was greater than that of pharmacists for the years 2009–2012. However, RR of pharmacists increased substantially over the years and exceeded the RR of physicians in 2013 (Table 4). This increase in RR of pharmacists may be explained by the fact that mostly pharmacists being employed as PvCPs.\n\nADRs by Seriousness\nOverall, 70.5 % of the reports included a serious ADR. This is expected since there is emphasis on reporting of serious ADRs in pharmacovigilance regulations in Turkey. Reporting of hospitalization or prolongation of existing hospitalization as seriousness criteria increased gradually over time and reached 48.3 per million inpatients in 2013 (Fig. 3). This may be a reflection of the increased awareness regarding ADRs and the overall increase in RRs.\n\nDuring the study period, the seriousness criterion was reported as congenital anomaly in 14 reports (Table 5). In two of the reports the suspected drugs were drospirenone/ethinylestradiol and isotretinoin which have a pregnancy category of X. In the first report, “therapeutic abortion due to anomaly” was reported with exposure to drospirenone/ethinylestradiol (Case 5). In the literature there are reports that relate oral contraceptive use to malformations of the genitals in male infants [25, 26]. However, in the report mentioned above, the anomaly was not specified. In the second report (Case 11), “Congenital hydrocephalus; Eyelid ptosis; Cleft palate; Ear malformation” were reported which are well-defined congenital anomalies related to isotretinoin exposure during pregnancy [27–29]. Two out of 14 reports concern drugs with a pregnancy category of D, dasatinib and ranibizumab. For dasatinib, congenital anomaly was not specified in the report (Case 4) but in the product information hydrops fetalis, fetal leukopenia and fetal thrombocytopenia were reported and the possibility of congenital malformations, including neural tube defects, were mentioned [30]. For ranibizumab, ventricular septal defect was reported (Case 13). As far as we know, there is no such case in the literature. Among the suspected drugs with pregnancy category C, only adefovir and olanzapine had been mentioned in congenital anomaly cases in the literature. Congenital heart defect was reported with paternal administration of adefovir in the literature [31], which is not associated with “phalanx deficiency” reported in our case (Case 2). An increased risk of neonatal extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder) were reported to be associated with exposure to antipsychotic drugs during the third trimester of pregnancy [32–34]. Neonatal hypotonia and cyanosis reported for olanzapine in our database (Case 12) is compatible with withdrawal symptoms. Additionally “talipes” was observed in the case. Although a specific pattern of fetal limb or organ malformation have not been reported to be related to antipsychotics, there is a case report where hip dysplasia was observed after olanzapine exposure during pregnancy [35]. Other drugs listed in Table 5 do not appear to be associated with an increased risk for major malformations. Interestingly, three congenital anomaly cases were reported for insulin analogs (Case 8–10) which are preferred during pregnancy owing to their inability to pass transplacentally. Congenital anomalies reported in these cases were: (1) 5-alfa reductase enzyme deficiency dependent ambiguous genitalia, left coronary artery variation anomaly and horse-shoe kidney, (2) congenital hand malformation and limb malformation, and (3) premature baby and breech presentation. The high relative reporting rate for this therapeutic group might be considered a coincidence since pregnancy exposure registries and patient support programmes have being conducted for use of insulin analogues during pregnancy in Turkey.\n\nADRs by System Organ Classification\nAmong 36 SOCs for ADRs, skin and subcutaneous tissue disorders, general disorders and administration site conditions, gastrointestinal disorders, and nervous system disorders were the most frequently reported ADR SOCs covering approximately 50 % of total ADRs (Fig. 4). This pattern is similar to the global pattern of ADRs between the years 2000–2009, where general disorders and administration site conditions, skin and subcutaneous tissue disorders, nervous system disorders and gastrointestinal disorders were the most frequently reported SOCs for ADRs [10].\n\nADRs by Therapeutic Groups\nIn the majority of the reports, only one drug was reported as the suspected drug. RRs per million boxes of drug consumption increased slightly over the study period (Table 1). Similar to patterns of ADRs in upper-middle income countries reported by Aagard et al. [10], drugs from ATC classes of “antiinfectives for systemic use” (24.5 %) and “nervous system” (14.4 %) had high rates of reporting in Turkey (Fig. 5). However, “Antineoplastic and immunomodulating agents” (26.5 %) was the most frequently reported ATC drug group in Turkey; although it was the eighth most common ATC group in the upper-middle income countries [10]. It should be noticed that the study by Aagard et al. analysed only spontaneous reports submitted to VigiBase from 2000 to 2009, whereas our study included both spontaneous reports and reports from studies submitted between 2005 and 2013. These differences in the inclusion criteria for report type and the study periods may be the reason for the difference in rank of reporting for ATC groups. Differences in the characteristics of consumption of these drugs could also be a factor affecting the frequency of reporting in each country. However, number of reports adjusted by the consumption of million boxes of drugs in Turkey was still highest for antineoplastic and immunomodulating agents (Supplementary Table 1). Estimated RRs for this ATC group even reached to 77 times the overall reporting rate in 2011. The most probable explanation for this remarkably high RR is the high number of antineoplastic and immunomodulating agents involved in patient support programmes in Turkey. Examples for these drugs include interferon, eculizumab, fingolimod, adalimumab, etanercept, golimumab, infliximab, tacrolimus and lenalidomide which are highly represented in the database with solicited reports from patient support programmes. Among these, five drugs, namely adalimumab, interferon, etanercept, peginterferon and infliximab were in the list of ten most commonly reported drugs over the study period (Table 6). Percentage of serious ADRs reported with these drugs was generally higher than the overall percentage of serious ADRs in the database. This may be a reflection of the legislation, since MAHs are responsible for notifying serious ADR reports to TUFAM. Accordingly antivirals, Ribavirin and Telaprevir which are also included in patient support programs are represented in the list of most commonly reported drugs with high percentage of serious ADRs. The rest of the drugs in the list were all anti-infectives for systemic use. RR for a million boxes of consumption in this therapeutic group is not different from overall RR for a million boxes of drug consumption (Supplementary Table 1). However, the high reporting rate for these therapeutic groups may be due to higher consumption of these drugs. Additionally these agents mostly cause immediate and easily observable reactions defined under skin and subcutaneous tissue disorders and general disorders, and administration site conditions, for which causality between the drug and the reaction can easily be made. Accordingly, the percentage of serious ADRs reported with these drugs was relatively low in the database (Table 6).\n\nConclusion\nThis study showed that annual RRs in Turkey increased gradually in the 9-year study period. Major factors that might increase RR are: training activities conducted by TUFAM that raise awareness of pharmacovigilance, widening the scope of hospitals to all hospitals for employment of PvCPs, initiation of PV inspections in March 2010, authorization of a large number of biotechnological drugs and initiation of patient support programmes for these drugs. Though regulations that allow patient reporting became effective in April 2014 with the publication of “Regulation on safety of medicines”, patient reports were started to be accepted by TUFAM in 2013. This is also a contributing factor for the increased rate of reporting in the study period.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (DOCX 16 kb)\n\n \n\nThe authors gratefully acknowledge Professor Hakan Ergun (Ankara University Faculty of Medicine) for his helpful comments and advice on the manuscript.\n\nCompliance with Ethical Standards\nConflict of interest\nGulnihal Ozcan, Emel Aykac, Yelda Kasap, Nergiz Temiz Nemutlu, Ebru Sen and Nigar Demet Aydinkarahaliloglu have no conflicts of interest that are directly relevant to the content of this study.\n\nEthical approval\nEthical approval was not required for the study.\n\nFunding\nNo sources of funding were used to assist in the preparation of this study.\n\nAuthor contributions\nN. D. Aydinkarahaliloglu, E. Aykac and G. Ozcan designed the study. G. Ozcan analysed the data and wrote the manuscript. N. D. Aydinkarahaliloglu, E. Aykac, G. Ozcan, Y. Kasap, N. T. Nemutlu, and E. Sen collected the data. All authors saw and approved the final version of the manuscript.\n==== Refs\nReferences\n1. Jönsson AK. Drug-related morbidity and mortality: pharmacoepidemiological aspects: Linköping, Sweden: Linköping University, Faculty of Health Sciences; 2007.\n2. Pirmohamed M James S Meakin S Green C Scott AK Walley TJ Farrar K Park BK Breckenridge AM Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients BMJ. 2004 329 7456 15 19 10.1136/bmj.329.7456.15 15231615 \n3. Sultana J Cutroneo P Trifiro G Clinical and economic burden of adverse drug reactions J Pharmacol Pharmacother. 2013 4 Suppl 1 S73 S77 10.4103/0976-500X.120957 24347988 \n4. Bates DW Spell N Cullen DJ Burdick E Laird N Petersen LA Small SD Sweitzer BJ Leape LL The costs of adverse drug events in hospitalized patients JAMA. 1997 277 4 307 311 10.1001/jama.1997.03540280045032 9002493 \n5. 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Asseray N Ballereau F Trombert-Paviot B Bouget J Foucher N Renaud B Roulet L Kierzek G Armand-Perroux A Potel G Schmidt J Carpentier F Queneau P Frequency and severity of adverse drug reactions due to self-medication: a cross-sectional multicentre survey in emergency departments Drug Saf. 2013 36 12 1159 1168 10.1007/s40264-013-0114-y 24163273 \n20. Schmiedl S Rottenkolber M Hasford J Rottenkolber D Farker K Drewelow B Hippius M Saljé K Thürmann P Self-medication with over-the-counter and prescribed drugs causing adverse-drug-reaction-related hospital admissions: results of a prospective, long-term multi-centre study Drug Saf. 2014 37 4 225 235 10.1007/s40264-014-0141-3 24550104 \n21. Martin RM Biswas PN Freemantle SN Pearce GL Mann RD Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies Br J Clin Pharmacol 1998 46 505 511 10.1046/j.1365-2125.1998.00817.x 9833605 \n22. Zopf Y Rabe C Neubert A Gabmann KG Rascher W Hahn EG Dormann H Women encounter ADRs more often than do men Eur J Clin Pharmacol 2008 64 999 1004 10.1007/s00228-008-0494-6 18604529 \n23. Fattinger K Roos M Vergeres P Holenstein C Kind B Masche U Stocker DN Braunschweig S Kullak-Ublick GA Galeazzi RL Follath F Gasser T Meier PJ Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine Br J Clin Pharmacol 2000 49 158 167 10.1046/j.1365-2125.2000.00132.x 10671911 \n24. Routledge PA O’Mahony MS Woodhouse KW Adverse drug reactions in elderly patients Br J Clin Pharmacol. 2004 57 2 121 126 10.1046/j.1365-2125.2003.01875.x 14748810 \n25. Hemminki E Gissler M Toukomaa H Exposure to female hormone drugs during pregnancy: effect on malformations and cancer Br J Cancer 1999 80 7 1092 1097 10.1038/sj.bjc.6690469 10362122 \n26. Kim MR Qazi QH Anderson VM Valencia GB A genetic male infant with female phenotype in camptomelic syndrome: a relationship to exposure to oral contraceptives during pregnancy Am J Obstet Gynecol 1995 172 1042 1043 10.1016/0002-9378(95)90042-X 7892846 \n27. Hersh JH Danhauer DE Hand ME Weisskopf B Retinoic acid embryopathy: timing of exposure and effects on fetal development JAMA 1985 254 909 910 10.1001/jama.1985.03360070047015 4021019 \n28. Benke PJ The isotretinoin teratogen syndrome JAMA 1984 251 3267 3269 10.1001/jama.1984.03340480049027 6587131 \n29. Braun JT Franciosi RA Mastri AR Drake RM O’Neil BL Isotretinoin dysmorphic syndrome Lancet 1984 1 506 507 10.1016/S0140-6736(84)92866-6 6142222 \n30. Product information: SPRYCEL(R) oral tablets, dasatinib oral tablets. Istanbul: Bristol-Myers Squibb Company (per manufacturer); 2015.\n31. Gu Y Ru T Zhou YH Hu Y Adefovir as a possible teratogen: evidence from paternal exposure Dig Liver Dis 2014 46 12 1134 1135 10.1016/j.dld.2014.08.035 25174874 \n32. Product information: ZYPREXA(R) solution for IM injection, oral tablets, orally disintegrating tablets, olanzapine solution for IM injection, oral tablets, orally disintegrating tablets. Istanbul: Eli Lilly and Company; 2013.\n33. Newport DJ Calamaras MR DeVane CL Donovan J Beach AJ Winn S Knight BT Gibson BB Viguera AC Owens MJ Nemeroff CB Stowe ZN Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes Am J Psychiatry. 2007 164 8 1214 1220 10.1176/appi.ajp.2007.06111886 17671284 \n34. Kulkarni J Storch A Baraniuk A Gilbert H Gavrilidis E Worsley R Antipsychotic use in pregnancy Expert Opin Pharmacother. 2015 16 9 1335 1345 10.1517/14656566.2015.1041501 26001182 \n35. Spyropoulou AC Zervas IM Soldatos CR Hip dysplasia following a case of olanzapine exposed pregnancy: a questionable association Arch Womens Ment Health. 2006 9 4 219 222 10.1007/s00737-006-0138-8 16755330\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2198-9788", "issue": "3(1)", "journal": "Drugs - real world outcomes", "keywords": null, "medline_ta": "Drugs Real World Outcomes", "mesh_terms": null, "nlm_unique_id": "101658456", "other_id": null, "pages": "33-43", "pmc": null, "pmid": "27747800", "pubdate": "2016-03", "publication_types": "D016428:Journal Article", "references": "10362122;25174874;26001182;6142222;18604529;24347976;24347988;24347987;7892846;23072620;24550104;15231615;9002493;24163273;9833605;4021019;6587131;17671284;16755330;10671911;14748810", "title": "Adverse Drug Reaction Reporting Pattern in Turkey: Analysis of the National Database in the Context of the First Pharmacovigilance Legislation.", "title_normalized": "adverse drug reaction reporting pattern in turkey analysis of the national database in the context of the first pharmacovigilance legislation" }

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{ "abstract": "Clozapine is a dibenzodiazepine antipsychotic used for resistant schizophrenia, which is known to be associated with side effects such as agranulocytosis, seizures, weight gain, and less commonly myocarditis/ cardiomyopathy. We present a case of a 20-year-old female who presented with chest pain, shortness of breath, and cough. She was later found to have clozapine-induced pericardial effusion that resolved after discontinuation of clozapine therapy. Our case discloses the importance to consider clozapine in the differential diagnosis of pericardial effusion as discontinuation of the drug leads to resolution of effusion, with no need for further treatment.", "affiliations": "Internal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.;Internal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.;Psychiatry, Bronson Health, Kalamazoo, USA.;Cardiology, Ascension Borgess Hospital, Kalamazoo, USA.", "authors": "Bath|Anandbir S|AS|;Garg|Abhinav|A|;Gajare|Nilanjan|N|;Gupta|Vishal|V|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.4890", "fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4890CardiologyInternal MedicinePsychiatryPericardial Effusion: Rare Adverse Effect of Clozapine Muacevic Alexander Adler John R Bath Anandbir S 1Garg Abhinav 1Gajare Nilanjan 2Gupta Vishal 3\n1 \nInternal Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA \n2 \nPsychiatry, Bronson Health, Kalamazoo, USA \n3 \nCardiology, Ascension Borgess Hospital, Kalamazoo, USA \nAnandbir S. Bath [email protected] 6 2019 6 2019 11 6 e489028 5 2019 11 6 2019 Copyright © 2019, Bath et al.2019Bath et al.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.This article is available from https://www.cureus.com/articles/20472-pericardial-effusion-rare-adverse-effect-of-clozapineClozapine is a dibenzodiazepine antipsychotic used for resistant schizophrenia, which is known to be associated with side effects such as agranulocytosis, seizures, weight gain, and less commonly myocarditis/ cardiomyopathy. We present a case of a 20-year-old female who presented with chest pain, shortness of breath, and cough. She was later found to have clozapine-induced pericardial effusion that resolved after discontinuation of clozapine therapy. Our case discloses the importance to consider clozapine in the differential diagnosis of pericardial effusion as discontinuation of the drug leads to resolution of effusion, with no need for further treatment.\n\npericardial effusionclozapineschizophreniaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nClozapine is a dibenzodiazepine antipsychotic used in cases of schizophrenia, which are partially or fully resistant to conventional antipsychotic therapy. Clozapine is well known to be associated with side effects such as agranulocytosis, seizures, weight gain, insulin resistance, and less commonly myocarditis/cardiomyopathy [1]. Herein, a case of clozapine-induced pericardial effusion is presented, a rare side effect with only a few published case reports.\n\nCase presentation\nA 20-year-old female presented to the emergency department with ongoing complaints of chest pain, shortness of breath, and productive cough for one week. Chest pain was sudden in onset and sharp in character. No variation with respiratory movements was noted. Medical history was significant for resistant schizophrenia on clozapine therapy. The patient denied any history of recent travel or illicit drug use. On physical examination, the patient was found to be tachycardic and tachypneic. No jugular venous distension was noted. Cardiac auscultation revealed regular S1 and S2 with no murmurs, rubs, or gallops. Laboratory investigations were found to be significant for leukocytosis with elevated C-reactive protein (CRP) of 217.9 mg/dL (reference range: 0-0.9 mg/dL) and erythrocyte sedimentation rate (ESR) of 97 mm/h (reference range: 0-29 mm/h). The respiratory infectious disease panel was negative for any viral pathogen and was pneumococcal and legionella antigen. There was no elevation noted in the procalcitonin. Rheumatological workup was also negative to delineate a cause for the effusion. CT chest revealed left lower lobe pneumonia with large pericardial effusion. The patient was started on the appropriate treatment for her community-acquired pneumonia, for which she completed seven days of therapy. Meanwhile, transthoracic echocardiogram further characterized the effusion as moderate circumferential pericardial effusion (Figure 1).\n\nFigure 1 Arrow showing circumferential pericardial effusion in parasternal short axis view of transthoracic echocardiogram\nThere was no evidence of tamponade physiology. Upon consultation with the patient’s psychiatrist, clozapine was stopped, as it was thought to be the cause for the patient’s non-resolving pericardial effusion. Following the discontinuation of the drug, there was a gradual improvement in the respiratory status with follow-up transthoracic echocardiogram after three months revealing a reduction in the size of pericardial effusion (Figure 2).\n\nFigure 2 Follow-up transthoracic echocardiogram (parasternal short axis view) after three months upon discontinuation of clozapine showing resolution of the pericardial effusion\nCRP and ESR also trended down. The patient was discharged to home with discontinuation of clozapine in a stable and improved condition.\n\nDiscussion\nClozapine is an atypical antipsychotic used for resistant schizophrenia. It is used when patients have failed two different antipsychotics [2]. Though being more effective than typical antipsychotics, it is also associated with a hefty side effect profile, which includes agranulocytosis, seizures, central nervous system depression, myopericarditis, and cardiomyopathy. Cardiac toxicity from clozapine can be fatal as there have been reported cases of sudden cardiac death attributed to myocarditis or tamponade from pericardial effusion [3].\n\nPolyserositis from clozapine can lead to pleural effusion, pericardial effusion, and ascites. There have been well-documented case reports of clozapine causing myocarditis and cardiomyopathy but only a few reported cases of clozapine-induced pericardial effusion. Pericardial effusion is a rare (< 1:10,000) and serious adverse effect of clozapine [4].\n\nThere is no well-documented pathophysiology behind its cardiac side effects. Postmortem myocardial biopsy in a few cases revealed eosinophilic infiltrates with myocytolysis. Peripheral eosinophilia and increased levels of IgE have also been noted, indicating the role of IgE-mediated type I hypersensitivity reaction. It can also be viewed as an acute drug reaction as pleuropericardial effusions often occur within one or two weeks of initiation of clozapine therapy [1].\n\nClozapine can cause pericardial effusion as early as one week after the start of treatment. The cases of delayed cardiac manifestations appearing up to months to years after the initiation of clozapine therapy have also been reported [5-7]. In our case, the patient has been taking clozapine for the past 10 months before developing significant cardiac manifestations.\n\nThe presentation of patients can range from mild viral illness to sudden death from cardiac tamponade. Patients usually have a fever with shortness of breath and pleuritic chest pain. Common physical exam findings include tachycardia and tachypnea associated with muffled heart sounds depending on the size of effusion. Troponin elevation can be seen in the scenario of myocardial injury. Inflammatory markers such as CRP and ESR are usually elevated. Suspicion for clozapine-induced pericardial effusion should be high in patients who have been on clozapine for a long time.\n\nSince pericardial effusion is not well documented as an adverse effect, clozapine is usually overlooked as a possible etiology. Baseline ECG and echocardiography should be performed in patients with previous cardiac history who are started on clozapine therapy. All other causes such as viral infection or rheumatological conditions should be ruled out. Patients should follow-up with cardiology if diagnosed with pericardial effusion. Repeat transthoracic echocardiogram after three months of discontinuation of clozapine is recommended to ensure remission [8]. In our case, inflammatory markers CRP and ESR down trended within one week of discontinuation of clozapine therapy, and the repeat transthoracic echocardiogram after three months revealed decreased pericardial effusion.\n\nMultiple case reports have shown that discontinuing clozapine therapy resulted in a decrease in the size of effusion [6,9]. No further treatment is indicated if clozapine is being considered as the most likely cause in the absence of definitive etiology. Follow-up ECG at three months is recommended although no official guidelines exist. There is a lack of evidence to formulate the clinical guidelines regarding clozapine rechallenge. A study showed successful rechallenge outcomes; depending upon the adverse effect clozapine was discontinued for [10].\n\nConclusions\nPericardial effusion from clozapine therapy is a rare adverse effect. The timing of cardiac manifestations and initiation of treatment is variable; discontinuation of clozapine results in improvement of symptoms and resolution of pericardial effusion. No further treatment is indicated, but a follow-up echocardiogram is recommended.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Myocarditis and cardiomyopathy associated with clozapine Lancet Kilian JG Kerr K Lawrence C Celermajer DS 1841 1845 354 1999 10584719 \n2 Treatment-resistant schizophrenia-the role of clozapine Curr Med Res Opin Meltzer Meltzer HY HY 1 20 14 1997 9524789 \n3 Clozapine and incidence of myocarditis and sudden death-long term Australian experience Int J Cardiol Khan AA Ashraf A Baker D 136 139 238 2017 28343762 \n4 Clozapine rechallenge following clozapine-induced pericarditis J Clin Psychiatry Crews MP Dhillon GS MacCabe JH 959 71 2010 20667298 \n5 Clozapine-induced pericardial effusion J Clin Psychopharmacol Dauner DG DeRemer CE Haburchak D 455 456 28 2008 18626276 \n6 Clozapine and pericarditis with pericardial effusion Am J Psychiatry Murko A Clarke S Black DW 494 159 2002 \n7 Clozapine-induced pericarditis Afr J Psychiatry Markovic J Momcilov-Popin T Mitrovic D Ivanovic-Kovacevic S Sekuli S Stojsic-Milosavljevic A 236 238 14 2011 \n8 Monitoring the safe use of clozapine CNS Drugs Berk M Fitzsimons J Lambert T 117 127 21 2007 17284094 \n9 Polyserositis associated with clozapine treatment Am J Psychiatry Daly JM Goldberg RJ Braman SS 1274 1275 149 1992 \n10 Clozapine rechallenge after major adverse effects: clinical guidelines based on 259 cases Am J Ther Manu P Lapitskaya Y Shaikh A Nielsen J 218 223 25 2018\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "11(6)", "journal": "Cureus", "keywords": "clozapine; pericardial effusion; schizophrenia", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e4890", "pmc": null, "pmid": "31423370", "pubdate": "2019-06-12", "publication_types": "D002363:Case Reports", "references": "10584719;11870026;1503144;17284094;18626276;20667298;21863209;28343762;29505490;9524789", "title": "Pericardial Effusion: Rare Adverse Effect of Clozapine.", "title_normalized": "pericardial effusion rare adverse effect of clozapine" }

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{ "abstract": "Tumor lysis syndrome(TLS)induced by chemotherapy for solid tumors is rare. We report a case of a 59-year-old woman with breast cancer who developed TLS. She underwent surgery to treat breast cancer in 1992. 19 years after surgery, however, she was diagnosed with multiple bone metastases(disease free interval, 13 years and 3 months). In March 2011, gemcitabine regimen was initiated(1,250mg/m2, 14 days followed by a 7-day rest period)because of worsening of multiple bone metastases. The patient was immediately admitted and treated for suspected TLS when she presented at our hospital with symptoms such as depressed level of consciousness, serious anemia, hypercalcemia, hyperuricemia, and liver/renal dysfunction on day 16 of the first line of regimen. Rasburicase was found to be effective for hyperuricemia.", "affiliations": "Dept. of Breast Oncology, Aichi Cancer Center Hospital.", "authors": "Kawaguchi Ushio|Aya|A|;Hattori|Masaya|M|;Kohno|Norio|N|;Kaise|Hiroshi|H|;Iwata|Hiroji|H|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0385-0684", "issue": "40(11)", "journal": "Gan to kagaku ryoho. Cancer & chemotherapy", "keywords": null, "medline_ta": "Gan To Kagaku Ryoho", "mesh_terms": "D000964:Antimetabolites, Antineoplastic; D001943:Breast Neoplasms; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008875:Middle Aged; D012008:Recurrence; D015275:Tumor Lysis Syndrome", "nlm_unique_id": "7810034", "other_id": null, "pages": "1529-32", "pmc": null, "pmid": "24231708", "pubdate": "2013-11", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Gemcitabine-induced tumor lysis syndrome caused by recurrent breast cancer in a patient without hemodialysis.", "title_normalized": "gemcitabine induced tumor lysis syndrome caused by recurrent breast cancer in a patient without hemodialysis" }

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{ "abstract": "Progressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of white matter due to the opportunistic reactivation of John Cunningham virus in an immunocompromised patient. PML is associated with many immune-mediated diseases, lymphoproliferative conditions, and immunosuppressive agents. In this case report, we present a 79-year-old female patient diagnosed with rheumatoid arthritis who developed posterior fossa PML while on rituximab. She presented with subacute cerebellar ataxia, dysarthria, and nystagmus, and her brain MRI showed right pontine and pontocerebellar lesion with diffusion restriction and heterogenous enhancement highly characteristic of PML. Though many cases of PML with rituximab were reported in the literature, our case describes a rare type of PML affecting the posterior fossa in an HIV-negative patient on rituximab.", "affiliations": "Radiology, Creighton University Medical Center, Omaha, USA.;Neurology, Creighton University Medical Center, Omaha, USA.;Family Medicine, Creighton University Medical Center, Omaha, USA.;Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA.;Internal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA.", "authors": "Guduru|Mounika|M|;Bendi|Venkata Sunil|VS|;Bebawy|Mariana S|MS|;Bande|Dinesh|D|;Matta|Abhishek|A|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.10888", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.10888\nNeurology\nInfectious Disease\nRheumatology\nPosterior Fossa Progressive Multifocal Leukoencephalopathy Secondary to Rituximab\nMuacevic Alexander Adler John R Guduru Mounika 1 Bendi Venkata Sunil 2 Bebawy Mariana S 3 Bande Dinesh 4 Matta Abhishek 4 \n1 \nRadiology, Creighton University Medical Center, Omaha, USA \n\n2 \nNeurology, Creighton University Medical Center, Omaha, USA \n\n3 \nFamily Medicine, Creighton University Medical Center, Omaha, USA \n\n4 \nInternal Medicine, University of North Dakota School of Medicine and Health Sciences, Fargo, USA \n\nAbhishek Matta [email protected]\n10 10 2020 \n10 2020 \n12 10 e108886 9 2020 9 10 2020 Copyright © 2020, Guduru et al.2020Guduru et al.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.This article is available from https://www.cureus.com/articles/22347-posterior-fossa-progressive-multifocal-leukoencephalopathy-secondary-to-rituximabProgressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of white matter due to the opportunistic reactivation of John Cunningham virus in an immunocompromised patient. PML is associated with many immune-mediated diseases, lymphoproliferative conditions, and immunosuppressive agents. In this case report, we present a 79-year-old female patient diagnosed with rheumatoid arthritis who developed posterior fossa PML while on rituximab. She presented with subacute cerebellar ataxia, dysarthria, and nystagmus, and her brain MRI showed right pontine and pontocerebellar lesion with diffusion restriction and heterogenous enhancement highly characteristic of PML. Though many cases of PML with rituximab were reported in the literature, our case describes a rare type of PML affecting the posterior fossa in an HIV-negative patient on rituximab.\n\npmlposterior fossaprogressive multifocal leukoencephalopathyrheumatoid arthritisrituximabThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nProgressive multifocal leukoencephalopathy (PML) is a rare fatal central nervous system disorder characterized by infection-induced demyelination of cerebral white matter. It is due to the reactivation of John Cunningham (JC) polyomavirus in an immunocompromised patient [1,2]. JC virus primary infection often occurs during childhood or early adolescence, but the virus stays dormant in body tissues (central nervous system, kidneys, epithelium, kidneys, bone marrow, and lymph nodes) for long periods in immunocompetent individuals. Several studies in the literature reported that up to 50% of adults may be seropositive for the JC virus [3]. However, an intact immune system suppresses viral activation. In an immunocompromised state, the virus becomes reactivated, resulting in disease [4].\n\nImmunocompromised states such as HIV infection, leukemia, lymphomas, and different malignancies are well known to be associated with PML. Several reported cases in the literature show a strong association of PML with some immunosuppressants such as natalizumab, fingolimod, dimethyl fumarate, and rituximab [4-6]. Rituximab is an anti-CD20 monoclonal antibody used in the treatment of many lymphoproliferative conditions and immune-mediated diseases such as non-Hodgkin's lymphoma, neuromyelitis optica, psoriasis, and rheumatoid arthritis [7]. The drug acts against CD20+ cells with various mechanisms of action such as antibody-dependent cytotoxicity, cell-mediated cytotoxicity, apoptosis, and direct sensitization of cells to chemotherapy [8].\n\nCase presentation\nA 79-year-old woman with a known history of rheumatoid arthritis on long-term prednisone (5 mg daily) and rituximab (1,000 mg every six months) presented to the emergency room with multiple falls, gait difficulty, slurred speech, and confusion. She had a past medical history of hypertension and left hemispheric ischemic stroke for which she was on clopidogrel daily. On hospital admission, her vital signs were stable, and her physical examination revealed right spastic hemiparesis (a known residual from her old cerebrovascular insult), axial and appendicular ataxia, slurred dysarthria, and vertical nystagmus. Computed tomography (CT) scan of the brain showed a right pontine and right cerebellar hypodense irregular lesion without significant surrounding edema or mass effect and left parietal cortical and subcortical encephalomalacia, likely sequelae of an old vascular insult (Figure 1).\n\nFigure 1 Brain CT axial (a) and coronal (b) sections showing a right cerebellar hypodense lesion with no significant surrounding edema or mass effect and left cortical and subcortical parietal encephalomalacia (on coronal section).\nMagnetic resonance imaging (MRI) with gadolinium of the brain and posterior fossa revealed the right pontine lesion (at the brachium pontis) as involving the right cerebellar white matter. The lesion was isointense on T1 and hyperintense on T2 and FLAIR (fluid-attenuated inversion recovery) sequences. The outer borders of the right pontocerebellar lesion were more defined than the inner border, and there was minimal surrounding edema, with no mass effect on the adjacent fourth ventricle. The lesions showed diffusion restriction on diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps. The contrast study showed heterogenous leading edge enhancement at the right pontocerebellar lesion (Figure 2). A smaller T2 and FLAIR hyperintense lesion was also noted in the left middle cerebellar peduncle, extending to the left cerebellar hemisphere with heterogeneous enhancement. These radiological features, along with the clinical features in a rituximab-treated immunocompromised patient, are highly suggestive of PML.\n\nFigure 2 MRI of the brain with contrast showing an irregular right pontine isointense lesion on T1 (a), hyperintense signal on T2 (c), and FLAIR (d) sequences, with the extension of the lesion to the right cerebellar hemisphere showing minimal edema adjacent to the fourth ventricle. The lesion shows restriction on DWI (e) and ADC map (f) and heterogeneous enhancement at the margins (b, g, and h). Another T2 hyperintense smaller lesion is demonstrated at the left middle cerebellar peduncle and left cerebellar hemisphere (c) with heterogeneous enhancement (h).\nFLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted images; ADC, apparent diffusion coefficient\n\nHer routine chemistry panel was unremarkable except for mild anemia, slightly elevated creatinine level, and hyperglycemia (Table 1).\n\nTable 1 Routine laboratory tests\nRBC, red blood cells; WBC, white blood cells; HIV, human immunodeficiency virus; HbsAg, hepatitis B surface antigen; HCV, hepatitis C virus\n\nLaboratory test \tAdmission 1 \tReference range \t\nHemoglobin \t11.5 \t13-15 g/dL \t\nRBC \t3.8 \t4.6-6.8 x 106/mcL \t\nWBC \t6.4 \t3.6-10.3 x 103/mcL \t\nPlatelets \t197 \t140-420 x 103/mcL \t\nBlood glucose \t119 \t70-100 mg/dL \t\nSodium \t139 \t135-145 mmol/L \t\nPotassium \t4.3 \t3.7-5.1 mmol/L \t\nChloride \t107 \t96-110 mmol/L \t\nBicarbonate \t22 \t22-32 mmol/L \t\nKetone screen \tNegative\t \t\nBlood urea \t17 \t6-24 mg/dL \t\nCreatinine \t1.36 \t0.6-1.3 mg/dL \t\nHIV \tNegative\t \t\nHbsAg \tNegative\t \t\nAnti-HCV \tNegative\t \t\nLumbar puncture with cerebrospinal fluid (CSF) studies and treatment options were discussed with the patient. However, the patient and her family decided to adopt a palliative approach, and the patient was discharged from the hospital to a nursing home where she died within a month.\n\nDiscussion\nIn general, the incidence of PML in HIV-negative patients receiving rituximab is about 1 in every 32,000 patients [4]. Rituximab is a typical monoclonal antibody used for the treatment of many immune-mediated disorders and lymphoproliferative conditions. Despite its efficacy, it has been reported to be associated with severe adverse events particularly PML. PML is estimated to occur in around 6% of patients receiving rituximab [9], and since 1990, many case reports and case series have been published reporting the occurrence of PML with rituximab usage [7]. The patient presented in this article represents a rare case of posterior fossa PML who was on rituximab for rheumatoid arthritis. PML requires a high index of suspicion for diagnosis, and clinicians should always be on alert to include it in the differential diagnosis in immunocompromised patients, particularly those on monoclonal antibody therapy. PML is diagnosed based on clinical, radiological, and laboratory testing. Clinically, the most common three presenting symptoms are hemiparesis, visual dysfunction, and disturbed mental state [6]. However, some patients may present with posterior fossa symptoms such as ataxia, slurred dysarthria, and nystagmus [6], which are also notable in our patient. Radiologically, PML appears as white matter demyelinating single or less often as multiple lesions that predominantly affect the supratentorial structures. The lesions are characteristically large subcortical with ill-defined inner borders and well-defined outer borders that show a restriction on diffusion sequences. The lesions enhance on contrast administration typically in an open-ring pattern. However, heterogeneous patterns of enhancement were reported [10]. CSF analysis in PML might show mildly elevated proteins and white blood cells, and a high viral load. The most accurate diagnostic test of PML is a brain biopsy of the suspected lesion.\n\nAlthough many cases of PML have been reported to develop in the context of rituximab therapy, the exact pathophysiological mechanism of rituximab-associated PML remains elusive. It is proposed that the rituximab-induced B-cell depletion, change in cytokine nature, and altered T-lymphocyte activity lead to reactivation of the JC virus [11]. Hematopoietic progenitor cells in the bone marrow are thought to be the site of viral latency, and when they get mobilized to the blood and central nervous system under the effect of monoclonal antibodies, they result in the hematogenous spread of the virus to the brain, activation, and development of PML [12]. As with natalizumab, the risk of PML development in patients receiving rituximab depends on the JC virus titer, the previous use of immunosuppressant medications, and the duration of use of the monoclonal antibody drug [5]. Additionally, low CD4b increases the risk of rituximab-associated PML [13]. The patient reported in this article has been on oral steroids and rituximab for years, increasing her risk of PML. As PML can be fatal, patients receiving rituximab should be meticulously monitored. Regular follow-up of CD4b is essential, and abrupt discontinuation of rituximab is fundamental to reduce mortality if PML is suspected [4]. The FDA has granted Orphan Drug designation to NT-I7 (efineptakin alfa) for the treatment of PML. Plasma exchange to remove the circulating drug as well as stopping the offending drug represent the treatment of choice for these cases [6].\n\nConclusions\nAs PML can be fatal, patients receiving rituximab should be meticulously monitored. Regular follow-up of CD4b is essential, and abrupt discontinuation of rituximab is fundamental to reduce mortality if PML is suspected. Although there is no definitive evidence that FDA approved the medication for PML to date, plasma exchange to remove the circulating drug as well as stopping the offending drug represent the treatment of choice for these cases.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Progressive multifocal leukoencephalopathy in autoimmune diseases Joint Bone Spine Palazzo E Yahia SA 351 355 79 2012 22281228 \n2 Progressive multifocal leukoencephalopathy: current treatment options and future perspectives Ther Adv Neurol Disord Pavlovic D Patera AC Nyberg F Gerber M Liu M 255 273 8 2015 26600871 \n3 Asymptomatic reactivation of JC virus in patients treated with natalizumab N Engl J Med Chen Y Bord E Tompkins T e t al 1067 1074 361 2009 19741227 \n4 Progressive multifocal leukoencephalopathy Neurol Clin Grebenciucova E Berger JR 739 750 36 2018 30366552 \n5 [Neuropathology of natalizumab-associated progressive multifocal leukoencephalopathy] Brain Nerve Kanda T 891 901 67 2015 26160817 \n6 Progressive multifocal leukoencephalopathy and monoclonal antibodies: a review Cancer Control Bohra C Sokol L Dalia S 1073274817729901 24 2017 28975841 \n7 Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis Arch Neurol Clifford DB Ances B Costello C 1156 1164 68 2011 21555606 \n8 Rituximab-associated infections Semin Hematol Gea-Banacloche JC 187 198 47 2010 20350666 \n9 Neuromyelitis optica spectrum disorders in Iran Mult Scler Relat Disord Eskandarieh S Nedjat S Azimi AR Moghadasi AN Sahraian MA 209 212 18 2017 29141812 \n10 Imaging manifestations of progressive multifocal leukoencephalopathy Clin Radiol Shah R Bag AK Chapman PR Curé JK 431 439 65 2010 20451009 \n11 Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project Blood Carson KR Evens AM Richey EA 4834 4840 113 2009 19264918 \n12 The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34 hematopoietic progenitor cells in humans Blood Zohren F Toutzaris D Klärner V Hartung HP Kieseier B Haas R 3893 3895 111 2008 18235044 \n13 Immunotherapy: past, present and future Nat Med Waldmann TA 269 277 9 2003 12612576\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "12(10)", "journal": "Cureus", "keywords": "pml; posterior fossa; progressive multifocal leukoencephalopathy; rheumatoid arthritis; rituximab", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e10888", "pmc": null, "pmid": "33178540", "pubdate": "2020-10-10", "publication_types": "D002363:Case Reports", "references": "30366552;28975841;26600871;19264918;22281228;19741227;21555606;20350666;18235044;29141812;26160817;12612576;20451009", "title": "Posterior Fossa Progressive Multifocal Leukoencephalopathy Secondary to Rituximab.", "title_normalized": "posterior fossa progressive multifocal leukoencephalopathy secondary to rituximab" }

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{ "abstract": "We present a case of a 43-year-old female patient with clinical stage IIIB (T3N2M0) anaplastic lymphoma kinase (ALK)-positive adenocarcinoma of the lung. Surgery was not performed initially because of multiple mediastinal lymph nodes invasion, although the mass was technically resected. With the assessment of upfront multidisciplinary consultation, administration of neoadjuvant crizotinib was selected to induce the downstaging and facilitate the subsequent surgical treatment. After 10 weeks of neoadjuvant crizotinib treatment, a partial response was achieved and the tumor could be radically resected. There were no sever toxic effects and treatment-related surgical delay during the whole neoadjuvant crizotinib therapy. The patient then successfully underwent video-assisted single port thoracoscopic right upper lobectomy and lymphadenectomy. Concurrent chemotherapy and radiotherapy were applied postoperatively. Perioperative targeted therapy demonstrated good curative effect in this case, and no recurrence was observed at the clinic 8 months after surgery. In this case, the safety and effectiveness of neoadjuvant crizotinib and subsequent surgery are preliminarily proved. We here intend to investigate the optimal setting of neoadjuvant targeted therapy combined with minimally invasive surgery and postoperative adjuvant therapy, inspire more potential targeted treatment based schedules and to apply these strategies in treating patients with locally advanced mutant-positive non-small cell lung cancer (NSCLC).", "affiliations": "Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.;Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China.", "authors": "Tian|Yu|Y|;Huang|Jia|J|;Li|Chongwu|C|;Jiang|Long|L|;Lin|Hao|H|;Lu|Peiji|P|;Luo|Qingquan|Q|;Yang|Guocai|G|", "chemical_list": null, "country": "China", "delete": false, "doi": "10.21037/atm-20-3927", "fulltext": "\n==== Front\nAnn Transl Med\nAnn Transl Med\nATM\nAnnals of Translational Medicine\n2305-5839\n2305-5847\nAME Publishing Company\n\natm-08-12-770\n10.21037/atm-20-3927\nCase Report\nPerioperative crizotinib in a patient with stage IIIB ALK-positive non-small cell lung cancer: a case report\nTian Yu 1#\nHuang Jia 1#\nLi Chongwu 1#\nJiang Long 1\nLin Hao 1\nLu Peiji 1\nLuo Qingquan 1\nYang Guocai 2\n1 Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China;\n2 Zhoushan Hospital, Wenzhou Medical University, Zhoushan, China\n# These authors contributed equally to this work.\n\nCorrespondence to: Guocai Yang. Zhoushan Hospital, Wenzhou Medical University, No. 739 Dingshen Road Lincheng New District, Zhoushan, China. Email: [email protected].\n6 2020\n6 2020\n8 12 77017 4 2020\n11 6 2020\n2020 Annals of Translational Medicine. All rights reserved.\n2020\nAnnals of Translational Medicine.\nWe present a case of a 43-year-old female patient with clinical stage IIIB (T3N2M0) anaplastic lymphoma kinase (ALK)-positive adenocarcinoma of the lung. Surgery was not performed initially because of multiple mediastinal lymph nodes invasion, although the mass was technically resected. With the assessment of upfront multidisciplinary consultation, administration of neoadjuvant crizotinib was selected to induce the downstaging and facilitate the subsequent surgical treatment. After 10 weeks of neoadjuvant crizotinib treatment, a partial response was achieved and the tumor could be radically resected. There were no sever toxic effects and treatment-related surgical delay during the whole neoadjuvant crizotinib therapy. The patient then successfully underwent video-assisted single port thoracoscopic right upper lobectomy and lymphadenectomy. Concurrent chemotherapy and radiotherapy were applied postoperatively. Perioperative targeted therapy demonstrated good curative effect in this case, and no recurrence was observed at the clinic 8 months after surgery. In this case, the safety and effectiveness of neoadjuvant crizotinib and subsequent surgery are preliminarily proved. We here intend to investigate the optimal setting of neoadjuvant targeted therapy combined with minimally invasive surgery and postoperative adjuvant therapy, inspire more potential targeted treatment based schedules and to apply these strategies in treating patients with locally advanced mutant-positive non-small cell lung cancer (NSCLC).\n\nKeywords:\n\nNon-small cell lung cancer (NSCLC)\nstage IIIB\nanaplastic lymphoma kinase-positive (ALK-positive)\nneoadjuvant therapy\ncase report\n==== Body\nIntroduction\n\nLocally advanced non-small cell lung cancer (NSCLC) has always been recognized as a highly heterogeneous clinical issue (1). Concurrent chemoradiotherapy and surgery along with chemotherapy or chemoradiotherapy, as the two main treatment modalities, have been offered for patients with locally advanced disease. Although neoadjuvant chemoradiotherapy has been recommended as one of the clinical practices based on current National Comprehensive Cancer Network guidelines, a multimodality regimen for this malignant disease is still heterogeneous, and the prognosis remains unsatisfactory (2). In previous research, neoadjuvant therapy prior to surgical resection has been demonstrated to provide favorable tumor shrinkage and disease-free survival (DFS) for patients with locally advanced NSCLC (3-5).\n\nThe anaplastic lymphoma kinase (ALK) gene rearrangement is one of the significant driver mutations that can be detected in 4% to 6% of NSCLC patients (6). Enormous progress in efficacy and long-term survival has been achieved by applying ALK receptor tyrosine kinase inhibitors (TKIs) in advanced NSCLC (7). Crizotinib, as a typical ALK-TKI drug, was proven to be superior to combined chemotherapy in the first-line setting for advanced ALK-positive NSCLC by the PROFILE 1014 trial (8), with an improved objective response rate (ORR) (74% vs. 45%) and progression-free survival (PFS) (10.9 vs. 7 months). Furthermore, crizotinib has shown a more rapid 6-week response compared to the 12-week response of chemotherapy (9). However, research focusing on applying ALK-targeted treatment in locally advanced NSCLC or neoadjuvant therapy has rarely been reported, and the scant trials and studies that are available are limited in offering reliable evidence due their small sample sizes.\n\nThus, definite conclusions concerning the efficacy and optimal settings of neoadjuvant ALK-TKIs urgently need to be found. Here, we present a patient with stage IIIB ALK-positive NSCLC who obtained significant response to perioperative crizotinib treatment. Clinicopathological features of the patient are described in this article in accordance with the CARE reporting checklist (available at http://dx.doi.org/10.21037/atm-20-3927).\n\nCase presentation\n\nA 43-year-old female patient was admitted with dry cough and a suspicious right upper lobe mass complicated by obstructive pneumonia. The patient represented maternal history of breast cancer. Personal history was negative for smoking and neoplastic diseases. Contrast-enhanced computed tomography (CT) scan (November 27, 2018) showed a 65.0 mm × 61.5 mm mass and obstructive symptoms, together with multiple enlarged hilar and mediastinal lymph nodes (Figure 1). The significant serum tumor markers included carcinoembryonic antigen (157.25 ng/mL), cancer antigen-125 (81.3 U/mL), and circulating cytokeratin 19 fragments (CYFRA21-1; 19.03 ng/mL). Positron emission tomography-CT (PET-CT) was performed revealing a high level of 18-fluorodeoxyglucose (FDG) uptake in the right upper lobe mass and right upper paratracheal nodes (2R) (Figure 2), which was highly indicative of malignant disease and lymph node (2R) metastasis with no signs of distant metastasis. A CT-guided percutaneous biopsy in the right lung neoplasm was performed. Pathological analysis showed a poorly differentiated adenocarcinoma. Immunohistochemistry revealed positive staining of cytokeratin (CK), CD56, and thyroid transcription factor-1 (TTF-1), and napsin A was partially positive. Gene mutation test was positive for ALK gene rearrangement. The patient was diagnosed with clinical stage IIIB (T3N2M0) pulmonary adenocarcinoma with hilar and mediastinal lymph node metastasis.\n\nFigure 1 Prior to neoadjuvant immunotherapy, computed tomography (CT) images of the chest in November 27, 2018 indicated a 65.0 mm × 61.5 mm mass (★ marked) in the right upper pulmonary lobe, together with enlarged hilar and mediastinal lymph nodes (★ marked).\n\nFigure 2 Positron emission tomography-computed tomography (PET-CT) images confirmed lung cancer in the right upper lobe (6.5 cm × 5.9 cm × 6.2 cm; SUV, 17.8) and mediastinal lymph node (2R) metastasis (1.6 cm; SUV, 10.4).\n\nThe patient preferred surgical treatment, and the primary tumor and involved lymph nodes were technically resectable. With the assessment of upfront multidisciplinary consultation, neoadjuvant crizotinib administration was selected to induce the downstaging and facilitate the subsequent surgical treatment. The patient proceeded to accept neoadjuvant targeted therapy with crizotinib (2×250 mg per day) from December 20, 2018 to March 4, 2019. Side effects were limited to grade 1 hepatic damage and mild edema of the lower limbs. Chest CT scan (March 10, 2019) after treatment showed that the lesion in the right upper lobe had obviously reduced to 29.3 mm × 28.3 mm, while the enlarged hilar and mediastinal lymph nodes had almost disappeared (Figure 3). Partial remission (PR) after neoadjuvant targeted therapy was achieved in the patient.\n\nFigure 3 Computed tomography (CT) scan after crizotinib immunotherapy demonstrating the therapeutic effect as partial remission (PR). Tumor shrinked (A and B) and enlarged lymph nodes almost disappeared (B).\n\nThe patient underwent right upper lobectomy with mediastinal lymph node dissection in single-port video-assisted thoracoscopic surgery, 2 weeks (March 22, 2019) after the last dose. Following an uneventful postoperative course, the patient was discharged on postoperative day 6. Postoperative pathological examination revealed changes of moderately-to-poorly differentiated acinar-predominant adenocarcinoma of the lung after targeted therapy. The resected residual tumor was 35 mm × 35 mm × 32 mm, and the right upper paratracheal (2R), right lower paratracheal (4R), and right interlobar (11R) lymph nodes were involved. Immunohistochemistry examination revealed the following: TTF-1 (+), napsin A (partly +), CD56 (+), and KI-67 (50%+). Postoperative staging was confirmed as ypT2N2M0 (stage IIIA).\n\nGiven his good recovery situation and the risk of recurrence, the patient received adjuvant concurrent chemo- and radiotherapy. Four cycles of pemetrexed (860 mg on day 1, every 4 weeks) and cisplatin (600 mg on day 1, every 4 weeks) were accepted. The postoperative radiotherapy was given at a dose of 1.8 Gy × 28 fx. During the combination therapy, the patient presented grade 1 hepatic damage which was relieved after symptomatic treatment. Treatment was completed by July 2019, and the compliance and tolerance of the patient appeared to be quite high (Figure 4). The patient was last followed up at the clinic 8 months after surgery (December 6, 2019), and no recurrence was observed (Figure 5).\n\nFigure 4 Timeline of diagnosis and treatment.\n\nFigure 5 Comparison of computed tomography (CT) scan after adjuvant chemoradiotherapy indicated no evidence of recurrence during the 8-month follow-up. Imagine of lung window (A) and imagine of vertical window (B).\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nDiscussion and conclusion\n\nSince ALK-TKI treatment was proven superior to chemotherapy for advanced ALK-positive NSCLC (9), the indication of ALK-TKI has tentatively been extended to the neoadjuvant therapy settings. In the case series report by Zhang et al. (4), crizotinib (250 mg twice per day) was administered to 11 patients with ALK-positive locally advanced NSCLC in the neoadjuvant setting. In total, 10 (90.9%) of 11 patients had a partial response, with the remaining patient experiencing stable disease response. Surgery was successfully performed on all patients after perioperative crizotinib, with 2 patients (18.2%) achieving pathologic complete response and 3 (27.3%) experiencing pathological node downstaging. Meanwhile, 6 patients had disease recurrence, and the median DFS time was 10.1 months (range, 5.3–20 months). Another case report showed that a patient with ALK-positive mediastinum-invasive NSCLC achieved radiological major response and pathological partial response after neoadjuvant crizotinib (10), with the DFS lasting 44 months as of publication. Previous trials demonstrate that neoadjuvant administration of crizotinib might be a promising therapy in providing an opportunity for resection and prolonged DFS for locally advanced ALK-positive NSCLC patients. The SAKULA trial was a multicenter single-arm phase II study aimed at assessing the efficacy and safety of neoadjuvant therapy with ceritinib followed by surgery in patients with ALK-positive resectable locally advanced NSCLC, with its preliminary results being reported in the 2019 World Conference on Lung Cancer . The ORR was 100% in the all 7 enrolled patients, and 6 out of 7 patients completed the full cycle of treatment and accepted surgery, with complete (R0) resection being achieved in 5 of them. Among the 7 evaluable patients, 4 patients achieved major pathologic response (57%, 95% CI: 18% to 90%) and 2 patients achieved pathologic complete response. Adverse events occurred in all the patients leading to 7 cases of dose interruption and 5 cases of dose reduction. The results revealed the efficacy of neoadjuvant ceritinib, but the optimal dose arrangement and further observation of safety require continued study.\n\nIn the case presented here, the patient achieved PR and pathological tumor downstaging in response to the neoadjuvant crizotinib, which suggests that locally advanced ALK-positive NSCLC patients may also benefit from minimally invasive surgery after the induction of targeted therapy. The administration of perioperative crizotinib provided a safe and efficacious chance for resection without increasing the difficulty and complications of the surgery. However, the duration of crizotinib therapy is still open to discussion as it concerns its optimal regimen. Considering that the effect of postoperative crizotinib remains unknown, we applied conventional chemotherapy and radiotherapy to achieve a better prognosis. Moreover, since the second-generation ALK inhibitors such as alectinib and brigatinib have been shown to be more effective than crizotinib in advanced NSCLC (11,12), their tentative application in the neoadjuvant setting is expected.\n\nIn conclusion, this is the first report of an ALK-positive stage IIIB NSCLC patient receiving neoadjuvant ALK-TKI treatment and radical minimally invasive surgery. This case demonstrated the safety and efficacy of crizotinib combined with minimally invasive surgery for the adjuvant setting. Further research focusing on neoadjuvant targeted therapy in locally advanced NSCLC can be expected to provide more substantive evidence and clarify the optimal regimen.\n\nAcknowledgments\n\nFunding: None.\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nOpen Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-3927\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3927). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Rigas JR Kelly K Current treatment paradigms for locally advanced non-small cell lung cancer. J Thorac Oncol 2007;2 Suppl 2 :S77-85. 10.1097/01.JTO.0000269735.21209.bc 17589303\n2 Yeh J Marrone KA Forde PM Neoadjuvant and consolidation immuno-oncology therapy in stage III non-small cell lung cancer. J Thorac Dis 2018;10 :S451-S459. 10.21037/jtd.2018.01.109 29593890\n3 Forde PM Chaft JE Smith KN Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378 :1976-86. 10.1056/NEJMoa1716078 29658848\n4 Zhang C Li SL Nie Q Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small Cell Lung Cancer with ALK Rearrangement. J Thorac Oncol 2019;14 :726-31. 10.1016/j.jtho.2018.10.161 30408570\n5 Perez-Gracia JL Sanmamed MF Melero I Neoadjuvant immunotherapy in non-small cell lung cancer: the sooner the better? Transl Lung Cancer Res 2018;7 :S356-S357. 10.21037/tlcr.2018.10.12 30705854\n6 Kwak EL Bang YJ Camidge DR Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363 :1693-703. 10.1056/NEJMoa1006448 20979469\n7 Shaw AT Yeap BY Solomon BJ Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 2011;12 :1004-12. 10.1016/S1470-2045(11)70232-7 21933749\n8 Solomon BJ Mok T Kim DW First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371 :2167-77. 10.1056/NEJMoa1408440 25470694\n9 Shaw AT Kim DW Nakagawa K Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368 :2385-94. 10.1056/NEJMoa1214886 23724913\n10 Kilickap S Onder S Dizdar O Short-time use of crizotinib as neoadjuvant in ALK-positive non-small cell lung carcinoma can be a chance for resectability. Cancer Chemother Pharmacol 2019;83 :1195-6. 10.1007/s00280-019-03810-9 30863883\n11 Hida T Nokihara H Kondo M Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 2017;390 :29-39. 10.1016/S0140-6736(17)30565-2 28501140\n12 Camidge DR Kim HR Ahn MJ Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2018;379 :2027-39. 10.1056/NEJMoa1810171 30280657\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2305-5839", "issue": "8(12)", "journal": "Annals of translational medicine", "keywords": "Non-small cell lung cancer (NSCLC); anaplastic lymphoma kinase-positive (ALK-positive); case report; neoadjuvant therapy; stage IIIB", "medline_ta": "Ann Transl Med", "mesh_terms": null, "nlm_unique_id": "101617978", "other_id": null, "pages": "770", "pmc": null, "pmid": "32647695", "pubdate": "2020-06", "publication_types": "D002363:Case Reports", "references": "30863883;29658848;25470694;29593890;30280657;28501140;21933749;20979469;17589303;30408570;30705854;23724913", "title": "Perioperative crizotinib in a patient with stage IIIB ALK-positive non-small cell lung cancer: a case report.", "title_normalized": "perioperative crizotinib in a patient with stage iiib alk positive non small cell lung cancer a case report" }

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{ "abstract": "BACKGROUND Thrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response. CASE REPORT Three of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib. CONCLUSIONS Avatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.", "affiliations": "Department of Medical Oncology, Gabrail Cancer Center, Canton, OH, USA.;Department of Medical Oncology, Gabrail Cancer Center, Canton, OH, USA.", "authors": "Gabrail|Nash|N|;Smith|Carrie|C|", "chemical_list": "D007191:Indazoles; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013844:Thiazoles; D013876:Thiophenes; D000246:Adenosine Diphosphate Ribose; C533238:avatrombopag; D011065:Poly(ADP-ribose) Polymerases; C545685:niraparib", "country": "United States", "delete": false, "doi": "10.12659/AJCR.927008", "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\n33191394\n10.12659/AJCR.927008\n927008\nArticles\nAvatrombopag Optimizes Response to Niraparib by Managing Thrombocytopenia Associated with Poly-ADP Ribose Polymerase (PARP) Inhibition in Ovarian Cancer and Breast Cancer: A Case Series\nGabrail Nash ABCDEF Smith Carrie AB Department of Medical Oncology, Gabrail Cancer Center, Canton, OH, U.S.A.\nCorresponding Author: Nash Gabrail, 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 \n16 11 2020 \n21 e927008-1 e927008-10\n23 6 2020 18 9 2020 03 10 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Case series\n\nPatients:—\n\nFinal Diagnosis: Breast cancer • ovarian cancer\n\nSymptoms: Thrombocytopenia\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Oncology\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nThrombocytopenia is a potentially treatment-limiting adverse event of particular interest with the PARP inhibitor niraparib. This adverse event may necessitate niraparib dose reduction or treatment discontinuation, resulting in suboptimal treatment outcomes. Here, we report on niraparib dose optimization in 2 patients with breast cancer and 4 patients with ovarian cancer through concurrent administration of the thrombopoietin receptor stimulating agent avatrombopag to mitigate thrombocytopenia, enabling niraparib reescalation and improved clinical response.\n\nCase Reports:\nThree of 6 patients received niraparib 300 mg daily, the highest recommended dose, for a sustained period. Avatrombopag therapy enabled niraparib dose escalation that led to reductions in biomarkers associated with disease progression. Before initiation of avatrombopag, increases in CA-125 levels, a marker for ovarian cancer, were observed in association with niraparib dose interruption, and in 2 patients with ovarian cancer CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. Further, in 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. In 1 patient with metastatic breast cancer, niraparib induced an intracranial response, while previous use of talazoparib had not, confirming preclinical findings of superior blood-brain-barrier penetrance with niraparib.\n\nConclusions:\nAvatrombopag is currently approved for use in chronic immune thrombocytopenia and thrombocytopenia associated with chronic liver disease in patients undergoing a surgical procedure. A clinical trial of avatrombopag for chemotherapy-induced thrombocytopenia is ongoing. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.\n\nMeSH Keywords:\nBreast NeoplasmsOvarian NeoplasmsPoly(ADP-ribose) PolymerasesReceptors, ThrombopoietinThrombocytopenia\n==== Body\nBackground\nBy interfering with DNA repair mechanisms, such as the homologous recombination repair pathway [1,2], poly-ADP ribose polymerase (PARP) inhibitors have been shown to be effective in the maintenance treatment of advanced ovarian cancer [3–8] and in advanced breast cancer with germline BRCA1/2 mutations [9]. Clinical trials of niraparib indicate responses in patients with both germline and somatic BRCA mutations, with a smaller degree of benefit in BRCA-negative homologous recombination deficiency (HRD)-positive patients, and the least benefit in BRCA-negative HRD-negative patients [3,6,10]. Most recently, on April 29, 2020, niraparib was approved for first-line maintenance treatment of ovarian cancer following complete or partial response to platinum-based chemotherapy [10,11]. In an analysis of the NOVA trial, niraparib improved progression-free survival outcomes in a dose-related manner [12]. Moreover, the unique pharmacology of niraparib, including improved blood-brain-barrier penetrance over other PARP inhibitors, has been shown to induce intracranial response in animal models [13].\n\nAlthough niraparib has unique characteristics, its therapeutic efficacy may be limited by adverse events such as thrombocytopenia [14]. The FDA-approved labeling for niraparib advises interruption of niraparib therapy or dose reduction for management of thrombocytopenia, which may compromise efficacy [12,14]. Unfortunately, there are no medications currently approved for management of this potential treatment-limiting adverse event [14]. Although one agent, oprelvekin, was approved for the management of chemotherapy-induced thrombocytopenia, this agent has been discontinued [15]. Based on the mechanism of action of thrombopoietin (TPO) receptor agonists, these agents have the potential to treat thrombocytopenia associated with therapeutic agents for cancer, such as niraparib [16–18].\n\nTPO receptor agonists increase platelet levels by interacting with the TPO receptor on megakaryocytes, the endogenous target of thrombopoietin. Given that TPO receptor agonists increase platelet production, use of these agents may counteract or mitigate PARP-induced thrombocytopenia [16]. Approved TPO receptor agonists are avatrombopag, eltrombopag, and lusutrombopag, all of which are administered orally, as well as romiplostim, which is administered as a subcutaneous injection [17–20]. Unlike eltrombopag, avatrombopag does not require regular monitoring for liver test abnormalities during therapy, which can reduce the complexity of monitoring in highly comorbid patients with cancer receiving maintenance treatment with niraparib. In addition, use of avatrombopag offers flexibility in oral dosing. Unlike eltrombopag, avatrombopag can be taken with polyvalent cations such as calcium, magnesium, and iron [17,18]. As a result, based on its mechanism of action, safety, and flexible dosing, avatrombopag is a rational choice for the prevention and management of thrombocytopenia associated with niraparib therapy.\n\nThis case series reviewed the treatment of 2 patients with breast cancer and 4 patients with ovarian cancer. All patients received niraparib for the maintenance treatment of advanced breast cancer or advanced ovarian cancer in combination with avatrombopag to reduce the risk of thrombocytopenia and improve the dose-intensity of niraparib therapy. By optimizing the dose-intensity of therapy, avatrombopag has the potential to optimize treatment outcomes, consistent with the dose-response relationship observed in multiple clinical trials of niraparib [3,6,10]. In this case series, outcomes were evaluated prospectively over the course of treatment for breast or ovarian cancer in 6 patients.\n\nCase Reports\nCase 1: Breast cancer with brain metastases\nA patient with breast cancer, born in 1977, was diagnosed with ER-positive HER2-negative stage III breast cancer in August 2016. From September 2016 to January 2017, she received 4 cycles of doxorubicin and cyclophosphamide followed by maintenance letrozole from a different provider. By January 2019, she had progressive disease with brain metastases. She received radiosurgery (Gamma Knife®) and subsequently started abemaciclib, which she did not tolerate well. Before presenting in July 2019 for her fourth opinion, she had previously been seen at multiple other centers.\n\nFrom July 2019 to October 2019, she received talazoparib and experienced progressive disease in the brain with no response to therapy. Radiosurgery (Gamma Knife®) was not feasible and she declined whole-brain radiotherapy. The patient was then switched to a different PARP inhibitor, niraparib. Niraparib was chosen based on its ability to cross the blood-brain barrier and favorable results in regression of intracranial tumors in animal models [13]. The patient started treatment with niraparib 300 mg daily in November 2019, with CT-verified response in early January and late February 2020. This response was accompanied by clinical improvement, including successful discontinuation of steroids and absence of reported seizures between December 2019 and March 2020. As of her latest CT scan performed April 16, 2020, this patient has experienced complete intracranial response (Figure 1).\n\nUse of avatrombopag in this patient\nBefore starting therapy with avatrombopag, this patient experienced a dramatic drop in platelet count to 31 000/µL on January 8, 2020, shortly after initiating niraparib 300 mg daily on December 29, 2019. After starting treatment with avatrombopag 20 mg daily, the patient experienced a dramatic increase in platelet counts, which peaked at a supranormal level of 757 000/µL on January 23, 2020. As this patient was extremely responsive to avatrombopag, avatrombopag was held and reinitiated at a lower total weekly dose of 60 mg (20 mg administered on Monday, Wednesday, and Friday each week) starting on February 5, 2020. The patient was able to take niraparib at the maximal dose of 300 mg daily while receiving avatrombopag. Before initiating avatrombopag, niraparib 300 mg daily had previously caused profound thrombocytopenia. After initiating avatrombopag, platelet counts exceeded 250 000/µL on 3 of 5 occasions from February 5, 2020 to March 11, 2020. During this time, the patient received the maximal dose of niraparib (300 mg daily) in combination with avatrombopag 60 mg weekly (Figure 2).\n\nCase 2: Breast cancer with brain metastases\nA female patient born in 1976 was diagnosed with locally advanced estrogen receptor (ER)-positive HER2-negative breast cancer in February 2016. She initially received alternative medicine. In November 2017, she sought conventional medical treatment. She had stage IV disease with liver metastases and pleural effusion and was enrolled in a clinical trial of carboplatin in combination with paclitaxel and a checkpoint inhibitor. On the clinical trial, the patient achieved partial response, until she developed progressive disease in July 2018. She received treatment with fulvestrant, palbociclib, leuprolide, and exemestane from July 2018 until the onset of progressive disease with brain metastases in April 2019. She refused cranial radiotherapy and experienced no response with single-agent doxorubicin. On May 30, 2019, she was started on niraparib and achieved partial response in the brain, liver, and lungs.\n\nUse of avatrombopag in this patient\nFrom May 30, 2019 to March 16, 2020, the patient received weekly dose of niraparib ranging from 200 mg to 2100 mg, co-administered with avatrombopag weekly doses ranging from 140 mg weekly to 280 mg weekly. Of note, following an interruption in niraparib dosing the week of June 15, 2019, there were a total of 3 weeks in which avatrombopag was not administered (the weeks of July 29, 2019, August 26, 2019, and November 25, 2019). The gap in use of avatrombopag during July and August led to subsequent low platelet levels on of 140 000/µL on September 26, 2019 and 148 000/µL on October 21, 2019. These low platelet levels due to a gap in avatrombopag therapy led to 2 additional interruptions in niraparib therapy the weeks of November 25, 2019, and December 26, 2019. Despite the interruption of avatrombopag therapy, use of avatrombopag in this patient aided in escalating the dose of niraparib from 1800 mg weekly to 2000 mg weekly from August 29, 2019 to October 27, 2019. Most recently, the dose of avatrombopag was increased from 140 mg weekly to 280 mg weekly, resulting in a rebound in platelet counts from 48 000/µL on February 25, 2020 to 94 000/µL on March 2, 2020. The increase in avatrombopag dose also enabled escalation of the weekly dose of niraparib from 200 mg weekly to 1400 mg weekly as of March 16, 2020. On August 26, 2019 and on January 8, 2020, CT assessments indicated intracranial partial response (Figure 3). In addition to 2 standard-dose platelet transfusions, continuous administration of avatrombopag for all but 3 weeks during the dose titration helped enable administration of the optimal dose of niraparib in this patient.\n\nCase 3: Ovarian cancer\nA patient with stage IV ovarian cancer, born in 1959, was diagnosed in October 2018. She received carboplatin, paclitaxel, and bevacizumab from November 2018 to February 2019. After experiencing partial response to primary treatment, she received maintenance niraparib therapy. On her last CT scan, January 26, 2020, she was found to have stable disease. Her CA-125 levels indicate response to treatment.\n\nUse of avatrombopag in this patient\nBefore receiving avatrombopag, this patient was initiated on a maximal dose of niraparib of 2100 mg weekly starting on March 18, 2019, which rapidly led to a profound reduction in platelet counts, as low as 36 000/µL. Following 2 interruptions of niraparib therapy the weeks of March 25, 2019 and April 29, 2019, CA-125 levels increased from 33 units/mL to 57 units/mL. When platelet counts had recovered by May 8, 2019, the patient was again initiated on niraparib at a reduced weekly dose of 1400 mg, which gradually increased to 1900 mg weekly by October 15, 2019. Although platelet counts were initially stable during dose escalation, shortly after the dose of niraparib was escalated to 2000 mg weekly on October 19, 2019, the patient’s platelet count dropped below 100 000/µL shortly afterward on October 29, 2019. As a result, the patient was prescribed avatrombopag at a dose of 20 mg daily (140 mg weekly) to stabilize platelet counts. Initiation of avatrombopag enabled further niraparib dose escalation to 2100 mg weekly on December 15, 2019. Notably, the patient’s last platelet count was 219 000/µL on March 17, 2020 on the same dose of niraparib that had previously caused a precipitous decline in platelet counts prior to receiving avatrombopag. Additionally, CA-125 levels in this patient have more than halved since initiating treatment with avatrombopag, falling from 69 units/mL to 32 units/mL. This reduction in CA-125 levels occurred concurrently with dose escalation of niraparib to 2000 mg/week and then 2100 mg/week, which was enabled by concurrent administration of avatrombopag (Figure 4).\n\nCase 4: Ovarian cancer\nA female patient born in 1954 was diagnosed with stage II ovarian cancer concurrent with uterine cancer and fallopian tube cancer in July 2017. She received debulking surgery followed by 6 cycles of carboplatin and docetaxel from August 2017 to December 2017. In August 2019, she developed recurrence in the liver and peritoneum. Following recurrence, from August 2019 to December 2019, she received carboplatin, paclitaxel, and bevacizumab, followed by maintenance therapy with bevacizumab plus niraparib. A recent CT scan indicated stable disease.\n\nUse of avatrombopag in this patient\nIn this patient, administration of avatrombopag 20 mg daily concurrently with initiation of niraparib 300 mg daily may have reduced the severity of platelet count reduction, to 63 000/µL by February 20, 2020. The use of avatrombopag 40 mg daily has enabled the patient to tolerate niraparib 300 mg daily, with a platelet count of 155 000/µL measured on March 19, 2020, 1 week after starting niraparib. CA-125 levels were stable in this patient while using niraparib in combination with avatrombopag.\n\nCase 5: Ovarian cancer\nA female patient born in 1966 was diagnosed with stage III ovarian cancer in October 2018. She received 6 cycles of carboplatin, paclitaxel, and bevacizumab from November 2018 to April 2019 followed by niraparib maintenance therapy. She declined dual maintenance therapy with bevacizumab and niraparib. Her CA-125 levels showed a rise when niraparib maintenance was interrupted, and a subsequent decline when niraparib therapy was reintroduced and the dose was escalated.\n\nUse of avatrombopag in this patient\nBefore starting avatrombopag, the patient experienced 3 episodes of platelet count declines in association with niraparib use from April 2019 to August 2019 (platelet counts were 1000/µL on May 20 and May 28, 2019, 10 000/µL on July 31, 2019, and 65 000/µL on August 28, 2019). After starting avatrombopag at a weekly dose of 140 mg, the patient was able to tolerate an increase in her weekly niraparib dose from 500 mg to 900 mg on December 2, 2019 and a further increase to 1000 mg weekly on March 18, 2020. On February 5, 2019, the dose of avatrombopag increased from 140 mg weekly to 280 mg weekly. Despite continued up-titration in the dose of niraparib, platelet counts continued to rise. CA-125 levels fell from 43 U/mL on February 5, 2020 to 37 U/mL by March 4, 2020 concurrent with continuous use of niraparib and avatrombopag in this patient.\n\nCase 6: Ovarian cancer\nA patient born in 1944 was diagnosed with stage III ovarian cancer in March 2019. From March 2019 to May 2019, she received 4 cycles of carboplatin, paclitaxel, and bevacizumab, followed by debulking surgery in June 2019. Following disease progression, she received 4 cycles of carboplatin and paclitaxel until September 2019, followed by rucaparib maintenance. CA-125 levels in this patient had normalized since surgical intervention and have remained stable throughout treatment. As of March 2020, she was disease-free.\n\nUse of avatrombopag in this patient\nIn this patient, niraparib therapy was initiated at a dose of 700 mg weekly on December 4, 2019, which was gradually increased to 2100 mg weekly by January 7, 2020. With upward dose titration, platelet counts fell from a peak of 199 000/µL on December 11, 2019 to 106 000/µL by December 26, 2019. As a result of this drop in platelet counts, avatrombopag was also initiated on December 26, 2019 at a daily dose of 20 mg (140 mg weekly). As a result of avatrombopag coadministration, the patient experienced an increase in platelet counts to 163 000/µL on January 7, 2020. To support further dose escalation and platelet count stabilization on January 7, 2020, the daily dose of avatrombopag was escalated to 40 mg daily (280 mg weekly) and the niraparib dose was escalated to the maximal dose of 2100 mg weekly. Although 2 troughs in platelet levels occurred despite avatrombopag therapy (47 000/µL on January 29, 2020 and 28 000/µL on March 4, 2020), these troughs were managed through niraparib dose reduction initially to 1400 mg weekly on January 29, 2020, and then to 700 mg weekly by March 11, 2020. Although dose reductions were necessary to maintain platelet counts above 100 000/µL, this patient has been able to continue niraparib therapy, which may not have been possible in the absence of avatrombopag therapy.\n\nResults\nThree of 6 patients were able to sustain treatment with the maximum dose of niraparib (300 mg daily) for at least 3 continuous weeks. Continuous administration of avatrombopag mitigated thrombocytopenia and enabled dose escalation of niraparib to induce CT-confirmed response in 2 patients with breast cancer (cases 1 and 2). Reductions in CA-125 levels were observed in association with niraparib therapy enabled by avatrombopag therapy in 2 of 4 patients with ovarian cancer (cases 3 and 5). The remaining 2 patients had stable CA-125 levels (cases 4 and 6). One of these patients (case 6) has experienced complete response and was disease-free as of March 2020. One patient with breast cancer who experienced profound thrombocytopenia (31 000/µL) on niraparib attained supranormal platelet counts (757 000/µL) within 3 weeks of initiating avatrombopag 20 mg daily and was transitioned to a reduced dose (20 mg 3 times weekly), which enabled continued therapy with niraparib and continued response (Table 1).\n\nDiscussion\nUse of niraparib is limited by potential adverse events, including thrombocytopenia [14], which can lead to dose interruption or treatment discontinuation, which may reduce efficacy [12,14]. With a lack of approved medications for management of thrombocytopenia, there is a need for new therapeutic options [14,15]. As demonstrated in this case series, the TPO receptor agonist avatrombopag can counteract thrombocytopenia by interacting with the TPO receptor on megakaryocytes, the endogenous target of thrombopoietin [16–18]. In this case series of 2 patients with breast cancer and 4 patients with ovarian cancer, concurrent administration of the TPO receptor agonist avatrombopag mitigated thrombocytopenia and enabled both niraparib dose reescalation and improved clinical response.\n\nIn 2 patients with metastatic breast cancer, intracranial response was observed in association with avatrombopag-enabled niraparib therapy. Notably, in 1 patient with metastatic breast cancer, niraparib induced intracranial response, while previous use of talazoparib had not. This observation is confirmatory of preclinical findings with niraparib indicating superior blood-brain-barrier penetrance over other PARP inhibitors [13].\n\nTo reduce the risk of adverse events with niraparib, including thrombocytopenia, the starting dose of niraparib may be adjusted based on baseline bodyweight and platelet count. Specifically, patients with a baseline bodyweight <77 kg or with a baseline platelet count <150 00/µL may receive a reduced starting dose of 200 mg of niraparib daily, rather than a starting dose of 300 mg daily. In the PRIMA trial evaluating niraparib in the first-line maintenance setting of ovarian cancer, this strategy was introduced as a protocol amendment, and was shown to reduce the risk of thrombocytopenia from 52.4% with fixed starting dose niraparib to 33.7% with individualized starting dose niraparib. However, the initial dose adjustment of niraparib does not eliminate the issue of thrombocytopenia, as 14.8% of patients receiving individualized starting dose niraparib in PRIMA experienced thrombocytopenia of grade 3 severity or higher. Based on this case series, the risk of developing treatment-limiting thrombocytopenia may be further reduced through the use of avatrombopag in appropriate patients [19,20].\n\nIn patients with ovarian cancer, prior to avatrombopag initiation, increases in CA-125 levels in association with niraparib dose interruption occurred as a result of suboptimal niraparib dosing in association with thrombocytopenia. Additionally, in 2 patients with ovarian cancer, CA-125 levels fell in response to niraparib dose escalation enabled by concurrent avatrombopag therapy. This result indicates a potential for improved clinical outcomes in association with niraparib dose optimization enabled by avatrombopag therapy. Preliminary results in these 6 patient cases demonstrate the need for a confirmatory trial of avatrombopag for optimizing the dose of niraparib.\n\nConclusions\nResponses in this small series of patients indicate a role for avatrombopag in optimizing the dose of niraparib in patients receiving maintenance treatment for ovarian cancer and breast cancer. In this case series, the adverse event profile of niraparib did not differ from those noted for avatrombopag in trials supporting its indication for use in immune thrombocytopenia. One potential limitation of this case series is the fact that thrombocytopenia induced by PARP inhibition might not share the same bone marrow suppression effect observed with chemotherapy-induced thrombocytopenia. Avatrombopag should be further investigated in thrombocytopenia induced by niraparib in a trial assessing bone marrow for megakaryocyte count over the course of niraparib therapy. These preliminary results, presented in the form of a case series, demonstrate the need for a large prospective trial to confirm our findings.\n\nEditorial support in the form of manuscript writing, styling, and submission was provided by BioCentric, Inc. (Collingswood, NJ), and funded by Dova Pharmaceuticals (Durham, NC).\n\nDepartment and Institution where work was done\n\nDepartment of Medical Oncology, Gabrail Cancer Center, Canton, OH, U.S.A.\n\nFigure 1. Case 1, change in brain CT scan in a patient with breast cancer and brain metastases.\n\nFigure 2. Case 1, platelet count, niraparib dose, and avatrombopag dose over time.\n\nFigure 3. Case 2, change in brain CT scan in a patient with ovarian cancer.\n\nFigure 4. Case 3, platelet count, niraparib dose, and avatrombopag dose over time.\n\nTable 1. Outcomes in patients receiving avatrombopag to optimize therapeutic outcomes with niraparib therapy in breast cancer and ovarian cancer.\n\n\tTherapeutic doses used*\tSustained maximal dose of niraparib** (Y/N)\tBiomarkers confirming clinical response\tKey notes on case\t\nCase 1 (breast cancer with brain metastases)\tAvatrombopag: 0–140 mg/week\nNiraparib: 0–2100 mg/week\tY\tCT-confirmed intracranial response and successful discontinuation of steroids and absence of reported seizures after intracranial response enabled by niraparib and avatrombopag\tUse of niraparib in this patient initially led to profound thrombocytopenia (31,000/µL), which was rapidly transformed to a supranormal platelet count (757,000/µL) when the patient received avatrombopag 20 mg daily. Dosing of avatrombopag 20 mg two to three times weekly (total weekly dose: 40 mg to 60 mg) enabled continued therapy with niraparib and clinical response\t\nCase 2 (breast cancer with brain metastases)\tAvatrombopag: 140–280 mg/week\nNiraparib: 0–2100 mg/week\tN\tCT-confirmed intracranial partial response confirmed on 2 occasions\tContinuous administration of avatrombopag for all but 3 weeks enabled titration to the maximal dose of niraparib, enabling intracranial partial response. Of note, a period when avatrombopag was interrupted led to a reduction in platelet counts in subsequent months\t\nCase 3 (ovarian cancer)\tAvatrombopag: 140 mg/week\nNiraparib: 0–2100 mg/week\tY\tReduction in CA-125 levels in association with treatment with niraparib enabled by avatrombopag therapy\tThe patient has been able to receive the maximal dose of niraparib while receiving avatrombopag. Notably, the maximal dose of niraparib caused profound thrombocytopenia (36,000/µL) when it was administered without avatrombopag. CA-125 levels increased upon niraparib dose interruption and increased upon niraparib dose escalation enabled by avatrombopag therapy\t\nCase 4 (ovarian cancer)\tAvatrombopag: 140–280 mg/week\nNiraparib: 0–2100 mg/week\tY\tCA-125 levels were stable during continued dosing of niraparib and avatrombopag\tUse of avatrombopag enabled the patient to tolerate a maximal dose of niraparib. CA-125 levels were stable during continued dosing of niraparib and avatrombopag\t\nCase 5 (ovarian cancer)\tAvatrombopag: 140–280 mg/week\nNiraparib: 0–2100 mg/week\tN\tDrop in CA-125 levels in association with continued dosing of niraparib and avatrombopag\tUse of avatrombopag enabled the patient to tolerate a weekly dose of 500 mg of niraparib, which was later escalated to 1000 mg of niraparib. A reduction in CA-125 levels was observed with niraparib dose optimization\t\nCase 6 (ovarian cancer)\tAvatrombopag: 0–280 mg/week\nNiraparib: 0–2100 mg/week\tN\tCA-125 levels were stable during continued dosing of niraparib and avatrombopag. The patient experienced complete response and is disease-free as of March 2020\tWhile receiving concurrent avatrombopag, the patient was able to maintain platelet counts above 100,000/µL while on niraparib with some niraparib dose reductions. Avatrombopag therapy enabled this patient to tolerate niraparib, which may not have been possible in the absence of avatrombopag\t\n* Total weekly dose of treatments administered daily;\n\n** defined as 3 or more consecutive weeks receiving niraparib 300 mg daily.\n==== Refs\nReferences:\n1. Sonnenblick A de Azambuja E Azim HA Jr Piccart M An update on PARP inhibitors – moving to the adjuvant setting Nat Rev Clin Oncol 2015 12 1 27 41 25286972 \n2. Weil MK Chen AP PARP inhibitor treatment in ovarian and breast cancer Curr Probl Cancer 2011 35 1 7 50 21300207 \n3. Mirza MR Monk BJ Herrstedt J Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer N Engl J Med 2016 375 22 2154 64 27717299 \n4. González-Martín A Pothuri B Vergote I Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2019 381 25 2391 402 31562799 \n5. Moore K Colombo N Scambia G Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2018 379 26 2495 505 30345884 \n6. Moore KN Secord AA Geller MA Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): A multicentre, open-label, single-arm, phase 2 trial [published correction appears in Lancet Oncol, 2019; 20(5): e242] Lancet Oncol 2019 20 5 636 48 30948273 \n7. Pujade-Lauraine E Ledermann JA Selle F Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol, 2017; 18(9): e510] Lancet Oncol 2017 18 9 1274 84 28754483 \n8. Coleman RL Oza AM Lorusso D Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet, 2017; 390(10106): 1948] Lancet 2017 390 10106 1949 61 28916367 \n9. Litton JK Rugo HS Ettl J Talazoparib in patients with advanced breast cancer and a germline BRCA mutation N Engl J Med 2018 379 8 753 –. doi: 10.1056/NEJMoa1802905 30110579 \n10. González-Martín A Pothuri B Vergote I Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2019 381 25 2391 402 31562799 \n11. FDA FDA approves niraparib for first-line maintenance of advanced ovarian cancer 2020 https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-niraparib-first-line-maintenance-advanced-ovarian-cancer \n12. Wang J Zhang Z Mirza MR The exposure-response relationship of niraparib in patients with gBRCAmut and non-gBRCAmut: Results from the ENGOT-OV16/NOVA trial ESMO 2017 Congress 9 8–12 2017 Madrid, Spain https://oncologypro.esmo.org/meeting-resources/esmo-2017-congress/The-Exposure-Response-Relationship-of-Niraparib-in-Patients-with-gBRCAmut-and-Non-gBRCAmut-Results-from-the-ENGOT-OV16-NOVA-Trial \n13. Sun K Mikule K Wang Z A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for niraparib efficacy in preclinical tumor models Oncotarget 2018 9 98 37080 96 30647846 \n14. ZEJULA (niraparib) [package insert] Research Triangle Park, NC GlaxoSmithKline 2020 \n15. FDA FDA Drug Shortages https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Oprelvekin%20(Neumega%C2%AE)%20Lyophilized%20Powder%20for%20Injection%20Rx&st=d&tab=tabs-4 \n16. Zufferey A Kapur R Semple JW Pathogenesis and therapeutic mechanisms in immune thrombocytopenia (ITP) J Clin Med 2017 6 2 16 \n17. DOPTELET (avatrombopag) [package insert] Durham, NC Dova Pharmaceuticals Inc 2019 https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210238s001lbl.pdf \n18. PROMACTA (eltrombopag) [package insert] East Hanover, NJ Novartis Pharmaceuticals Corporation 2018 https://www.accessdata.fda.gov/drug-satfda_docs/label/2018/022291s021lbl.pdf \n19. Berek JS Matulonis UA Peen U Safety and dose modification for patients receiving niraparib Ann Oncol 2018 29 8 1784 92 29767688 \n20. González-Martín A Pothuri B Vergote I Niraparib in patients with newly diagnosed advanced ovarian cancer N Engl J Med 2019 381 25 2391 402 31562799\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": "D000246:Adenosine Diphosphate Ribose; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D007191:Indazoles; D010051:Ovarian Neoplasms; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D013844:Thiazoles; D013876:Thiophenes; D013921:Thrombocytopenia", "nlm_unique_id": "101489566", "other_id": null, "pages": "e927008", "pmc": null, "pmid": "33191394", "pubdate": "2020-11-16", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "28916367;30948273;27717299;29767688;30345884;21300207;28754483;25286972;30647846;31562799;30110579", "title": "Avatrombopag Optimizes Response to Niraparib by Managing Thrombocytopenia Associated with Poly-ADP Ribose Polymerase (PARP) Inhibition in Ovarian Cancer and Breast Cancer: A Case Series.", "title_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series" }

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AVATROMBOPAG OPTIMIZES RESPONSE TO NIRAPARIB BY MANAGING THROMBOCYTOPENIA ASSOCIATED WITH POLY-ADP RIBOSE POLYMERASE (PARP) INHIBITION IN OVARIAN CANCER AND BREAST CANCER: A CASE SERIES. AMERICAN JOURNAL OF CASE REPORTS. 2020?4:3144", "literaturereference_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201203", "receivedate": "20201203", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18573179, "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" }, { "companynumb": "US-TOLMAR, INC.-21US025565", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "LEUPROLIDE ACETATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUBCUTANEOUS INJECTION", "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ELIGARD" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "PALBOCICLIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PALBOCICLIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "FULVESTRANT" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": "201904", "drugenddateformat": "610", "drugindication": "DISEASE PROGRESSION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": "201807", "drugstartdateformat": "610", "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FULVESTRANT." } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Metastases to central nervous system", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Disease progression", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201904" } }, "primarysource": { "literaturereference": "GABRAIL N., SMITH C.. AVATROMBOPAG OPTIMIZES RESPONSE TO NIRAPARIB BY MANAGING THROMBOCYTOPENIA ASSOCIATED WITH POLY?ADP RIBOSE POLYMERASE (PARP) INHIBITION IN OVARIAN CANCER AND BREAST CANCER: A CASE SERIES. AMERICAN JOURNAL OF CASE REPORTS. 2020?21:1?10", "literaturereference_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210219", "receivedate": "20210219", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18916310, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" }, { "companynumb": "US-MYLANLABS-2021M1015189", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "200170", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DOXORUBICIN" } ], "patientagegroup": null, "patientonsetage": "5", "patientonsetageunit": "800", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "GABRAIL N, SMITH C. AVATROMBOPAG OPTIMIZES RESPONSE TO NIRAPARIB BY MANAGING THROMBOCYTOPENIA ASSOCIATED WITH POLY?ADP RIBOSE POLYMERASE (PARP) INHIBITION IN OVARIAN CANCER AND BREAST CANCER: A CASE SERIES. AM?J?CASE?REP 2020?21:1?10.", "literaturereference_normalized": "avatrombopag optimizes response to niraparib by managing thrombocytopenia associated with poly adp ribose polymerase parp inhibition in ovarian cancer and breast cancer a case series", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210315", "receivedate": "20210315", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19009600, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210420" } ]

{ "abstract": "OBJECTIVE\nWhen we published the diagnostic criteria for \"ictal epileptic headache\" in 2012, we deliberately and consciously chose to adopt restrictive criteria that probably underestimate the phenomenon, rather than spread panic among patients and physicians who are reluctant to accept this entity.\n\n\nMETHODS\nHere we discuss four intriguing clinical cases to highlight why we believe, to this day, that it is necessary to follow these restrictive diagnostic criteria.\n\n\nCONCLUSIONS\nEEG is not recommended as a routine examination for children diagnosed with headache, but it is mandatory and must be carried out promptly in cases of prolonged headache that does not respond to antimigraine drugs, if epilepsy is suspected or has been diagnosed previously. This is not a marginal or irrelevant question because possible isolated, non-motor, ictal manifestations should be taken into account before declaring that an epileptic patient is \"seizure free\" so as to ensure that any decision taken to suspend anticonvulsant therapy is safe.", "affiliations": "Child Neurology, NESMOS Department, Chair of Pediatrics, Faculty of Medicine and Psychology, Sapienza University c/o Sant'Andrea Hospital, Via di Grottarossa, 1035-1039, 00189, Rome, Italy. Electronic address: [email protected].;Department of Pediatrics, University of Perugia, Perugia, Italy.;Neuropsychiatry Ward, Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\", Trieste, Italy.;Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, \"G. Gaslini\" Institute, Genoa, Italy.;Neuropsychiatry Ward, Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\", Trieste, Italy.;Neuropsychiatry Ward, Institute for Maternal and Child Health - IRCCS \"Burlo Garofolo\", Trieste, Italy.;Emergency Pediatric Department, \"Bambino Gesù\" Children's Hospital, IRCCS, Rome, Italy.;Child Neurology, NESMOS Department, Chair of Pediatrics, Faculty of Medicine and Psychology, Sapienza University c/o Sant'Andrea Hospital, Via di Grottarossa, 1035-1039, 00189, Rome, Italy.;Neurology Clinic, Department of Neuroscience, Sant'Anna Hospital, Como, Italy.", "authors": "Parisi|Pasquale|P|;Verrotti|Alberto|A|;Costa|Paola|P|;Striano|Pasquale|P|;Zanus|Caterina|C|;Carrozzi|Marco|M|;Raucci|Umberto|U|;Villa|Maria Pia|MP|;Belcastro|Vincenzo|V|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1059-1311", "issue": "31()", "journal": "Seizure", "keywords": "Autonomic seizures; Autonomic status epilepticus; Epilepsy; Headache; Ictal epileptic headache; Migraine; Status migrainosus; Tension-type headache", "medline_ta": "Seizure", "mesh_terms": "D000293:Adolescent; D002648:Child; D003937:Diagnosis, Differential; D004569:Electroencephalography; D004827:Epilepsy; D005260:Female; D006261:Headache; D006801:Humans; D008297:Male", "nlm_unique_id": "9306979", "other_id": null, "pages": "56-63", "pmc": null, "pmid": "26362378", "pubdate": "2015-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Diagnostic criteria currently proposed for \"ictal epileptic headache\": Perspectives on strengths, weaknesses and pitfalls.", "title_normalized": "diagnostic criteria currently proposed for ictal epileptic headache perspectives on strengths weaknesses and pitfalls" }

[ { "companynumb": "IT-JNJFOC-20150918532", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "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": "IBUPROFEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "IBUPROFEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "019012", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HEADACHE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": "3", "patientonsetage": "9", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pallor", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "18.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Seizure", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "PARISI P, VERROTTI A, COSTA P, STRIANO P, ZANUS C, CARROZZI M, ET AL. DIAGNOSTIC CRITERIA CURRENTLY PROPOSED FOR ^ICTAL EPILEPTIC HEADACHE^: PERSPECTIVES ON STRENGTHS, WEAKNESSES AND PITFALLS. SEIZURE 2015?31:56-63.", "literaturereference_normalized": "diagnostic criteria currently proposed for ictal epileptic headache perspectives on strengths weaknesses and pitfalls", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20151007", "receivedate": "20151007", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11604812, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160304" } ]

{ "abstract": "This study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV).\n\n\n\nWe analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy.\n\n\n\nA total of 141 patients (median age 39 (IQR 33-45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3-3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time.\n\n\n\nPH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV.", "affiliations": "Division of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.;Department of Medicine, Division of Respirology, University Health Network, Toronto, Ontario, Canada.;Department of Pediatrics, Division of Cardiology, The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.;Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.", "authors": "Van De Bruaene|Alexander|A|0000-0002-0469-8640;Toh|Norihisa|N|;Hickey|Edward J|EJ|;Benson|Lee|L|;Horlick|Eric|E|;Granton|John T|JT|;Williams|William G|WG|;Roche|S Lucy|SL|", "chemical_list": "D020097:Natriuretic Peptide, Brain", "country": "England", "delete": false, "doi": "10.1136/heartjnl-2019-314756", "fulltext": null, "fulltext_license": null, "issn_linking": "1355-6037", "issue": "105(19)", "journal": "Heart (British Cardiac Society)", "keywords": "VAD; heart failure; pulmonary hypertension; systemic right ventricle; transposition of the great arteries", "medline_ta": "Heart", "mesh_terms": "D000328:Adult; D006328:Cardiac Catheterization; D004452:Echocardiography; D005260:Female; D016027:Heart Transplantation; D006352:Heart Ventricles; D006353:Heart-Assist Devices; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010101:Oxygen Consumption; D015995:Prevalence; D012189:Retrospective Studies; D014262:Tricuspid Valve Insufficiency; D018487:Ventricular Dysfunction, Left", "nlm_unique_id": "9602087", "other_id": null, "pages": "1471-1478", "pmc": null, "pmid": "31053610", "pubdate": "2019-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pulmonary hypertension in patients with a subaortic right ventricle: prevalence, impact and management.", "title_normalized": "pulmonary hypertension in patients with a subaortic right ventricle prevalence impact and management" }

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{ "abstract": "Tendon or muscle rupture is a rare complication of statins that could potentially be disabling and result in a significant burden to patients. The co-administration of statin and gemfibrozil should warrant prescribers' awareness of tendon-related complications of statin use, particularly in high-risk populations with poor renal function or musculoskeletal comorbidities.", "affiliations": "Division of Infectious Diseases Mayo Clinic Rochester Minnesota.;BronxCare Health System Bronx New York.;Parkview Medical Center Pueblo Colorado.;BronxCare Health System Bronx New York.;BronxCare Health System Bronx New York.", "authors": "Cano Cevallos|Edison Jose|EJ|https://orcid.org/0000-0002-0154-2544;Shaikh|Danial Haris|DH|;Gonzalez|Jose|J|;Sanchez|William|W|;Patel|Madanmohan|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.2387", "fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2387CCR32387Case ReportCase ReportsTendon rupture associated with concomitant simvastatin and gemfibrozil use: Biological and pharmacokinetic implications CANO CEVALLOS et al.Cano Cevallos Edison Jose https://orcid.org/0000-0002-0154-2544\n1\[email protected] Shaikh Danial Haris \n2\nGonzalez Jose \n3\nSanchez William \n2\nPatel Madanmohan \n2\n\n1 \nDivision of Infectious Diseases\nMayo Clinic\nRochester\nMinnesota\n\n2 \nBronxCare Health System\nBronx\nNew York\n\n3 \nParkview Medical Center\nPueblo\nColorado\n* Correspondence\n\nEdison Jose Cano Cevallos, Division of Infectious Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905.\n\nEmail: [email protected]\n28 8 2019 10 2019 7 10 10.1002/ccr3.v7.101919 1922 07 2 2019 18 7 2019 21 7 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nTendon or muscle rupture is a rare complication of statins that could potentially be disabling and result in a significant burden to patients. The co‐administration of statin and gemfibrozil should warrant prescribers’ awareness of tendon‐related complications of statin use, particularly in high‐risk populations with poor renal function or musculoskeletal comorbidities.\n\nadverse effectsgemfibrozilmuscle rupturestatintendon rupture source-schema-version-number2.0component-idccr32387cover-dateOctober 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.7.0 mode:remove_FC converted:11.10.2019\n\n\nCano Cevallos \nEJ \n, \nShaikh \nDH \n, \nGonzalez \nJ \n, \nSanchez \nW \n, \nPatel \nM \n. Tendon rupture associated with concomitant simvastatin and gemfibrozil use: Biological and pharmacokinetic implications . Clin Case Rep . 2019 ;7 :1919 –1922 . 10.1002/ccr3.2387 \n\n\n\nWork carried at BronxCare Health System, 1650 Grand Concourse; Bronx, NY 10457. All the authors were affiliated with the above institution at the time the work was performed.\n==== Body\n1 INTRODUCTION\nStatins remain a widely used lipid‐lowering drug class. They have shown a reduction in all‐cause mortality, major vascular events, and revascularizations in people with and without cardiovascular disease.1, 2, 3 Combination with fibrates, such as gemfibrozil and fenofibrate, has shown even greater reductions in total cholesterol, LDL cholesterol, and triglycerides than either type of drug alone; however, this combination therapy is associated with an increased risk of hepatic dysfunction, renal insufficiency, and disorders of the musculoskeletal system.4 Muscle and tendon rupture has been described as a very rare complication of statin therapy, yet has not been reported in association with fibrates. We present a patient with normal kidney function and long‐standing use of simvastatin presenting with spontaneous myotendinous junction rupture of the plantaris muscle after recent initiation of gemfibrozil.\n\n2 CASE HISTORY/EXAMINATION\nA 53‐year‐old female presented to the emergency department complaining of sudden onset right calf pain. Her pain occurred after standing from a sitting position. It was intense, pressure‐like, nonradiating, and worsened by movement. The patient denied any history of direct or indirect trauma. Her medical comorbidities included hypertension, dyslipidemia, anemia, and right rotator cuff tear.\n\nHer home medications included simvastatin 10 mg daily, hydrochlorothiazide, amlodipine, benazepril, naproxen, ferrous sulfate, multivitamins, and calcium supplements. Three weeks ago, she was started on gemfibrozil 600 mg twice a day and had since reported worsening of her right shoulder pain, for which she did not seek medical attention.\n\nOn examination, she was awake, alert, oriented, and vital signs were within normal limits. The right lower extremity was bruised, tender, deformed, and warm in the calf area. Pain on palpation and passive movement was out of proportion to the apparent injury. The surgeon was called for assessment, and his impression was muscle rupture with suspected compartment syndrome due to intense pain and stiffness on examination. Pulses and sensations were preserved distally. Intracompartmental pressure measured on admission was 22 mm Hg, which would improve to <10 mm Hg in the following days.\n\n2.1 Differential diagnosis, investigations, and treatment\nOn laboratory (Table 1), kidney and liver tests were normal, serum creatinine kinase levels were 103, 167, and 180 units/L on days 1, 2, and 4, respectively. Serum aldolase values remained negative. Lipid panel was normal. Ultrasound of right lower extremity was negative for deep vein thrombosis and showed intermuscular hematoma with a possible muscle tear. Magnetic resonance imaging of the right lower extremity (Figures 1 and 2) showed an acute large hematoma within the posteromedial right lower leg, superficial to the soleus muscle and deep to the medial gastrocnemius, deemed secondary to rupture of the myotendinous junction of the plantaris muscle, with an otherwise intact musculature and no fracture.\n\nTable 1 Laboratory results\n\nLaboratory test\tValue\tNormal range\t\nWhite blood cells\t12.0 k/µL\t4.8‐10.8 k/µL\t\nNeutrophiles (%)\t78.6%\t40%‐70%\t\nBUN\t10 mg/dL\t6‐20 mg/dL\t\nSerum creatinine\t0.5 mg/dL\t0.5‐1.5 mg/dL\t\nEstimated GFR\t133 mL/min/1.73m2\n\t51‐120 mL/min/1.73m2\n\t\nC‐reactive protein\t<5 mg/dL\t<5 mg/dL\t\nCreatine kinase\t167 units/L\t20‐200 units/L\t\nAldolase\t4.6 units/L\t<8.1 units/L\t\nAST\t20 units/L\t9‐36 units/L\t\nALT\t15 units/L\t5‐40 units/L\t\nTotal cholesterol\t163 mg/dL\t162‐240 mg/dL\t\nHDL cholesterol\t43 mg/dL\t34‐82 mg/dL\t\nLDL cholesterol\t100 mg/dL\t<160 mg/dL\t\nTriglycerides\t102 mg/dL\t25‐150 mg/dL\t\nAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen.\n\nJohn Wiley & Sons, LtdFigure 1 Acute hematoma (*) within the posteromedial right lower leg measuring 5.0 × 1.9 cm transversely and approximately 15 cm craniocaudally, lying superficially to the soleus muscle and deep to the medial gastrocnemius, secondary to rupture of the myotendinous junction of the plantaris muscle\n\nFigure 2 Redemonstrated hematoma and mild edema‐like signal (arrow) noted within the medial gastrocnemius muscle adjacent to the hematoma probably representing a partial tear or strain of the medial gastrocnemius; otherwise intact musculature and no fracture\n\nThe patient was provided analgesics and strict limb elevation. A diagnosis of tendon rupture was made and an association to statin and fibrate combination was suspected, necessitating discontinuation of these medications. Pain improved notably in the following days. The orthopedic team deemed surgical intervention as not necessary and recommended evaluation for physical therapy with outpatient follow‐up. Discontinuation of gemfibrozil was ensured at the time of discharge.\n\n2.2 Outcome and follow‐up\nAt the 3‐month follow‐up with her primary care physician, she was able to walk with minimal support, had received 10 weeks of physical therapy and decided not to take any lipid‐lowering therapy but instead start a low‐fat diet and implement lifestyle changes. Her calculated 10‐year ASCVD risk was 2.6%.\n\n3 DISCUSSION\nLipid‐lowering medications can adversely induce myopathy, tendinopathy, and rhabdomyolysis secondary to their inhibitory effect on the conversion of hydroxymethyl glutaryl coenzyme A (HMG‐CoA) to mevalonic acid, a rate‐limiting step in the cholesterol synthesis pathway. This decreases the production of coenzyme Q10, an important element in the electron transport chain, ultimately impairing myocyte energy production. Mitochondrial dysfunction, genetic predisposition, and alterations in gene expression may also play a role in the pathogenic mechanisms.5\n\n\nTendons’ extracellular matrix consists mainly of type 1 collagen which is highly resistant to proteolytic cleavage. Statins promote an imbalance between the synthesis and degradation of matrix metalloproteinases, which can induce microdamage in muscles and tendons alike. They are also known to inhibit tendon cell proliferation, thus having a negative impact on tendon healing.6 Simvastatin use has also been shown to promote apoptosis in fibroblasts of patients with rheumatoid arthritis and induce arrest at the G1/S transition of the cell cycle, further suggesting an association between statin use and tendon disorders.7\n\n\nGemfibrozil is responsible for PPARα activation and is rarely (<1%) associated with myopathy or rhabdomyolysis. Skeletal muscle toxicity has been described in type I muscle fibers in rats and the proposed mechanism might include oxidative stress and tissue damage from elevated peroxisomal and mitochondrial β‐oxidation.8 Gemfibrozil inhibits the metabolism of all statins, including simvastatin, and has shown to increase plasma concentrations of simvastatin acid (the active form of simvastatin) in pharmacokinetic studies.9 Some studies reported an increased risk of muscle toxicity, as high as 1 to 5 percent when statins were co‐administered with Gemfibrozil.10, 11\n\n\nMyopathy secondary to statin use has been described in the presence of normal creatine kinase, as seen in this patient, with microscopic evidence of ragged red fibers, abnormally increased lipid stores and lack of fibers staining for cytochrome oxidase activity.12\n\n\nStudies have implicated atorvastatin as the most commonly involved statin, and diseases such as rheumatoid arthritis, systemic lupus erythematosus, gout, diabetes mellitus, hyperparathyroidism, and chronic kidney disease are inherent risk factors for tendon rupture.\n\nTendinopathy most often occurs within the first year of statin initiation and the Achilles tendon is usually the most frequent site of rupture. A pharmacovigilance study from France reported 30 possible cases of spontaneous tendon rupture attributed to the use of simvastatin.13 As of April 2018, the Food and Drug Administration adverse event reporting system (FAERS) database contained 280 reports of tendon rupture associated with simvastatin therapy, and one case of tendon rupture associated with gemfibrozil, since 1994.14 Despite a considerable number of cases in which simvastatin was involved, cases with concomitant use of fibrates, particularly gemfibrozil, remain unknown.\n\nFenofibrate appears to be safer than gemfibrozil because renal excretion of statins appears to be significantly inhibited by gemfibrozil but not by fenofibrate.15, 16 Meta‐analyses of randomized trials have found no increase in muscle or tendon‐related adverse events in patients taking fenofibrate plus a statin compared with a statin alone.17, 18 Studies have also failed to show an increase in the incidence of myopathy or tendinopathy in patients with combined hyperlipidemia who were prescribed pravastatin plus gemfibrozil.19\n\n\nAlthough myopathy and myositis are common adverse outcomes, tendon rupture remains a seldom reported entity of statin‐gemfibrozil combination use. Even more unusual is that our patient did not possess any comorbidities predisposing to tendon rupture and endured the injury in an uncommon location. This case represents a probable adverse drug reaction (Naranjo score of 7).20 She was on simvastatin therapy for about a year and had only recently been started on gemfibrozil with unchanged liver or kidney function. Her triglyceride level prior to starting gemfibrozil was unknown, however, when she presented to us her level was 102 mg/dL. To our knowledge, this is the first case of tendon rupture associated with gemfibrozil and simvastatin combination use.\n\nIn conclusion, we suggest that prescribers should be aware of the tendon‐related complications of statin use, especially with co‐administration of gemfibrozil, and particularly so in patients with comorbidities that are known to increase the risk. Routine musculoskeletal examination may be beneficial in statin‐treated patients on gemfibrozil, especially during the first year of combination therapy. The use of fenofibrate in patients who require combined therapy with a statin appears safe, whereas pravastatin appears to have little muscle/tendon toxicity when used in combination with gemfibrozil.\n\nCONFLICT OF INTEREST\nNo conflicts of interest have been declared.\n\nAUTHOR CONTRIBUTIONS\nEdison J. Cano: resident who admitted the patient and carried initial assessment and management. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. Danial H. Shaikh: resident who took care of the patient and carried subsequent management. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. Jose A. Gonzalez: resident who took care of the patient and carried subsequent management. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. William Sanchez: resident who carried follow‐up of the patient. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission. Madanmohan Patel: attending on file that assessed and managed the patient. Contributed by conceptualizing idea of case report; gathering and interpreting clinical data; drafting and critically reviewing the manuscript before submission.\n==== Refs\nREFERENCES\n1 \n\nTaylor \nF \n, \nHuffman \nMD \n, \nMacedo \nAF \n, et al. Statins for the primary prevention of cardiovascular disease . Cochrane Database Syst Rev . 2013 ;1 :CD004816 \n10.1002/14651858.CD004816.pub5 \n\n2 \nCholesterol Treatment Trialists’ (CTT) Collaborators \n, \nMihaylova \nB \n, \nEmberson \nJ \n, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta‐analysis of individual data from 27 randomised trials . Lancet . 2012 ;380 :581 ‐590 .22607822 \n3 \nHeart Protection Study Collaborative Group \n. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high‐risk individuals: a randomised placebo‐controlled trial . Lancet . 2002 ;360 :7 ‐22 .12114036 \n4 \n\nChoi \nHD \n, \nShin \nWG \n, \nLee \nJ‐Y \n, \nKang \nBC \n. Safety and efficacy of fibrate‐statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta‐analysis . Vascul Pharmacol . 2015 ;65–66 :23 ‐30 .\n5 \n\nAuer \nJ \n, \nSinzinger \nH \n, \nFranklin \nB \n, \nBerent \nR \n. Muscle‐ and skeletal‐related side‐effects of statins: tip of the iceberg? \nEur J Prev Cardiol . 2016 ;23 :88 ‐110 .25230981 \n6 \n\nde Oliveira \nLP \n, \nVieira \nCP \n, \nGuerra \nF \n, \nde Almeida \nM \n, \nPimentel \nER \n. Statins induce biochemical changes in the Achilles tendon after chronic treatment . Toxicology . 2013 ;311 :162 ‐168 .23831763 \n7 \n\nYokota \nK \n, \nMiyoshi \nF \n, \nMiyazaki \nT \n, et al. High concentration simvastatin induces apoptosis in fibroblast‐like synoviocytes from patients with rheumatoid arthritis . J Rheumatol . 2008 ;35 :193 ‐200 .18203325 \n8 \n\nBurri \nL \n, \nHege Thoresen \nG \n, \nBerge \nRK \n. The role of PPARα activation in liver and muscle . PPAR Research . 2010 ;2010 :1 ‐11 .\n9 \n\nBackman \nJT \n, \nKyrklund \nC \n, \nKivistö \nKT \n, \nWang \nJS \n, \nNeuvonen \nPJ \n. Plasma concentrations of active simvastatin acid are increased by gemfibrozil . Clin Pharmacol Ther . 2000 ;68 :122 ‐129 .10976543 \n10 \n\nDuell \nPB \n, \nBarton Duell \nP \n, \nConnor \nWE \n, \nRoger \nID \n. Rhabdomyolysis after taking atorvastatin with gemfibrozil . Am J Cardiol . 1998 ;368 ‐369 .9468088 \n11 \n\nPierce \nLR \n, \nRoss \nPL \n. Myopathy and Rhabdomyolysis Associated With Lovastatin‐Gemfibrozil Combination Therapy . JAMA: J Am Med Assoc . 1990 ;264 (1 ):71 .\n12 \n\nPhillips \nPS \n, \nHaas \nRH \n, \nBannykh \nS \n, et al. Statin‐associated myopathy with normal creatine kinase levels . Ann Intern Med . 2002 ;137 :581 ‐585 .12353945 \n13 \n\nMarie \nI \n, \nDelafenêtre \nH \n, \nMassy \nN \n, \nThuillez \nC \n, \nNoblet \nC \n, Network of the French Pharmacovigilance Centers \n. Tendinous disorders attributed to statins: a study on ninety‐six spontaneous reports in the period 1990–2005 and review of the literature . Arthritis Rheum . 2008 ;59 :367 ‐372 .18311771 \n14 \nQlik Sense . [cited 25 Apr 2018]. Available: https://fis.fda.gov/sense/app/777e9f4d-0cf8-448e-8068-f564c31baa25/sheet/33a0f68e-845c-48e2-bc81-8141c6aaf772/state/analysis.\n15 \n\nPrueksaritanont \nT \n, \nZhao \nJJ \n, \nMa \nB \n, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins . J Pharmacol Exp Ther . 2002 ;301 (3 ):1042 ‐1051 .12023536 \n16 \n\nBallantyne \nCM \n, \nDavidson \nMH \n. Possible differences between fibrates in pharmacokinetic interactions with statins . Arch Intern Med . 2003 ;163 (19 ):2394 .14581261 \n17 \n\nGeng \nQ \n, \nRen \nJ \n, \nChen \nH \n, \nLee \nC \n, \nLiang \nW \n. Adverse events following statin‐fenofibrate therapy versus statin alone: A meta‐analysis of randomized controlled trials . Clin Exp Pharmacol Physiol . 2013 ;40 (3 ):219 ‐226 .23324122 \n18 \n\nGuo \nJ \n, \nMeng \nF \n, \nMa \nN \n, et al. Meta‐analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia . Am J Cardiol . 2012 ;110 :1296 ‐1301 .22840347 \n19 \n\nAthyros \nVG \n, \nPapageorgiou \nAA \n, \nHatzikonstandinou \nHA \n, et al. Safety and efficacy of long‐term statin‐fibrate combinations in patients with refractory familial combined hyperlipidemia . Am J Cardiol . 1997 ;80 (5 ):608 ‐613 .9294990 \n20 \n\nNaranjo \nCA \n, \nBusto \nU \n, \nSellers \nEM \n, et al. A method for estimating the probability of adverse drug reactions [Internet] . Clin Pharmacol Ther . 1981 ;30 (2 ):239 ‐245 .7249508\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2050-0904", "issue": "7(10)", "journal": "Clinical case reports", "keywords": "adverse effects; gemfibrozil; muscle rupture; statin; tendon rupture", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "1919-1922", "pmc": null, "pmid": "31624609", "pubdate": "2019-10", "publication_types": "D002363:Case Reports", "references": "12353945;18203325;10976543;7249508;23440795;22607822;25451563;20847941;23831763;12114036;9468088;18311771;23324122;14581261;25230981;22840347;12023536;2355431;9294990", "title": "Tendon rupture associated with concomitant simvastatin and gemfibrozil use: Biological and pharmacokinetic implications.", "title_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications" }

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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLIN CASE REP. 2019?00:1-4", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190925", "receivedate": "20190925", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16851282, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20191005" }, { "companynumb": "US-APOTEX-2019AP021777", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "1", 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. DOI: 10.1002/CCR3.2387. 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS.. 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. 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TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. 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null, "drugindication": "SUPPLEMENTATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CALCIUM" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "FERROUS SULFATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "SUPPLEMENTATION THERAPY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FERROUS SULFATE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "AMLODIPINE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BENAZEPRIL HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "BENAZEPRIL" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMFIBROZIL" }, "drugadditional": "1", "drugadministrationroute": "065", "drugauthorizationnumb": "077836", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, BID, 3 WEEKS AGO", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRODUCT USED FOR UNKNOWN INDICATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMFIBROZIL." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "NAPROXEN." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematoma muscle", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Musculoskeletal pain", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tendon rupture", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CANO CEVALLOS EJ, SHAIKH DH, GONZALEZ J, SANCHEZ W, PATEL M. TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLINICAL CASE REPORTS. 2019?00:1 TO 4", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190925", "receivedate": "20190916", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16808225, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20191005" }, { "companynumb": "US-009507513-1909USA002327", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMINS" }, "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": "VITAMINS (UNSPECIFIED)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "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": "CALCIUM (UNSPECIFIED)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "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": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "NAPROXEN" }, "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": "NAPROXEN." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "FERROUS SULFATE" }, "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": "FERROUS SULFATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BENAZEPRIL HYDROCHLORIDE" }, "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": "BENAZEPRIL HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "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": "AMLODIPINE" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "SIMVASTATIN" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "019766", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": "10 MILLIGRAM, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ZOCOR" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMFIBROZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "600 MILLIGRAM, TWICE A DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "600", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMFIBROZIL." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haematoma muscle", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tendon rupture", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "CANO CEVALLOS EJ, SHAIKH DH, GONZALEZ J, SANCHEZ W, PATEL M. TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLINICAL CASE REPORTS. 2019?1-4", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191216", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16804163, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200122" }, { "companynumb": "US-DRREDDYS-USA/USA/19/0114214", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NAPROXEN" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "078486", "drugbatchnumb": "UNKNOWN", "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": "NAPROXEN." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BENAZEPRIL HYDROCHLORIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "BENAZEPRIL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VITAMINS" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "MULTIVITAMINS" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CALCIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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, 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"003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMFIBROZIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HYDROCHLOROTHIAZIDE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "HYDROCHLOROTHIAZIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "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": "AMLODIPINE" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "FERROUS SULFATE" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", 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"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": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SIMVASTATIN." } ], "patientagegroup": null, "patientonsetage": "53", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tendon rupture", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "CANO CEVALLOS EJ, SHAIKH DH, GONZALEZ J, SANCHEZ W, PATEL M. TENDON RUPTURE ASSOCIATED WITH CONCOMITANT SIMVASTATIN AND GEMFIBROZIL USE: BIOLOGICAL AND PHARMACOKINETIC IMPLICATIONS. CLINICAL CASE REPORTS. 2019. DOI: 10.1002/CCR3.2387.", "literaturereference_normalized": "tendon rupture associated with concomitant simvastatin and gemfibrozil use biological and pharmacokinetic implications", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20191216", "receivedate": "20190913", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16804833, "safetyreportversion": 4, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "Although patients with cancer and immunosuppression are at a risk of functional hyposplenism, how to detect it promptly remains unclear. Since hyposplenism allows erythrocytes with nuclear remnants (Howell-Jolly bodies [HJBs]) to appear in the peripheral blood, HJB detection by a routine microscopic examination may help identify patients with functional hyposplenism. This prospective study was thus performed to determine the underlying diseases in patients who presented with HJBs. Of 100 consecutive patients presenting with HJBs, 73 had a history of splenectomy. The remaining 27 had hematologic cancer (n = 6, 22%), non-hematologic cancer (n = 8, 30%), hepatic disorders (n = 4, 15%), premature neonates (n = 3, 11%), hemolytic anemia (n = 2, 7%), autoimmune disorders (n = 2, 7%) and miscellaneous diseases (n = 2, 7%), and their prior treatments included chemotherapy (n = 8, 30%), steroids (n = 7, 26%) and molecular-targeted therapy (n = 3, 11%). Among the 27 patients, 22 had computed tomography scans available: 3 (14%) had underlying diseases in the spleen, and the remaining 19 (86%) were all found to have a decreased splenic volume, including 11 (50%) with more than 50% of the ideal value. The present findings suggest that HJB detection identifies patients with potentially functional hyposplenism who should receive appropriate interventional treatment, such as vaccination and prophylactic antibiotics.", "affiliations": "Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Radiology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.;Department of Radiology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan.;Department of Clinical Laboratory, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.;Department of Clinical Laboratory, Aichi Medical University Hospital, Nagakute, Aichi, Japan.;Department of Internal Medicine, Division of Hematology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan. [email protected].", "authors": "Nakagami|Yuya|Y|;Uchino|Kaori|K|;Okada|Hiroaki|H|;Suzuki|Kojiro|K|;Enomoto|Megumi|M|;Mizuno|Shohei|S|;Yamamoto|Hidesuke|H|;Hanamura|Ichiro|I|;Nakayama|Takayuki|T|;Tani|Hiroya|H|;Takami|Akiyoshi|A|http://orcid.org/0000-0002-1822-9976", "chemical_list": null, "country": "Japan", "delete": false, "doi": "10.1007/s12185-020-02925-7", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "112(4)", "journal": "International journal of hematology", "keywords": "Functional hyposplenism; Howell−Jolly body; Peripheral blood smear", "medline_ta": "Int J Hematol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004908:Erythrocyte Inclusions; D004912:Erythrocytes; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013158:Splenic Diseases; D055815:Young Adult", "nlm_unique_id": "9111627", "other_id": null, "pages": "544-552", "pmc": null, "pmid": "32572828", "pubdate": "2020-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Potential role of Howell-Jolly bodies in identifying functional hyposplenism: a prospective single-institute study.", "title_normalized": "potential role of howell jolly bodies in identifying functional hyposplenism a prospective single institute study" }

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POTENTIAL ROLE OF HOWELL?JOLLY BODIES IN IDENTIFYING FUNCTIONAL HYPOSPLENISM: A PROSPECTIVE SINGLE?INSTITUTE STUDY. 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POTENTIAL ROLE OF HOWELL?JOLLY BODIES IN IDENTIFYING FUNCTIONAL HYPOSPLENISM: A PROSPECTIVE SINGLE?INSTITUTE STUDY. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2020?112(4):544?552.", "literaturereference_normalized": "potential role of howell jolly bodies in identifying functional hyposplenism a prospective single institute study", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20210128", "receivedate": "20210115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18748956, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210419" } ]

{ "abstract": "Depression constitutes the most frequent comorbid condition associated with rheumatoid arthritis (RA), with prevalence rates ranging from 14% to 48%. This wide range can be explained by several factors including subtypes of depression considered, instrument of measure (i.e. self-questionnaires versus clinical interview), threshold applied but also the overlap of symptoms between the two conditions. Despite being a frequent comorbid condition in RA, depressive states are repeatedly underdiagnosed and thus, often remain untreated. Consequences are dramatic as conclusive evidence show that depression deleteriously impacts just about all outcomes of RA, including disease activity, arthritis-related complications, level of pain, chance of remission, quality of life and mortality. Importantly, links between depression and RA appear to be bidirectional as if RA patients show increased prevalence of depression. Conversely, patients with depression compared to the general population have higher risk to develop RA. Among the factors explaining this strong association between depression and RA, recent advances have underlined the putative role of models based on the inflammatory hypothesis. Pro-inflammatory cytokines such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-18 are involved in RA pathogenesis, but also in depression. Furthermore, the connections between the central nervous system, the peripheral system and the immune system are now better understood. As a consequence of the strong comorbidity and the aggravate prognostic, the management of patient showing this dual diagnosis should be carefully monitor. The common physiopathology also opens the path to utilization of RA treatment in severe depression or treatment-resistant depression.", "affiliations": "Psychiatry department, University Hospital of Saint Etienne, Saint Etienne, France; INSERM, U1028; CNRS, UMR5292; Lyon Neuroscience Research Center, PSYR2 Team, Lyon, France.;Rheumatology department, University Hospital of Saint Etienne, Saint Etienne, France; Inserm U1059, Equipe LBTO, Université de Lyon, Saint-Étienne, France. Electronic address: [email protected].", "authors": "Fakra|Eric|E|;Marotte|Hubert|H|", "chemical_list": "D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha", "country": "France", "delete": false, "doi": "10.1016/j.jbspin.2021.105200", "fulltext": null, "fulltext_license": null, "issn_linking": "1297-319X", "issue": "88(5)", "journal": "Joint bone spine", "keywords": "Common characteristics; Depression; Inflammation; Rheumatoid arthritis", "medline_ta": "Joint Bone Spine", "mesh_terms": "D001172:Arthritis, Rheumatoid; D016207:Cytokines; D003863:Depression; D006801:Humans; D011788:Quality of Life; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "100938016", "other_id": null, "pages": "105200", "pmc": null, "pmid": "33932572", "pubdate": "2021-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Rheumatoid arthritis and depression.", "title_normalized": "rheumatoid arthritis and depression" }

[ { "companynumb": "DE-LUPIN PHARMACEUTICALS INC.-2020-05197", "fulfillexpeditecriteria": "2", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DICLOFENAC" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "204132", "drugbatchnumb": "UNKNOWN", "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": "DICLOFENAC" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEFLUNOMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "LEFLUNOMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "CITALOPRAM HYDROBROMIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "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": "CITALOPRAM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "67", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Abdominal pain upper", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KELLNER H. RHEUMATOID ARTHRITIS AND DEPRESSION. MMW-FORTSCHR-MED. 2009?151(51):49", "literaturereference_normalized": "rheumatoid arthritis and depression", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20201013", "receivedate": "20201013", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18375370, "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" } ]

{ "abstract": "Infliximab and adalimumab are widely used in the treatment of patients with ulcerative colitis (UC). There are few published data on the treatment persistence of infliximab and adalimumab in patients with UC.\n\n\n\nWe aimed to compare the treatment persistence rates of infliximab versus adalimumab as first- and second-line tumor necrosis factor antagonists (anti-TNF), to identify factors potentially associated with persistence, and to evaluate reasons for withdrawal in UC patients. We performed a retrospective, single-center cohort study of UC patients treated with infliximab or adalimumab for at least 6 months between June 2002 and May 2018.\n\n\n\nThe median (interquartile range [IQR]) duration of follow-up was 5.4 (3.2-8.3) years. For first-line anti-TNF agent, data on 160 patients with UC were analyzed. The mean (SD) duration of persistence was 3.4 (3.5) years and 2.1 (2.0) years in the infliximab and adalimumab subgroups, respectively (P = 0.24). Concomitant use of 5-aminosalicylate was associated with higher persistence of first-line anti-TNF treatment in the overall population (hazard ratio [HR] 0.5; 95% CI, 0.3-0.8; P = 0.002). For second-line anti-TNF agent, data on 43 patients were analyzed. The mean (SD) duration of persistence was 2.0 (1.7) years and 3.2 (3.1) years in the infliximab and adalimumab subgroups, respectively (P = 0.95). No factors were associated with persistence of second-line anti-TNF treatment.\n\n\n\nInfliximab and adalimumab showed similar levels of persistence as first- and second-line anti-TNF treatments. Concomitant use of 5-aminosalicylates was associated with higher persistence of first-line anti-TNF treatment.", "affiliations": "INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.;Clinical Research Support Facility PARC, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;Clinical Research Support Facility PARC, Nancy University Hospital, Vandoeuvre-lès-Nancy, France.;INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.;INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.;Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan, Italy.;INSERM U954 and Department of Hepatogastroenterology, Nancy University Hospital, Université de Lorraine, Vandoeuvre-lès-Nancy, France.", "authors": "Pouillon|Lieven|L|;Baumann|Cédric|C|;Rousseau|Hélène|H|;Choukour|Myriam|M|;Andrianjafy|Charlotte|C|;Danese|Silvio|S|;Peyrin-Biroulet|Laurent|L|", "chemical_list": "D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1093/ibd/izy322", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0998", "issue": "25(5)", "journal": "Inflammatory bowel diseases", "keywords": "adalimumab; clinical experience; infliximab; persistence; ulcerative colitis", "medline_ta": "Inflamm Bowel Dis", "mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000893:Anti-Inflammatory Agents; D003093:Colitis, Ulcerative; D005260:Female; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies", "nlm_unique_id": "9508162", "other_id": null, "pages": "945-954", "pmc": null, "pmid": "30329067", "pubdate": "2019-04-11", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D064888:Observational Study", "references": null, "title": "Treatment Persistence of Infliximab Versus Adalimumab in Ulcerative Colitis: A 16-Year Single-Center Experience.", "title_normalized": "treatment persistence of infliximab versus adalimumab in ulcerative colitis a 16 year single center experience" }

[ { "companynumb": "FR-JNJFOC-20190819563", "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": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB, RECOMBINANT" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ADALIMUMAB" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "40", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ADALIMUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Skin disorder", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthralgia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Arthritis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neoplasm", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "BAUMANN C, ROUSSEAU H, CHOUKOUR M, ANDRIANJAFY C, DANESE S, PEYRIN-BIROULET L, POUILLON L. TREATMENT PERSISTENCE OF INFLIXIMAB VERSUS ADALIMUMAB IN ULCERATIVE COLITIS: A 16-YEAR SINGLE-CENTER EXPERIENCE. INFLAMMATORY BOWEL DISEASES. 2019?25 (5):945-954.", "literaturereference_normalized": "treatment persistence of infliximab versus adalimumab in ulcerative colitis a 16 year single center experience", "qualification": "1", "reportercountry": "FR" }, "primarysourcecountry": "FR", "receiptdate": "20190822", "receivedate": "20190822", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 16729379, "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": "Sublingual buprenorphine/naloxone, a common treatment for opioid dependence, is frequently abused by intravenous injection. Inadvertent intra-arterial injection of buprenorphine/naloxone can produce acute ischemic insult to the hand due to gelatin embolism. Our purpose was to review a series of these patients in order to describe the clinical entity, review the outcomes, and propose a rational treatment algorithm.\n\n\n\nClinical records of all patients evaluated by the hand surgery team between 2011 and 2015 for ischemia of the hand after buprenorphine/naloxone injection were reviewed. Treatment, complications, and amount of tissue loss were recorded. Patients presenting within 48 hours of the injection were treated with intravenous heparin for 5 days, followed by oral aspirin and clopidogrel for 30 days. Those presenting after 48 hours were treated with aspirin and clopidogrel only.\n\n\n\nTen patients presented during the review period. Average follow-up time was 13 weeks. Eight had ischemia of the radial side of the hand, 1 of the ulnar side, and 1 had bilateral ischemia. Three patients were treated with intravenous heparin and 5 with oral agents. Two presented with dry gangrene and did not receive anticoagulation. All patients experienced tissue loss. There was no difference in outcome regardless of treatment.\n\n\n\nWith the increasing use of sublingual buprenorphine/naloxone in opioid dependency, ischemic hand injuries will be seen with greater frequency. Whereas outcomes did not vary with treatment modality in this series, further study is needed to determine the most effective treatment of these injuries.", "affiliations": "1 University of Kentucky, Lexington, USA.;1 University of Kentucky, Lexington, USA.;1 University of Kentucky, Lexington, USA.", "authors": "Wilson|Ryan M|RM|;Elmaraghi|Shady|S|;Rinker|Brian D|BD|", "chemical_list": "D000069479:Buprenorphine, Naloxone Drug Combination; D005343:Fibrinolytic Agents; D009292:Narcotic Antagonists; D010975:Platelet Aggregation Inhibitors; D006493:Heparin; D000077144:Clopidogrel; D001241:Aspirin", "country": "United States", "delete": false, "doi": "10.1177/1558944716672198", "fulltext": null, "fulltext_license": null, "issn_linking": "1558-9447", "issue": "12(5)", "journal": "Hand (New York, N.Y.)", "keywords": "Suboxone; arterial injection; buprenorphine; drug injection; drug use; gangrene; hand; injection injury; ischemia; opioid abuse", "medline_ta": "Hand (N Y)", "mesh_terms": "D000328:Adult; D001241:Aspirin; D000069479:Buprenorphine, Naloxone Drug Combination; D000077144:Clopidogrel; D005260:Female; D005343:Fibrinolytic Agents; D006225:Hand; D006493:Heparin; D006801:Humans; D007269:Injections, Intra-Arterial; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D055815:Young Adult", "nlm_unique_id": "101264149", "other_id": null, "pages": "507-511", "pmc": null, "pmid": "28832211", "pubdate": "2017-09", "publication_types": "D016428:Journal Article", "references": "24857945;15945530;21466501;21565452;19368419;10432001;26179339;25221984;24680219;20403021;22048730;16284682", "title": "Ischemic Hand Complications From Intra-Arterial Injection of Sublingual Buprenorphine/Naloxone Among Patients With Opioid Dependency.", "title_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency" }

[ { "companynumb": "US-TEVA-2019-US-997368", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838574, "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": "US-OREXO US, INC.-ORE201810-000114", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598684, "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-LANNETT COMPANY, INC.-US-2019LAN000179", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16022874, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000112", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598704, "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-2019-US-997363", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Dry gangrene", "reactionmeddraversionpt": "21.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838634, "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": "US-MYLANLABS-2019M1000859", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15801537, "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": "US-OREXO US, INC.-ORE201810-000111", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598687, "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-MYLANLABS-2019M1000916", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15803508, "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": "US-TEVA-2019-US-997361", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838508, "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": "US-TEVA-2019-US-997365", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838628, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000181", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023188, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000110", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "US", "receiptdate": "20181107", "receivedate": "20181107", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15595448, "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-LANNETT COMPANY, INC.-US-2019LAN000186", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023598, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000116", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598686, "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-2019-US-997366", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838536, "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": "US-TEVA-2019-US-997364", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838629, "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": "US-OREXO US, INC.-ORE201810-000117", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598679, "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" }, { "companynumb": "US-MYLANLABS-2019M1000911", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Dry gangrene", "reactionmeddraversionpt": "21.1", "reactionoutcome": "4" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799849, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20190417" }, { "companynumb": "US-MYLANLABS-2019M1000863", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190110", "receivedate": "20190110", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15809142, "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": "US-MYLANLABS-2019M1000868", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190114", "receivedate": "20190114", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15820422, "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": "US-TEVA-2019-US-997367", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838570, "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": "US-MYLANLABS-2019M1000922", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799950, "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": "US-MYLANLABS-2019M1000914", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15801590, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000183", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000119", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598680, "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-OREXO US, INC.-ORE201810-000113", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598705, "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-MYLANLABS-2019M1000904", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190109", "receivedate": "20190109", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15801535, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000187", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023595, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-OREXO US, INC.-ORE201810-000115", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598685, "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-2019-US-997371", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838571, "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": "US-OREXO US, INC.-ORE201810-000118", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "204242", "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": "BUPRENORPHINE / NALOXONE" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Wrong technique in product usage process", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RYAN M W, SHADY E, BRIAN D R. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12 (5):507-11.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": null, "receiptdate": "20181108", "receivedate": "20181108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15598691, "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-2019-US-997362", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838631, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000184", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023661, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-LANNETT COMPANY, INC.-US-2019LAN000177", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16022621, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-MYLANLABS-2019M1000926", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799943, "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": "US-TEVA-2019-US-997369", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUPRENORPHINE\\NALOXONE" }, "drugadditional": "3", "drugadministrationroute": "013", "drugauthorizationnumb": "091149", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE/NALOXONE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190117", "receivedate": "20190117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15838573, "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": "US-LANNETT COMPANY, INC.-US-2019LAN000180", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023353, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-LANNETT COMPANY, INC.-US-2019LAN000185", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023653, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-LANNETT COMPANY, INC.-US-2019LAN000182", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "205022", "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": "BUPRENORPHINE HCL AND NALOXONE HCL" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Intentional product use issue", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Foreign body embolism", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND. 2017?12(5):507-511", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190301", "receivedate": "20190301", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16023833, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20190418" }, { "companynumb": "US-MYLANLABS-2019M1000910", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "BUPRENORPHINE HYDROCHLORIDE\\NALOXONE HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "013", "drugauthorizationnumb": "207607", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INADVERTENT INTRA-ARTERIAL INJECTION OF SUBLINGUAL FORM OF BUPRENORPHINE/NALOXONE", "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": "BUPRENORPHINE HYDROCHLORIDE/NALOXONE HYDROCHLORIDE" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Tissue injury", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Incorrect route of product administration", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug abuse", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Peripheral ischaemia", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "WILSON RM, ELMARAGHI S, RINKER BD. ISCHEMIC HAND COMPLICATIONS FROM INTRA-ARTERIAL INJECTION OF SUBLINGUAL BUPRENORPHINE/NALOXONE AMONG PATIENTS WITH OPIOID DEPENDENCY. HAND 2017?12(5):507-511.", "literaturereference_normalized": "ischemic hand complications from intra arterial injection of sublingual buprenorphine naloxone among patients with opioid dependency", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190108", "receivedate": "20190108", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15799853, "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\nPriapism is a common concern in sickle cell disease. With a high frequency of recurrences and serious long-term sequela, a preventative, rather than traditionally reactive approach, needs to be taken in these patients. Reports have shown successful use of sildenafil as a prophylactic treatment but have failed to address adverse outcomes, including vasoocclusive pain crises, of chronic sildenafil therapy in sickle cell patients.\n\n\nOBJECTIVE\nWe wish to draw attention to the potential adverse outcomes of this therapy on the overall state of the patient's disease for consideration in future studies.\n\n\nMETHODS\nWe used sildenafil in a patient suffering from almost daily attacks of priapism.\n\n\nRESULTS\nSildenafil was successful in decreasing the frequency of priapism; however, our patient experienced an increased frequency of vasoocclusive crises, something not previously addressed.\n\n\nCONCLUSIONS\nFuture studies of sildenafil use in sickle cell disease need to assess the global state of the disease, not just the frequency of priapism.", "affiliations": "Florida State University College of Medicine, Tallahassee, FL 32114, USA. [email protected]", "authors": "Lane|Andrew|A|;Deveras|Ruby|R|", "chemical_list": "D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate", "country": "Netherlands", "delete": false, "doi": "10.1111/j.1743-6109.2011.02440.x", "fulltext": null, "fulltext_license": null, "issn_linking": "1743-6095", "issue": "8(11)", "journal": "The journal of sexual medicine", "keywords": null, "medline_ta": "J Sex Med", "mesh_terms": "D000328:Adult; D000755:Anemia, Sickle Cell; D006801:Humans; D008297:Male; D010410:Penile Erection; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011317:Priapism; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones", "nlm_unique_id": "101230693", "other_id": null, "pages": "3193-5", "pmc": null, "pmid": "21883942", "pubdate": "2011-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Potential risks of chronic sildenafil use for priapism in sickle cell disease.", "title_normalized": "potential risks of chronic sildenafil use for priapism in sickle cell disease" }

[ { "companynumb": "US-PFIZER INC-2011222763", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SILDENAFIL CITRATE" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "020895", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "50 MG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "PRIAPISM", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "50", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SILDENAFIL CITRATE." } ], "patientagegroup": null, "patientonsetage": "25", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Sickle cell anaemia with crisis", "reactionmeddraversionpt": "23.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "LANE, A.. POTENTIAL RISKS OF CHRONIC SILDENAFIL USE FOR PRIAPISM IN SICKLE CELL DISEASE. JOURNAL OF SEXUAL MEDICINE. 2011?8 (11):3193-3195", "literaturereference_normalized": "potential risks of chronic sildenafil use for priapism in sickle cell disease", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20201103", "receivedate": "20110929", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 8161507, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20210114" } ]

{ "abstract": "Malakoplakia (from the Greek malakos, 'soft' and plakos 'plaque') is a granulomatous inflammatory condition, commonly presenting as a plaque in the genitourinary system, but has been shown to affect a wide variety of structures including the skin. Presentation is varied and a high degree of clinical suspicion is needed to make a diagnosis. We report a case of cutaneous malakoplakia presenting as an inguinal swelling in a 48-year-old kidney transplant patient with temporally associated graft dysfunction. New groin swelling in an immunosuppressed patient often prompts investigation centred on a malignant cause. While this is often appropriate, less common infectious and inflammatory causes should be considered. This case highlights the importance of thorough workup and investigation, including histopathology, in immunosuppressed cohorts and acts as a reminder that less common and more complex diagnoses warrant consideration in this group.", "affiliations": "School of Medicine, University of Glasgow, Glasgow, UK.;Department of Pathology, NHS Greater Glasgow and Clyde, Glasgow, UK.;Transplant Unit, NHS Greater Glasgow and Clyde, Glasgow, UK.;Department of Radiology, NHS Greater Glasgow and Clyde, Glasgow, UK.", "authors": "Macdonald|Ross Andrew|RA|http://orcid.org/0000-0001-8655-9435;Moyes|Colin|C|;Clancy|Marc|M|;Douglas|Peter|P|", "chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone", "country": "England", "delete": false, "doi": "10.1136/bcr-2018-227460", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "12(4)", "journal": "BMJ case reports", "keywords": "infectious diseases; pathology; renal transplantation", "medline_ta": "BMJ Case Rep", "mesh_terms": "D061605:Administration, Intravenous; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D003251:Constriction, Pathologic; D003937:Diagnosis, Differential; D004487:Edema; D006119:Groin; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008287:Malacoplakia; D008297:Male; D008875:Middle Aged; D035583:Rare Diseases; D012867:Skin; D012871:Skin Diseases; D016896:Treatment Outcome; D014515:Ureteral Diseases", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "31015237", "pubdate": "2019-04-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "23793204;1084356;21393896;27935636;11393074;9036125;3570595;8029173;8842176;10084511;7036058;20137752;15753643;8655720;5013466;10901721;20101508;10982022;28566412;10503277;9557790;7770942;26793484;21965504;4130030;200843;25663335", "title": "Cutaneous malakoplakia presenting as a groin swelling and graft failure.", "title_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure" }

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CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REPORT. 2019?12(4)", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191029", "receivedate": "20191029", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16971484, "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": "GB-STRIDES ARCOLAB LIMITED-2019SP010685", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "90055", "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "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": "RENAL TRANSPLANT", "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": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "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": "TACROLIMUS" }, "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": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Mass", "reactionmeddraversionpt": "22.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P.. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REP. 2019?12(4):E227460", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191107", "receivedate": "20191101", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16985136, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" }, { "companynumb": "GB-ACCORD-129494", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "1", "drugadministrationroute": "048", "drugauthorizationnumb": "202555", "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": "MYCOPHENOLATE MOFETIL/MYCOPHENOLATE SODIUM/MYCOPHENOLIC ACID" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "1", "drugadministrationroute": "048", "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": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Swelling", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Genitourinary tract infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REPORTS. 2019?12(4):ARTICLE NUMBER E227460. DOI:10.1136/BCR-2018-227460.", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190528", "receivedate": "20190528", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16360679, "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": "GB-VELOXIS PHARMACEUTICALS, INC.-2019VELGB1537", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "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": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "206406", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "PROLONGED-RELEASE TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RENAL TRANSPLANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ENVARSUS XR" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Transplant dysfunction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ureteric anastomosis complication", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Escherichia infection", "reactionmeddraversionpt": "22.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Hydronephrosis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ CASE REP. 2019?12(4):E227460", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20190529", "receivedate": "20190529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16365381, "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": "GB-MYLANLABS-2019M1102131", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091248", "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": "MYCOPHENOLIC ACID." }, { "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": "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": "48", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cutaneous malacoplakia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MACDONALD RA, MOYES C, CLANCY M, DOUGLAS P. CUTANEOUS MALAKOPLAKIA PRESENTING AS A GROIN SWELLING AND GRAFT FAILURE. BMJ-CASE-REP 2019?12:NO. 4.", "literaturereference_normalized": "cutaneous malakoplakia presenting as a groin swelling and graft failure", "qualification": "3", "reportercountry": "GB" }, "primarysourcecountry": "GB", "receiptdate": "20191031", "receivedate": "20191031", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16978563, "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 report a case of acute hepatic injury and acute renal failure secondary to rhabdomyolysis associated with fluvastatin-gemfibrozil combination therapy for hyperlipidemia.\n\n\nMETHODS\nA 56-year-old woman with a history of hyperlipidemia presented with fatigue, weakness in her lower extremities, and red-colored urine. One month prior, she had started combination therapy of fluvastatin 80 mg/day and gemfibrozil 1200 mg/day. On physical examination, she had a serious loss of motor function in the upper and lower extremities. Her laboratory tests revealed severe liver enzyme elevation and abnormal renal function. Abdominal ultrasound did not show hepatic cholestasis, renal parenchymal abnormality, or obstruction.\n\n\nCONCLUSIONS\nStatins and fibric acid derivatives have complementary effects on mixed hyperlipidemia. However, such combination therapy increases the risk of myopathy, which may result in life-threatening rhabdomyolysis. Several reports have suggested that combination fluvastatin-gemfibrozil therapy is both effective and safe in mixed lipid disorders. In our patient, severe rhabdomyolysis with serious hepatocellular injury was observed one month after the combination antihyperlipidemic therapy was started. Assessment with the Naranjo probability scale determined that an adverse drug reaction was probable. The mechanism of this combined toxicity is difficult to clarify, although in vivo and in vitro studies to date have reported considerable data concerning antihyperlipidemic drug interactions.\n\n\nCONCLUSIONS\nClinicians should carefully consider the risks and benefits of treating dyslipidemia with fluvastatin-gemfibrozil combination therapy.", "affiliations": "Nephrology Unit, Hacettepe University School of Medicine, Ankara, Turkey.", "authors": "Akoglu|Hadim|H|;Yilmaz|Rahmi|R|;Kirkpantur|Alper|A|;Arici|Mustafa|M|;Altun|Bulent|B|;Turgan|Cetin|C|", "chemical_list": "D000960:Hypolipidemic Agents", "country": "United States", "delete": false, "doi": "10.1345/aph.1H251", "fulltext": null, "fulltext_license": null, "issn_linking": "1060-0280", "issue": "41(1)", "journal": "The Annals of pharmacotherapy", "keywords": null, "medline_ta": "Ann Pharmacother", "mesh_terms": "D058186:Acute Kidney Injury; D056486:Chemical and Drug Induced Liver Injury; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents; D008107:Liver Diseases; D008875:Middle Aged; D009102:Multiple Organ Failure; D012206:Rhabdomyolysis", "nlm_unique_id": "9203131", "other_id": null, "pages": "143-7", "pmc": null, "pmid": "17148651", "pubdate": "2007-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Combined organ failure with combination antihyperlipidemic treatment: a case of hepatic injury and acute renal failure.", "title_normalized": "combined organ failure with combination antihyperlipidemic treatment a case of hepatic injury and acute renal failure" }

[ { "companynumb": "TR-PFIZER INC-2019227392", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "FLUVASTATIN SODIUM" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "3", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "80 MG, DAILY (COMBINATION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FLUVASTATIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "GEMFIBROZIL" }, "drugadditional": "1", "drugadministrationroute": null, "drugauthorizationnumb": "018422", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1200 MG, DAILY (COMBINATION)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HYPERLIPIDAEMIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1200", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GEMFIBROZIL." } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Rhabdomyolysis", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatocellular injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Drug interaction", "reactionmeddraversionpt": "22.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Acute kidney injury", "reactionmeddraversionpt": "22.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "AKOGLU, H.. COMBINED ORGAN FAILURE WITH COMBINATION ANTIHYPERLIPIDEMIC TREATMENT: A CASE OF HEPATIC INJURY AND ACUTE RENAL FAILURE. THE ANNALS OF PHARMACOTHERAPY. 2007?41(1):143-147", "literaturereference_normalized": "combined organ failure with combination antihyperlipidemic treatment a case of hepatic injury and acute renal failure", "qualification": "1", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20190530", "receivedate": "20190529", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16367871, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20190711" } ]

{ "abstract": "We present the case of a 35-year-old man with thoracic back pain and stiffness, whose only medical history was cystic acne treated with repeated courses of retinoids. His thoracic spine was severely limited in range of movement and was found, on X-ray, to have unilateral hyperostosis typical of diffuse idiopathic skeletal hyperostosis (DISH)--an often asymptomatic condition rarely found in those under 50. Back stiffness in young patients with prolonged retinoid exposure should be investigated.", "affiliations": "Department of Rheumatology, Aintree University Hospital, Liverpool, UK.;Department of Rheumatology, Aintree University Hospital, Liverpool, UK.", "authors": "Zhao|Sizheng|S|http://orcid.org/0000-0002-3558-7353;Goodson|Nicola J|NJ|", "chemical_list": "D000700:Analgesics; D003879:Dermatologic Agents; D015474:Isotretinoin", "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": "D000152:Acne Vulgaris; D000328:Adult; D000700:Analgesics; D001416:Back Pain; D003879:Dermatologic Agents; D003937:Diagnosis, Differential; D004334:Drug Administration Schedule; D006801:Humans; D004057:Hyperostosis, Diffuse Idiopathic Skeletal; D015474:Isotretinoin; D008297:Male; D011859:Radiography; D013904:Thoracic Vertebrae", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "26106176", "pubdate": "2015-06-23", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "18637435;935390;8167624;11368702;2645586;24843807;2970477;11679606;16013982", "title": "Diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne.", "title_normalized": "diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne" }

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{ "abstract": "The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients.\nSeven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated.\nThe histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan.\nDecreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.", "affiliations": "Department of Neurosurgery, Fujita Health University, Japan.;Department of Neurosurgery, Chiba University, Japan.;Department of Neurosurgery, Nara Medical University, Japan.;Department of Neurosurgery, Kanazawa University, Japan.;Department of Neurosurgery, Nakamura Memorial Hospital, Japan.;Department of Neurosurgery, Sainte-Anne Hospital, Paris, France.;Department of Neurosurgery, Keio University School of Medicine, Japan.", "authors": "Muto|Jun|J|;Matsutani|Tomoo|T|;Matsuda|Ryosuke|R|;Kinoshita|Masashi|M|;Oikawa|Mitsuteru|M|;Pallud|Johan|J|0000-0002-1652-9844;Sasaki|Hikaru|H|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1093/nop/npz034", "fulltext": null, "fulltext_license": null, "issn_linking": "2054-2577", "issue": "7(1)", "journal": "Neuro-oncology practice", "keywords": "adverse events; hemodialysis patients; malignant glioma; temozolomide", "medline_ta": "Neurooncol Pract", "mesh_terms": null, "nlm_unique_id": "101640528", "other_id": null, "pages": "111-117", "pmc": null, "pmid": "32025326", "pubdate": "2020-01", "publication_types": "D016428:Journal Article", "references": "21874248;22578793;15756519;20805645;16969025;15758009;7016384;1739631;17929115;19506159", "title": "Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients.", "title_normalized": "temozolomide radiochemotherapy for high grade glioma patients with hemodialysis a case series of 7 patients" }

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ET. AL. TEMOZOLOMIDE RADIOCHEMOTHERAPY FOR HIGH-GRADE GLIOMA PATIENTS WITH HEMODIALYSIS: A CASE SERIES OF 7 PATIENTS. NEUROONCOL PRACT. 2020 JAN?7(1):111-117. EPUB 2019 DEC 3.", "literaturereference_normalized": "temozolomide radiochemotherapy for high grade glioma patients with hemodialysis a case series of 7 patients", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200224", "receivedate": "20200224", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17450298, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "JP-009507513-2008JPN000971", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "75 MILLIGRAM/SQ. METER, FOR 36 DAYS, INITIAL CHEMOTHERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "150 MILLIGRAM/SQ. METER, FOR 5 DAYS, EVERY 28?DAY CYCLE, 3 CYCLES, MAINTENANCE THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." } ], "patientagegroup": null, "patientonsetage": "57", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia staphylococcal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "MUTO J, MATSUTANI T, MATSUDA R, KINOSHITA M, OIKAWA M, PALLUD J, ET AL.. TEMOZOLOMIDE RADIOCHEMOTHERAPY FOR HIGH?GRADE GLIOMA PATIENTS WITH HEMODIALYSIS: A CASE SERIES OF 7 PATIENTS. 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METER, FOR 5 DAYS, EVERY 28?DAY CYCLE, 8 CYCLES, MAINTENANCE THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." } ], "patientagegroup": null, "patientonsetage": "66", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumonia bacterial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MUTO J, MATSUTANI T, MATSUDA R, KINOSHITA M, OIKAWA M, PALLUD J, ET AL.. TEMOZOLOMIDE RADIOCHEMOTHERAPY FOR HIGH?GRADE GLIOMA PATIENTS WITH HEMODIALYSIS: A CASE SERIES OF 7 PATIENTS. NEURO?ONCOLOGY PRACTICE. 2020?7(1):111?7", "literaturereference_normalized": "temozolomide radiochemotherapy for high grade glioma patients with hemodialysis a case series of 7 patients", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200804", "receivedate": "20200804", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18109479, "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": "JP-009507513-2008JPN000972", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "75 MILLIGRAM/SQ. METER; FOR 42 DAYS, INITIAL CHEMOTHERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOBLASTOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "75", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "150 MILLIGRAM/SQ. METER, FOR 5 DAYS, EVERY 28?DAY CYCLE, 12 CYCLES, MAINTENANCE THERAPY", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "150", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMOZOLOMIDE." } ], "patientagegroup": null, "patientonsetage": "64", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lymphopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukoencephalopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MUTO J, MATSUTANI T, MATSUDA R, KINOSHITA M, OIKAWA M, PALLUD J, ET AL.. TEMOZOLOMIDE RADIOCHEMOTHERAPY FOR HIGH?GRADE GLIOMA PATIENTS WITH HEMODIALYSIS: A CASE SERIES OF 7 PATIENTS. NEURO?ONCOLOGY PRACTICE. 2020?7(1):111?7", "literaturereference_normalized": "temozolomide radiochemotherapy for high grade glioma patients with hemodialysis a case series of 7 patients", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20200804", "receivedate": "20200804", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18109480, "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": "Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib. Patients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected. Results: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R 2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7-16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8-1.6 m) vs. 4.3 m (95% CI: 3.3-5.3 m), p < 0.05]. Conclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.", "affiliations": "Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital and Institute, Beijing, China.;State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.;Department of Oncology, Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, China.;Department of Oncology, Xinqiao Hospital, Chongqing, China.;Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital and Institute, Beijing, China.;Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Department of Respiratory Medicine, Guigang City People's Hospital, Guigang, China.;Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China.;Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.;Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China.;Department of Party Affairs, The First Affiliated Hospital of University of South China, Hengyang, China.;Department of Oncology, Xinqiao Hospital, Chongqing, China.;Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China.;Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.;Department of Oncology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.;Department of Respiratory Medicine, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.;Department of Oncology, Haian People's Hospital, Nantong, China.;Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China.;Department of Thoracic Surgery, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China.;Department of Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, China.;Geneplus-Beijing, Beijing, China.;Geneplus-Beijing, Beijing, China.;Geneplus-Beijing, Beijing, China.;Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.", "authors": "Yuan|Bo|B|;Zhao|Jun|J|;Zhou|Chengzhi|C|;Wang|Xiumei|X|;Zhu|Bo|B|;Zhuo|Minglei|M|;Dong|Xilin|X|;Feng|Jiemei|J|;Yi|Cuihua|C|;Yang|Yunpeng|Y|;Zhang|Hua|H|;Zhou|Wangyan|W|;Chen|Zhengtang|Z|;Yang|Sheng|S|;Ai|Xinghao|X|;Chen|Kehe|K|;Cui|Xuefan|X|;Liu|Difa|D|;Shi|Chunmei|C|;Wu|Wei|W|;Zhang|Yanjun|Y|;Chang|Lianpeng|L|;Li|Jin|J|;Chen|Rongrong|R|;Yang|Shuanying|S|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3389/fonc.2020.00729", "fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00729\nOncology\nOriginal Research\nCo-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib\nYuan Bo 1† Zhao Jun 2† Zhou Chengzhi 3 Wang Xiumei 4 Zhu Bo 5 Zhuo Minglei 2 Dong Xilin 1 Feng Jiemei 6 Yi Cuihua 7 Yang Yunpeng 8 Zhang Hua 9 Zhou Wangyan 10 Chen Zhengtang 5 Yang Sheng 11 Ai Xinghao 12 Chen Kehe 13 Cui Xuefan 14 Liu Difa 15 Shi Chunmei 11 Wu Wei 16 Zhang Yanjun 17 Chang Lianpeng 18 Li Jin 18 Chen Rongrong 18 Yang Shuanying 1* 1Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China\n2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital and Institute, Beijing, China\n3State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China\n4Department of Oncology, Inner Mongolia Autonomous Region Cancer Hospital, Hohhot, China\n5Department of Oncology, Xinqiao Hospital, Chongqing, China\n6Department of Respiratory Medicine, Guigang City People's Hospital, Guigang, China\n7Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China\n8Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China\n9Department of Oncology, Shaanxi Provincial People's Hospital, Xi'an, China\n10Department of Party Affairs, The First Affiliated Hospital of University of South China, Hengyang, China\n11Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China\n12Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China\n13Department of Oncology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China\n14Department of Respiratory Medicine, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China\n15Department of Oncology, Haian People's Hospital, Nantong, China\n16Department of Thoracic Surgery, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing, China\n17Department of Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, China\n18Geneplus-Beijing, Beijing, China\nEdited by: Ye Wang, Qingdao University Medical College, China\n\nReviewed by: Yuxiang Zhao, Biotrans Technology Co. LTD, China; Rossano Lattanzio, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy\n\n*Correspondence: Shuanying Yang [email protected] article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology\n\n†These authors have contributed equally to this work and share first authorship\n\n\n12 5 2020 \n2020 \n10 72925 12 2019 16 4 2020 Copyright © 2020 Yuan, Zhao, Zhou, Wang, Zhu, Zhuo, Dong, Feng, Yi, Yang, Zhang, Zhou, Chen, Yang, Ai, Chen, Cui, Liu, Shi, Wu, Zhang, Chang, Li, Chen and Yang.2020Yuan, Zhao, Zhou, Wang, Zhu, Zhuo, Dong, Feng, Yi, Yang, Zhang, Zhou, Chen, Yang, Ai, Chen, Cui, Liu, Shi, Wu, Zhang, Chang, Li, Chen and YangThis 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.Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib.\n\nPatients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected.\n\nResults: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7–16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8–1.6 m) vs. 4.3 m (95% CI: 3.3–5.3 m), p < 0.05].\n\nConclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.\n\nnon-small cell lung cancerERBB2 exon 20 insertionco-occurring alterationsafatinibclonality statusNational Natural Science Foundation of China10.13039/501100001809Natural Science Foundation of Shaanxi Province10.13039/501100007128\n==== Body\nIntroduction\nAberrations in human epidermal growth factor receptor 2 (HER-2, ERBB2) have emerged as oncogenic drivers and therapeutic targets in 1–4% of non-small cell lung cancer (NSCLC) and up to 6% of EGFR/KRAS/ALK-negative lung adenocarcinoma (LUAD) (1, 2). Most of ERBB2 mutations is characterized by inframe insertion occurring at exon 20 in the protein kinase domain (3). Prior studies showed that pan-ERBB family inhibitor (afatinib, dacomitinib) (4, 5), ado-trastuzumab (T-DM1) (6) as well as some new agents such as poziotinib (7), pyrotinib (8) may elicit an objective response in patients with ERBB2 exon 20 insertion (ERBB2ex20ins); however, no therapy has been approved as a standard treatment yet.\n\nAfatinib has been demonstrated its suppressive effect on lung cancer cell lines with ERBB2ex20ins in vivo (9). Previous studies also revealed clinical outcomes of afatinib with a 13–19% objective response rate (ORR) and a disease control rate (DCR) around 70% in three separate cohorts (10–12); Nevertheless, there exists profound efficacy heterogeneity on them, such as patients with the same subtype displayed discordant benefits and duration of time.\n\nSeveral prior studies revealed that genetic co-alterations were independent variables associated with unfavorable prognosis of EGFR-TKIs (13, 14). However, because of its low frequency, researches focused on ERBB2ex20ins have generally been limited to insufficient number of cases from single institution and prevent making a broad assessment of co-existing alteration patterns of ERBB2ex20ins, which may reflect its genomic background heterogeneity and contribute to the variable responsiveness to the targeted therapy. Therefore, making a comprehensive analysis of concomitant mutation spectrum of ERBB2ex20ins in a large cohort and correlating its co-mutation status with prognosis are urgently warranted.\n\nMoreover, growing number of studies are paying attention to the clonality heterogeneity of targetable somatic alterations and adapting the cancer-treatment strategy to taking into account how a tumor evolves (15). It seems that therapy targeted clonal (“trunk”) mutations may be more effective than targeted subclonal (“branch”) ones (16, 17). Nevertheless, how the clonality status of driver aberrations modulates the efficacy of therapy is unclear.\n\nUsing the next-generation sequencing (NGS) method, we here described the co-occurring molecular spectrum of ERBB2ex20ins in a cohort of 112 NSCLC patients from 17 hospitals in China. We also compared our spectrum with the western population from Memorial Sloan Kettering Cancer Center (MSKCC) and investigated the impact of co-mutation status on the prognosis of them. Furthermore, we retrospectively assessed the efficacy and tried to identify efficacy predictive factors of afatinib in 18 patients with ERBB2ex20ins.\n\nMaterials and Methods\nPatient Cohort and Clinical Data Collection\nWe retrospectively screened 112 patients (from 17 hospitals) harboring ERBB2ex20ins in a College of American Pathologists (CAP) Laboratory (Geneplus-Beijing, Beijing, People's Republic of China) from July 2016 to December 2018. Samples of tumor tissue, plasma or effusion were analyzed by next-generation sequencing (NGS) assay using two versions (59 or 1,021 cancer-related genes) of capture-based targeted sequencing panel. Gene lists of two versions of sequencing panel are shown in Table S1. The sample type and panel for each patient are shown in Figure 1A. A total of 55 and 57 samples were sequenced using 1,021 or 59-gene panel, respectively. Clinicopathological features were abstracted from the accompanying pathology report submitted by the ordering physician. All patients provided written informed consent for our study. This study was approved by the institutional review board of The Second Affiliated Hospital of Xi'an Jiaotong University and all participating hospital.\n\nFigure 1 (A) Sample types and sequencing panel details of study design. (B) Pie chart visualizing eight specified insertion subtypes combined with insertion site. Multi, multiple alterations; Co-Amp, co-amplification; Co-SNV, co-single nucleotide variant. (C) Top 18 genes in the highest co-occurring frequency with ERBB2 exon 20 insertion (no relation to the total numbers analyzed). Only the genes with concurrent frequency over 5% are shown. *The genes included in the 59-gene panel.\n\nThe sequencing data of the Memorial Sloan Kettering Cancer Center (MSKCC) Cohort was downloaded from an open-access database named the Cancer Genome Atlas Database, which is publicly available at http://www.cbioportal.org [MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017)] (18, 19). The data of overall survival (OS) was acquired from the cbioportal website directly. OS was measured from the date when the tumor specimen was collected to the date of death or last follow-up visit (20).\n\nResponse Evaluation\nThe clinical outcomes of 18 patients treated with afatinib were collected by each contributing doctor in charge and pooled for analysis. Patients were administered afatinib depending on their performance status and other comorbidities at a starting dose of 30, 40, or 50 mg daily. Best response evaluation was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1). The progression free survival (PFS) for afatinib treatment was defined as the time from the start of afatinib treatment to the date of disease progression or death.\n\nDNA Extraction\nCirculating DNA and Genomic DNA for genomic testing were isolated from 3 ml of plasma or effusion and FFPE samples, respectively. Peripheral blood lymphocytes (PBL) DNA were extracted for germline reference (Supplemental Online Methods).\n\nTarget Capture and Next-Generation Sequencing\nKAPA Library Preparation Kit (Kapa Biosystems, Wilmington, MA, USA) was applied to prepare Indexed Illumina NGS libraries from peripheral blood lymphocytes (PBL) DNA, and tumor DNA or plasma DNA according to the manufacturer's protocol. Capture probes were designed to cover coding sequences or hot exons of 59 or extended 1,021 genes that are frequently mutated in NSCLC and other common solid tumors (details of sequencing region for each gene are uploaded in Table S1). Libraries were hybridized to custom-designed biotinylated oligonucleotide probes (Integrated DNA Technologies, Iowa, IA, USA). DNA sequencing was performed on the HiSeq 3000 Sequencing System (Illumina, San Diego, CA) with 2 × 101 bp paired-end reads.\n\nSequencing Data Analysis\nTerminal adaptor sequences and low-quality data were removed from the raw data. The BWA (0.7.12-r1039) was employed to align clean reads to the reference human genome (hg19) (21). MuTect2 (3.4-46-gbc02625) and GATK was applied to call single nucleotide variants (SNVs) and small insertions and deletions (Indels), respectively. Somatic copy number variants (CNVs) were identified using CONTRA (2.0.8) (22). Moreover, we employed the NoahCare Tool Kit using NCfilter (software developed by self, version 1.5.0) for fastq data QC, NCbamInfo (version 0.2.0) for alignment QC, NCanno (version 0.1.1) for annotation with multiple databases, and NChot (version 0.1.0) for hotspot region variant review and recall. All final candidate variants were all manually verified using the Integrative Genomics Viewer (IGV) Browser.\n\nClonality Analysis\nThe subclonal architecture of all DNA samples were constructed by PyClone run with 20,000 interactions and default parameters (23). Variants were clustered as previously described (23), briefly, the copy number information of each SNV was used as input for PyClone analysis (24, 25), and the cancer cell fraction (CCF) was inferred. Variants located in the cluster with greatest mean CCF were defined as clonal, the rest were subclonal (23).\n\nStatistical Analysis\nAll statistical analyses were performed using SPSS version 19.0 (SPSS Company, Chicago, IL). Categorical and continuous variables were compared by Fisher's exact test and Kruskal-Wallis H-test, respectively. The Pearson correlation coefficient was applied to assess the linear correlation degree of co-occurring genes' frequency appearing in Our Cohort and MSKCC Cohort. The OS and PFS were estimated using the Kaplan-Meier method and compared with the log-rank test. A multi-variant regression model was calculated for HRs and 95% CIs. All statistical tests were two-sided, and p < 0.05 was defined as statistical significance.\n\nResult\nPatients With ERBB2 exon 20 Insertion\nOne hundred and twelve patients carrying ERBB2ex20ins were screened from July 2016 to December 2018 (Figure 1A). The clinical characteristics for these patients were summarized in Table 1. In all, patients were predominantly in the stage IV (80/112, 72%) and had the histology of adenocarcinoma (68%,76/112). There were slightly more female (54%; 60/112) than male (46%; 52/112), with a median age of 61.5 years (range: 28–87 years).\n\nTable 1 Clinical characteristics of patients with ERBB2 exon 20 insertion in different positions.\n\nCharacteristics\tA775ins (n = 79)\tG776indel (n = 19)\tP780ins (n = 14)\tSum\tP-value\t\nAge at initial diagnosis\t\n Median (range)\t62 (28–83)\t58 (29–87)\t64 (48–83)\t61.5 (28–87)\t0.425\t\n Unknown\t6\t0\t2\t8\t\t\nGender\t\n Female\t39 (49%)\t11(58%)\t10 (71%)\t60 (54%)\t0.287\t\n Male\t40 (51%)\t8 (42%)\t4 (29%)\t52 (46%)\t\t\nHistology\t\n NSCLC NOS\t14 (18%)\t3 (16%)\t1 (7%)\t18 (16%)\tnc\t\n Adenocarcinoma\t55 (70%)\t11(58%)\t10 (72%)\t76 (68%)\t\t\n Squamous carcinoma\t0\t0\t1(7%)\t1(1%)\t\t\n Unknown\t10 (12%)\t5 (26%)\t2 (14%)\t17 (15%)\t\t\nStage\t\n I–III\t15 (19%)\t2 (10%)\t2 (14%)\t19 (16%)\t0.850\t\n IV\t55 (70%)\t14 (74%)\t11 (79%)\t80 (72%)\t\t\n Unknown\t9 (11%)\t3 (16%)\t1 (7%)\t13 (12%)\t\t\nP-values are calculated with Fisher's exact test except for age using the Kruskal-Wallis H-test.\n\nins, insertion; indel, insertion and deletion; NSCLC NOS, non-small cell lung cancer not other specified; nc, not calculate.\n\nTotally, eight specific insertion types of ERBB2ex20ins were identified. Considering the fact that certain studies discussing the efficacy of targeted therapy for ERBB2ex20ins are always based on the different insertion sites, we classified them into three subtypes. The most common subtype was four amino acids insertion at codon 775 (A775ins; 70.5%), followed by insertion combined with deletion occurring at codon 776 (G776indel; 17.0%), and three amino acids insertion at codon 780 (P780ins; 12.5%). Multi-alterations were present in five patients, with two patients harboring concurrent ERBB2 amplification and three patients carrying ERBB2ex20ins with ERBB2 single nucleotide variant (SNV) referring to p.A775_G776insYVMA+ p.R897Q, p.P780_Y781insGSP+ p.G519R, and p.G776delinsAVGC+ p.G776A (Figure 1B).\n\nMoreover, insertion-subtype abundance was not significantly different among the sample types (p = 0.41; Table S2). It indicated that distinct sample type was not biased toward the detection of certain ERBB2 subtype.\n\nCo-occurring Genomic Profile of ERBB2 exon 20 Insertion\nSpectrum of Co-occurring Alterations and Characteristics in Different Insertion Sites\nOn the basis of 59 genes strongly associated with cancer, 80.4% (90/112) of patients had at least one additional alteration, with 48.9% (44/90) of them carrying one and 27.8% (25/90) carrying two. Three or more concomitant alterations were present at the rest of 23.3% (21/90) patients. TP53 was the most frequent gene co-mutant with ERBB2ex20ins, making up 66.1% (74/112) cases, with predominant alteration type of missense mutation (63.5%, 47/74), concentrating on exon 5, 8, 6, 7 (76.7%, 56/74; range: exon 4-exon 11) (Figure S1A, Table S3). The remaining prevalent co-occurring genes were LRP1B (18.2%, 10/55), EPHA5 (9.1%, 5/55), MLL3 (9.1%, 5/55), and RB1 (8.0%; 9/112) (no relation to the total numbers analyzed). FOXA1 appeared in 5.5% (3/55) of patients and became the most common co-mutant gene in the form of amplification (Figure 1C). Putative driver aberrations including EGFR (L858R or 19del), ROS1 fusions, ALK receptor tyrosine kinase gene (ALK) rearrangement, KRAS, BRAF (V600E) were not found in this cohort, probably mutually exclusive from ERBB2ex20ins.\n\nOf the pathway level, we classified the co-mutant genes according to the pathway involved. 86.7% (78/90) of patients, who carried at least one additional mutation, had the co-altered genes enriched in the cell cycle, followed by receptor tyrosine kinase/growth factor signaling (RTK) (15.2%) and DNA damage/repair (8.9%) (Figure 2B). Furthermore, some patients had co-mutant genes involved multiple important pathways simultaneously, while some patients had more than one co-mutant genes involving one single pathway (Table S4).\n\nFigure 2 A comprehensive comparison of the co-occurring profile between our cohort and MSKCC cohort for the frequency of (A) totally matched 28 genes (the genes included in the analysis were matched in both cohorts' panel with the frequency over 5%; the genes labeled are significantly different between the two cohorts). (B) Pathway enriched (Only genes included in 59-gene panel were analyzed; *the pathway significantly different between the two cohorts). RTK, receptor tyrosine kinase/growth factor signaling. (C) Kaplan–Meier curve showing the difference of median overall survival (OS) among patients harboring three different ERBB2 insertion subtypes. (D) Kaplan–Meier curve visualizing the effect of TP53 alteration on OS.\n\nWe also explored the co-occurring alteration feature among A775ins (n = 79), G776indel (n = 19), and P780ins (n = 14). No substantial discrepancy was observed among the three groups at either the co-occurring somatic alterations (only TP53 was included in the analysis) or pathway enriched, the clinical details were as well (Figures S2A,C, Table 1). The location and exon distribution of TP53 mutation were comparable in three insertion-site subtypes (Figures S1B–E); however, when considering TP53 mutation types, there was a tendency that G776indel may be less adept at co-occurring with TP53 missense mutations, with no statistically significant (p = 0.06; Figure S2B).\n\nSpectrum Comparison With the Western Population From the MSKCC Cohort\nNext, we compared our data with the findings previously reported by the MSKCC, which included 1,563 tumor specimens from patients with NSCLC. Totally 30 patients harboring ERBB2ex20ins involved in this cohort.\n\nOverall, both the proportion of three subtypes and the whole molecular co-occurring mutation spectrum (genes that co-altered at a frequency over 5% in each cohort) were similar between the two cohorts (R2 = 0.74, P < 0.01), although the co-mutant frequencies of certain genes were higher in the MSKCC cohort than in ours(Figure 2A, Table S5). Notably, these genes in slightly higher frequency were in the form of copy number variant (CNV) (Figure S2D), and it is probably caused by the low detection rate of CNV due to the mixed plasma samples in our samples.\n\nFor the pathway analysis, the enrichment of each pathway in our cohort was in accord with the MSKCC cohort, with a slightly higher frequency of cell-cycle pathway enriched in MSKCC cohort (36.7 vs. 17.9%, P = 0.044) on account of the higher frequency of CDKN2A alteration (Figure 2B, Table S4).\n\nImpact of Insertional-Site Subtypes and Co-occurring Mutational Status on OS\nBased on the complete overall survival (OS) from the MSKCC cohort, prognosis impact of ERBB2 insertion-site subtypes and genes co-occurring over 5 or more cases in either cohort were evaluated. Statistic descriptive of co-occurring genes included in the analysis were summarized in Figure S3A. There was a trend that patients harboring co-occurring genes enriched in cell-cycle pathway showed a worse survival, with no significantly statistic difference (p = 0.059; Figure S3B). However, worse overall survival was seen in patients with co-mutations in TP53 [median OS:14.5 m (95% CI:12.7–16.3 m) vs. 30.3 m (95% CI: not reached); log-rank test], while OS was not significantly different among three subtypes (p = 0.72, Figures 2C,D).\n\nPrior study revealed TP53 mutation in exons 5, 7, 8, and 9 sharing a better prognosis than other sites in the advanced NSCLC (26). In this regard, we investigate the prognosis value of co-occurring TP53 mutation in exons 5, 7, 8, and 9 and whether they can be even more relevant in a specific subgroup of patients with ERBB2ex20ins mutation (i.e., A775ins, G776indel, and P780ins subgroups) but found negative result (log rank, p = 0.095; Fisher exact test, p = 0.427; Figures S3C,D).\n\nClinical Outcomes of Afatinib for Patients Harboring ERBB2ex20ins\nAfatinib Treatment Efficacy Overview\nThe basic clinical and molecular characteristics of 18 patients treated with afatinib were summarized in Table 2. Nearly all of patients were in the advanced stage and 61.1% (12/18) of patients receiving afatinib as 2 line or more.\n\nTable 2 Clinical and molecular characteristics of patients treated with afatinib.\n\nCharacteristics\tNCB (n = 8)\tDCB (n = 10)\tSum (n = 18)\tP-value\t\nAge at initial diagnosis, years\t\n Median (range)\t56.5 (40–75)\t54 (29–69)\t55.5 (29.75)\t\t\n <65\t5\t9\t14 (77.8%)\t0.28\t\n ≥65\t3\t1\t4 (22.2%)\t\t\nGender\t\n Female\t5\t5\t10 (55.6%)\t0.66\t\n Male\t3\t5\t8 (44.4%)\t\t\nTobacco use\t\n Never\t5\t4\t9 (50.0%)\t0.15\t\n Former or current\t3\t2\t5 (27.8%)\t\t\n Unknown\t0\t4\t4 (22.2%)\t\t\nHistology\t\n Adenocarcinoma\t8\t10\t18 (100.0%)\t\t\nBrain metastasis\t\n Yes\t3\t4\t7 (38.9%)\t0.34\t\n No\t3\t6\t9 (50.0%)\t\t\n NA\t2\t0\t2 (11.1%)\t\t\nTumor stage\t\n IIIa\t1\t0\t1 (5.6%)\tnc\t\n IV\t6\t10\t16 (88.8%)\t\t\n Unknown\t1\t0\t1 (5.6%)\t\t\nNo. line of afatinib treatment\t\n 1\t3\t3\t6 (27.8%)\t1.00\t\n ≥2\t5\t7\t12 (61.1%)\t\t\nERBB2ex20ins subtypes\t\n A775 insertion\t6\t7\t13 (72.2%)\t1.00\t\n G776 indel\t1\t2\t3 (16.7%)\t\t\n P780 insertion\t1\t1\t2 (11.1%)\t\t\nConcurrent TP53 alteration\t\n Yes\t7\t6\t13 (72.2%)\t0.31\t\n No\t1\t4\t5 (27.8%)\t\t\nConcurrent TP53 missense mutation\t\n Yes\t6\t4\t10 (55.6%)\t0.19\t\n No\t2\t6\t8 (44.4%)\t\t\nDCB, durable clinical benefit; NCB, no durable benefit; nc, not calculate.\n\nOf the 18 patients, tumor remission data according to RECIST 1.1 criteria were available for 15 patients. Among them, 5 patients achieved PR (33.3%) and 4 patients achieved SD (26.7%). All PRs were, respectively, observed in 3 separate insertion subtypes, whereas the patients with PD only involved in the subtype of A775ins. The median time on treatment with afatinib was 3.7 months (95% CI: 2.1–5.3 m; range: 0.7–13.4 m). The median duration time for patients responding to afatinib was 4.5 months (95% CI: 3.6–5.4 m; range: 2.5 m−13.4 months). The response details and duration of response (DoR) of afatinib for each patient were showed in Figure 3A. One patient harboring G776delinsVC was treated for afatinib as first-line therapy with PR for over 13.4 months and didn't achieve disease progression until the last follow-up in this study. As for the rest of patients, 3 cases (16.7%) responding to afatinib had a DoR over 6 months.\n\nFigure 3 (A) Swimming plot visualizing the response details for afatinib in each patient (n = 18). (B) Kaplan-Meier comparing PFS for ERBB2ex20ins as clonal or subclonal variant (p-values determined by multi-variant regression analysis and HR with 95% CI are shown). (C) The distribution of ERBB2 clonality status between the DCB group and the NDB group. DCB, durable clinical benefit; NDB, no durable benefit.\n\nImpact of Clonality Status and Co-occurring Mutations of ERBB2ex20ins on Afatinib Treatment Outcome\nFor 18 patients treated with afatinib, we identified 54 somatic SNVs, 4 CNVs and 18 somatic indels in 18 samples, for an average of 4.3 somatic variants per sample. In this regard, we applied method PyClone to evaluate whether the ERBB2ex20ins carried by the patients were clonal or subclonal mutations.\n\nResult revealed that ERBB2ex20ins as subclonal variants was significantly associated with shorter PFS of afatinib [median PFS: 1.2 m (95% CI: 0.8–1.6 m) vs. 4.3 m (95% CI: 3.3–5.3 m), p < 0.01], while co-occurring TP53 mutation and insertion-site subtypes had no significant impact on the efficacy of afatinib. This result remained significant when adjusted for ERBB2 insertion subtypes, TP53 mutation, TP53 missense mutation and no. line of afatinib [HR: 0.025 (0.002–0.41); p = 0.01)] (Figure 3B, Table S6).\n\nNext, we divided the patients into durable clinical benefit (DCB) cohort and no durable benefit (NDB) cohort (The DCB was defined as the patients achieving PR or SD and having the duration of PFS for over 3 months; the NDB referred to the patients having the PFS <3 months). Clinical baseline parameters for two groups of patients are displayed in Table 2 and basically similar among each parameter. The variables including concurrent TP53 mutation and TP53 missense mutation were not significantly different between the two groups (data not show, Fisher's exact test, p > 0.05) except for the ERBB2ex20ins clonality status (Fisher exact test, p < 0.01; Figure 3C).\n\nDynamic Detection and Afatinib Resistance\nTo gain some insight into the potential mechanism upon afatinib resistance, we analyzed two patients conducting NGS at two time points in the course of afatinib treatment. The clinical characteristics and test details for two patients were summarized in Table S7. Both patients were non-smoking female. For the Patient#1, ERBB2 amplification [copy number (CN) = 3.1] occurred in the repeat biopsy sample upon the progression of afatinib. Similarly, the patient#2 also presented the ERBB2 amplification (CN = 2.74) which was undetected in the initial plasma sample after taking afatinib for half of a month, unfortunately, we did not examine the ERBB2 CN status at the time of progression on afatinib. Despite this, it can be speculated that ERBB2 amplification may represent a potential resistance mechanism of afatinib.\n\nDiscussion\nIn this study, we delineate the co-occurring alterations and common pathway involved addicted to ERBB2ex20ins in a representative NSCLC cohort of 112 patients and correlate co-mutation patterns with the prognosis of patients harboring ERBB2ex20ins. Moreover, to our knowledge, we present the first time to examine the impact of clonality status of oncogenic drivers in relation to the efficacy of targeted therapy.\n\nThe recent widespread use of NGS enables us to move researches from concentrating solely on the driver gene to the full view of genomic co-alterations, which may have prognostic implications. To date, somatic mutations in TP53 are the most prevalent co-mutation in EGFR-mutant lung adenocarcinoma (LUAD) with a frequency of 54.6–64.6% and several studies have identified TP53 co-alteration as a negative prognosis marker, with consistently predicting worse clinical outcomes receiving EGFR-TKI therapy (27). In our study, TP53 ranked as the most common accompanying somatic altered gene with a frequency of 66%; this frequency was slightly higher than the previously reported 51.6% (10), possibly due to the fewer proportion of female in our cohort (28). Our results showed that patients had a worse OS when co-occurring mutation in TP53, which is also validated in a previous study (29). Recently, the different prognosis value was recognized in distinct exons and alteration types of TP53 mutation and the results were inconsistent. Exons 5, 7, 8 and 9 were reported to share a better prognosis than other sites (26); it is worth mentioning that the study referred here sought to reveal the prognostic value of TP53 alterations in advanced NSCLC compared to most of studies limited to the early stage or EGFR-mutant background (30, 31). Unfortunately, TP53 mutations in exons 5, 7, 8, and 9 did not produce more favorable prognosis than other sites in the advanced NSCLC patients carrying ERBB2 mutation. Clinicopathological characteristics and treatment status should be well-defined to clearly investigate the prognosis impact of various TP53 exons. Moreover, there is a tendency that G776indel subtype may be less adept at co-occurring with TP53 missense mutations, however, whether this characteristic will have a beneficial effect on the prognosis for them remains to be explored. Interestingly, we found neither the co-mutant frequency of TP53 nor pathway enrichment was significantly different among three insertion subtypes, and the OS was comparable as well. For the clinical practice, we suppose that the co-occurring mutation status may have greater impact on the prognosis for this subset of patients than the insertion subtypes itself. Moving forward, the study highlighted multiple concurrent mutations besides ERBB2 insertion subtypes should be tested prospectively in order to provide better predictions of prognosis for them.\n\nIn order to systematically understand the co-mutation profile of ERBB2ex20ins, we cataloged co-altered genes based on existing biological pathway knowledge and the cell-cycle (86.7%), receptor tyrosine kinase/growth factor signaling (RTK) (15.2%) and DNA Damage/Repair (8.9%) showed predominance among all the involved pathways. Prior study found that cell-cycle and DNA-damage response pathway are involved in leptomeningeal metastasis of NSCLC (32). This finding was somehow inter-correspondent with the likely unfavorable prognosis for the patients with the co-occurring genes enriched in the cell-cycle pathway in our study, although the survival discrepancy was not significant maybe on account of the insufficient follow-up time or limited sub-group sample size. Unfortunately, we cannot collect the detailed metastasis status for each patient; however, for the patients treated with afatinib, we found seven in 16 of patients having brain metastasis. Moreover, a recent retrospective study found patients carrying ERBB2 mutations in lung cancer developed more brain metastases on treatment than patients with KRAS mutations [28 vs. 8%; hazard ratio (HR), 5.2; p < 0.001] and trended more than patients with EGFR mutations [28 vs. 16%; HR, 1.7; p = 0.06; (33)]. These findings may underline the central nervous system (CNS) surveillance practices in patients with ERBB2 alterations and the urgent need for the development of novel HER2-targeted agents with active efficacy in the CNS.\n\nThe co-occurring genomic spectrum of ERBB2ex20ins in our cohort of Chinese people had an overall strong concordance with the MSKCC cohort from the United States (R2 = 0.74, p < 0.01). In a retrospective study collated two cohorts of patients with ERBB2 alteration from the MSKCC and Guangdong General Hospital, they also found great consistency with each other in the aspect of the prevalence and baseline clinical parameters of patients possessing ERBB2 mutation (34). These findings, on the one hand, can be supporting evidence for U.S.-China collaborations in clinical trials to accelerate new drug development for this infrequent mutation; on the one hand, highlight the robustness of our results.\n\nAn important aspect of our study is that we found the clonality status of ERBB2ex20ins was an independent potential indicator for response to afatinib. It is well-known that there exists substantial intratumor heterogeneity and tumor evolves in a trunk-branch model. The “trunk” mutation (clonal mutation) was known as taking place in the early development of cancer and expected to present in every tumor subclone and region, whereas the mutation defined as “branch” would present in a certain fraction of tumor cells and regions (17). Thus, alterations closer to the clonal variant were associated with numerical greater variant allele frequency (VAF). Driver mutations in lung cancer can occur both clonally and subclonally (35). Rachiglio et al. (36) reported that patients harboring EGFR alteration in a lower VAF presented shorter PFS than not, to some extent, this reflecting the clonality status may affect the efficacy of TKIs. These lead us to speculate that other small molecule TKIs in other molecularly defined cohorts may be even more efficacious when targeting the driver mutation as the clonal variants. In this study, however, we should make this result conclusive with caution due to the limited sample size, further exploration in a large cohort named DARWIN trial (Deciphering Anti-tumor Response With intratumor Heterogeneity; Clinical Trials No. NCT02183883) is ongoing (37, 38).\n\nERBB2 amplification has been identified as a resistance mechanism induced upon treatment with erlotinib or gefitinib (39, 40) and was observed in 12% of tumor samples obtained from patients at resistance to EGFR TKI therapy (41); however, its role in afatinib resistance is unclear. Chuang et al. (42) reported a patient carrying ERBB2ex20ins, whose plasma samples were obtained upon progression on her initial chemotherapy, erlotinib and afatinib, and results showed that the ERBB2 copy number (CN) level increased over time. In our study, we also found two patients treated with afatinib acquired ERBB2 CN gain after taking afatinib for half of a month and upon gained resistance; notably, for the first patient, the biopsy from the initial lesion was taken, respectively, before and upon progression on afatinib, which makes the result more reliable. This makes us speculate that the patients carrying combined ERBB2 mutation and amplification may be less benefit from afatinib. Further basic research may explore this hypothesis.\n\nAdmittedly, our study exists several limitations. Firstly, the sequencing panel in the cohort is not uniform, which impeded us making the deep understanding of co-occurring landscape of ERBB2ex20ins, and we can only analyze co-mutant feature of TP53 among the three insertion-site subgroups. Large-panel NGS should be conducted uniformly in further studies when enrolling patients for the research. Another limitation is due to its retrospective nature, a small sample size of the study, selected bias and various imaging intervals are inevitable in the process of assessing the clinical outcomes of afatinib; nonetheless, the ORR and PFS of afatinib treatment was almost correlated well with prior studies. Furthermore, since we used single tumor sample taken at a one-time point in the disease course, we may not verify the true clonality status of each mutation; however, this single-point samples may be more likely to underestimate the true extent of heterogeneity within tumors rather than distinguishing clonal from subclonal variants. Importantly, although multifocal or repeated tumor biopsies is better for tracking the true evolution process of tumor development, single sampling may be easier to achieve in the clinical practice.\n\nIn summary, our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, highlighting the greater impact of the co-mutation patterns than insertion-site subtypes on the prognosis of this group of patients. Furthermore, our clinical outcome data for afatinib confirmed its certain efficacy for patients with ERBB2ex20ins and suggested the clonality status of ERBB2 mutation may be a potential indicator of response to afatinib.\n\nData Availability Statement\nThe original contributions presented in the study are publicly available. This data can be found here: European Variation Archive (EVA) (www.ebi.ac.uk/eva) (PRJEB37583).\n\nEthics Statement\nThe study involving human participants were reviewed and approved by the institutional review board of The Second Affiliated Hospital of Xi'an Jiaotong University and all participating hospitals (including Peking University Cancer Hospital and Institute, The First Affiliated Hospital of Guangzhou Medical University, Inner Mongolia Autonomous Region Cancer Hospital, Xinqiao Hospital, Guigang City People's Hospital, Qilu Hospital of Shandong University, Sun Yat-sen University Cancer Center, Shaanxi Provincial People's Hospital, The First Affiliated Hospital of University of South China, Fujian Medical University Union Hospital, Shanghai Chest Hospital, The People's Hospital of Guangxi Zhuang Autonomous Region, The First Affiliated Hospital with Nanjing Medical University, Haian People's Hospital, The First Hospital Affiliated to AMU (Southwest Hospital), Shaanxi Provincial Cancer Hospital).\n\nAuthor Contributions\nShuY, LC, BY, and JZ designed the study. BY, JZ, JL, and RC contributed to data analysis. BY and JZ prepared the manuscript of the study. CZ, XW, BZ, MZ, XD, JF, CY, YY, HZ, WZ, ZC, SheY, XA, KC, XC, DL, CS, WW, and YZ collected the samples and assembled the clinical data. All authors read and approved the final manuscript.\n\nConflict of Interest\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\nWe thank the Geneplus-Beijing Institute (Beijing, People's Republic of China) for technical support and bioinformatic analysis.\n\nFunding. This study was supported by the National Natural Science Foundation of China (Grant No. 81672300) and the Basic Research Plan of Natural Science of Shaanxi Province (Grant No. 2018ZDXM-SF-042).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.00729/full#supplementary-material\n\nClick here for additional data file.\n\n Click here for additional data file.\n\n Click here for additional data file.\n==== Refs\nReferences\n1. Arcila ME Chaft JE Nafa K Roy-Chowdhuri S Lau C Zaidinski M . Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas\n. Clin Cancer Res . (2012 ) 18 :4910 –8\n. 10.1158/1078-0432.CCR-12-0912 22761469 \n2. Mazieres J Peters S Lepage B Cortot AB Barlesi F Beau-Faller M . Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives\n. J Clin Oncol . 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J Thorac Oncol . (2017 ) 12 :833 –42\n. 10.1016/j.jtho.2017.01.023 \n28167203\n\n", "fulltext_license": "CC BY", "issn_linking": "2234-943X", "issue": "10()", "journal": "Frontiers in oncology", "keywords": "ERBB2 exon 20 insertion; afatinib; clonality status; co-occurring alterations; non-small cell lung cancer", "medline_ta": "Front Oncol", "mesh_terms": null, "nlm_unique_id": "101568867", "other_id": null, "pages": "729", "pmc": null, "pmid": "32477948", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "25584892;26545934;28445112;22461637;24633410;29686424;27075079;30596880;28167203;28838393;22474122;30089598;29106415;25003521;30857358;22761469;19451168;23610105;25877892;26852079;29596544;28481359;31406302;15753357;29068003;30685684;22588877;25899785;24434212;31469421;30096481;29989854;21353324;29030356;26530965;23550210;22956644;27780855;26598547;26899019;30425522", "title": "Co-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib.", "title_normalized": "co occurring alterations of erbb2 exon 20 insertion in non small cell lung cancer nsclc and the potential indicator of response to afatinib" }

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PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-028577", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFATINIB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "201292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NON-SMALL CELL LUNG CANCER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILOTRIF" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "AFATINIB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "201292", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "GENE MUTATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "GILOTRIF" } ], "patientagegroup": null, "patientonsetage": "56", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Malignant neoplasm progression", "reactionmeddraversionpt": "23.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "YANG S, YUAN B, ZHAO J, ZHOU C, WANG X, ZHU B, ET AL. CO-OCCURRING ALTERATIONS OF ERBB2 EXON 20 INSERTION IN NON-SMALL CELL LUNG CANCER (NSCLC) AND THE POTENTIAL INDICATOR OF RESPONSE TO AFATINIB. FRONTIERS IN ONCOLOGY. 2020 MAY 12?10:729.", "literaturereference_normalized": "co occurring alterations of erbb2 exon 20 insertion in non small cell lung cancer nsclc and the potential indicator of response to afatinib", "qualification": "3", "reportercountry": "CN" }, "primarysourcecountry": "CN", "receiptdate": "20200612", "receivedate": "20200612", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17887042, "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": "CN-B.I. 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{ "abstract": "Medical assistance in dying (MAID) and similar right-to-die laws are becoming increasingly common in jurisdictions across North America and elsewhere. To be eligible for MAID in Canada, requesters must have a serious illness, intolerable suffering, and a reasonably foreseeable natural death. They must also undergo two assessments to confirm eligibility. Although a growing body of literature now exists to help clinicians understand and support patients around requests for assisted death, a dearth of literature exists on how best to support those patients who are deemed ineligible. Here, we report on a case series of three patients who attempted suicide after being found ineligible for MAID. Two patients were ineligible because they did not appear to have reasonably foreseeable natural death. The third patient was ineligible because of concerns around decisional capacity. All three cases had previous diagnoses of depressive disorders and mild cognitive impairment, and two cases had histories of suicide attempts. In at-risk patients, we speculate that the period surrounding a finding of MAID ineligibility may represent a period of particular vulnerability. Clinicians must be vigilant and prepared for the possibility of heightened risk, including risk of self-harm, after a finding of ineligibility for assisted death.", "affiliations": "Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: [email protected].;Ethics Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.;Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.;Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.", "authors": "Isenberg-Grzeda|Elie|E|;Bean|Sally|S|;Cohen|Carole|C|;Selby|Debbie|D|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.jpainsymman.2020.02.016", "fulltext": null, "fulltext_license": null, "issn_linking": "0885-3924", "issue": "60(1)", "journal": "Journal of pain and symptom management", "keywords": "Assisted death; attempted suicide; end-of-life care; palliative care; risk assessment; suicide", "medline_ta": "J Pain Symptom Manage", "mesh_terms": "D002170:Canada; D006801:Humans; D012106:Research; D017236:Suicide, Assisted; D013406:Suicide, Attempted", "nlm_unique_id": "8605836", "other_id": null, "pages": "158-163", "pmc": null, "pmid": "32105792", "pubdate": "2020-07", "publication_types": "D016428:Journal Article", "references": null, "title": "Suicide Attempt After Determination of Ineligibility for Assisted Death: A Case Series.", "title_normalized": "suicide attempt after determination of ineligibility for assisted death a case series" }

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{ "abstract": "Asparaginase plays an integral role in chemotherapy for acute lymphoblastic leukemia (ALL). We present a 69-year old woman with refractory ALL, who developed asparaginase-induced hepatotoxicity and cholangiopathy after starting intravenous PEG-L-asparaginase-based chemotherapy. The patient was ultimately treated with the combination of L-carnitine and vitamin B complex, resulting in normalization of liver enzymes levels. This case highlights the consideration of PEG-L asparaginase chemotherapy-induced liver steatosis, injury, and cholangiopathy as well as the role of L-carnitine and vitamin B complex as treatment.", "affiliations": "Internal Medicine, University of Minnesota Medical School, Minneapolis, USA.;Division of Gastroenterology, Hepatology, and Nutrition/Transplant Hepatology and Critical Care Medicine, University of Minnesota, Minneapolis, USA.;Gastroenterology and Hepatology, University of Minnesota, Minneapolis, USA.", "authors": "Lee|Christina|C|;Leventhal|Thomas M|TM|;Anugwom|Chimaobi M|CM|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.16917", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.16917\nInternal Medicine\nGastroenterology\nOncology\nL-Asparaginase-Induced Hepatotoxicity Treated Successfully With L-Carnitine and Vitamin B Infusion\nMuacevic Alexander\nAdler John R\nLee Christina 1\nLeventhal Thomas M 2\nAnugwom Chimaobi M 3\n1 Internal Medicine, University of Minnesota Medical School, Minneapolis, USA\n2 Division of Gastroenterology, Hepatology, and Nutrition/Transplant Hepatology and Critical Care Medicine, University of Minnesota, Minneapolis, USA\n3 Gastroenterology and Hepatology, University of Minnesota, Minneapolis, USA\nChristina Lee [email protected]\n5 8 2021\n8 2021\n13 8 e1691731 7 2021\nCopyright © 2021, Lee et al.\n2021\nLee et al.\nhttps://creativecommons.org/licenses/by/3.0/ 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.\nThis article is available from https://www.cureus.com/articles/64764-l-asparaginase-induced-hepatotoxicity-treated-successfully-with-l-carnitine-and-vitamin-b-infusion\nAsparaginase plays an integral role in chemotherapy for acute lymphoblastic leukemia (ALL). We present a 69-year old woman with refractory ALL, who developed asparaginase-induced hepatotoxicity and cholangiopathy after starting intravenous PEG-L-asparaginase-based chemotherapy. The patient was ultimately treated with the combination of L-carnitine and vitamin B complex, resulting in normalization of liver enzymes levels. This case highlights the consideration of PEG-L asparaginase chemotherapy-induced liver steatosis, injury, and cholangiopathy as well as the role of L-carnitine and vitamin B complex as treatment.\n\nsevere hepatotoxicity\ndrug-induced hepatotoxicity\ncholangiopathy\nacute lymphocytic leukemia\nasparaginase\nl-carnitine\nvitamin b\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nDrug-induced liver injury is a complex and diverse syndrome that has been attributed to a variety of therapeutic and non-therapeutic agents [1]. The toxic effect of cancer chemotherapy on the liver ranges from sub-clinical disease to fatal cases of acute liver failure; and management of these toxicities are largely supportive [1]. Here, we describe a case of severe hepatic steatosis and cholangiopathy due to PEG-Asparaginase toxicity, with the resolution of liver injury after discontinuation of PEG-asparaginase use and concomitant treatment with an L-carnitine supplement and vitamin B complex.\n\nCase presentation\n\nA 69-year-old female was seen in hospital consultation for abdominal pain and altered mental status, after being admitted five days prior for a planned chemotherapy treatment.\n\nShe has a medical history of T-cell ALL, diagnosed six months prior to presentation. This diagnosis was made based on biopsies of her submandibular lymph nodes and subsequently, her bone marrow. She had undergone induction chemotherapy with the PETHEMA protocol (vincristine, prednisone, daunorubicin, asparaginase, and cyclophosphamide) two months after diagnosis, followed by Hyper-CVAD therapy (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone, Methotrexate, and Cytarabine) for persistent disease after induction. \n\nA month prior to her hospitalization, a repeat bone marrow biopsy demonstrated low-level but persistent lymphoblastic leukemia. Additional chemotherapies were attempted, but she was unable to tolerate treatment with Vincristine and Nelarabine secondary to adverse side effects, which ultimately lead to the scheduled hospitalization for augmented hyper-CVAD therapy with PEG-asparaginase. \n\nAt the time of evaluation, she reported mild nausea but denied vomiting, diarrhea, fever or chills. With ambient air her oxygen saturation was 98%, she was afebrile, but demonstrated tachycardia and tachypnea. Physical examination also elucidated scleral icterus as well as right upper quadrant and epigastric tenderness. Laboratory tests revealed an aspartate aminotransaminase (AST) of 45 U/L, alanine aminotransaminase (ALT) of 72 U/L, alkaline phosphatase (Alk phos) of 282 U/L and total bilirubin (TB) was 2.0 mg/dL. Lipase was elevated at 1687 U/L; greater than three times the upper limit of normal at our laboratory. She was diagnosed with probable drug-induced pancreatitis and drug-induced cholestatic liver injury. An extensive investigation was carried out to determine any other causes of liver injury and pancreatitis. Serological testing revealed that she was immune to Hepatitis B and Hepatitis A, and negative for Hepatitis C infection. An ultrasound of the abdomen revealed hepatic steatosis, absent gall bladder, and absence of ascites (Figure 1).\n\nFigure 1 Ultrasound of the liver\n\nAbdominal ultrasound showing hepatic steatosis, absence of a gall bladder, and no masses or ascites.\n\nTo further evaluate biliary disease, a magnetic resonance cholangiopancreatography (MRCP) was obtained, which showed interstitial edematous pancreatitis, bilateral pleural effusions, but absent intrahepatic or extrahepatic biliary dilatation or changes concerning for cholangitis (Figure 2).\n\nFigure 2 MRCP\n\nMagnetic resonance cholangiopancreatography (MRCP) with evidence of edematous pancreatitis (white arrows); the common bile duct as seen here is not dilated (white arrow head) and no other biliary abnormalities were noted. \n\nThere was a suspicion of PEG-Asparaginase as the cause of her symptoms and multi-organ injury given the presence of concomitant hepatitis and pancreatitis. Her symptoms of nausea, abdominal pain, and altered mental status improved with a low-fat diet, intravenous fluid resuscitation, and analgesia. She was concomitantly started on L-carnitine supplementation and Vitamin B complex for presumed Asparaginase-induced liver injury. As her liver enzymes and bilirubin continued to increase despite these interventions, a liver biopsy was performed. The pathology revealed severe hepatic steatosis and moderate cholestasis (Figure 3, Figure 4), and mild small duct injury/cholangiopathy (Figure 5); consistent with the limited literature description of histologic characterization of asparaginase hepatotoxicity. \n\nFigure 3 Liver biopsy with hematoxylin and eosin stain (100x)\n\nLiver biopsy with hematoxylin and eosin stain showing diffuse steatosis made up of mixed micro and macro-vesicular steatosis, together affecting up to 70%-75% of the parenchyma. Hepato-canalicular cholestasis also shown by the black arrow.\n\nFigure 4 Liver biopsy with Prussian blue staining (400x)\n\nLiver biopsy with Prussian blue staining (400x) showing significant hemosiderosis (stained bright blue). Bile pigments (cholestasis) also noted in the specimen (stained brown) and marked by black arrows. \n\nFigure 5 Liver biopsy with hematoxylin and eosin stain (400x)\n\nLiver biopsy with hematoxylin and eosin stain (400x) showing diffuse steatosis. Diseased bile duct (cholangiopathy) is demonstrated in this figure with the black arrow. Iron pigments also noted diffusely in the figure, and marked by the black arrowheads.\n\nThere was no evidence of leukemia, nodular regenerative hyperplasia, granulomas or significant fibrosis. Her liver enzymes, alkaline phosphatase, and bilirubin started to show improvement on day 10 of IV L-carnitine and continued toward normalization thereafter (Figure 6, Figure 7).\n\nFigure 6 Serum AST and ALT\n\nSerum aspartate aminotransferase and alanine aminotransferase are seen decreasing through the course of the patient's hospitalization.\n\nFigure 7 Serum alkaline phosphatase and total bilirubin\n\nSerum alkaline phosphatase and total bilirubin are seen decreasing through the course of the patient's hospitalization. \n\nSince discharge, the patient has had a bone marrow biopsy without ALL on morphology but 0.06% abnormal lymphoblasts on flow. In order to maintain remission while working on performance status, the patient was started on maintenance chemotherapy with POMP (6-Mercaptopurine, Vincristine, Methotrexate, Prednisone) and she continues to tolerate her current therapy. She is planning to be a part of a clinical trial with CAR-T (chimeric antigen receptor T cell) immunotherapy, once her performance status improves.\n\nDiscussion\n\nSince its introduction to the field of pediatric oncology in the 1960s, Asparaginase has been an integral part of chemotherapy regimens for treating ALL [2, 3]. It is isolated from pathogenic bacteria and is available as L-asparaginase; and PEG-asparaginase - a pegylated form made by adding a mono-methoxypolyethylene moiety [3]. Leukemic cells cannot synthesize L-asparagine and so depend on extracellular sources. Asparaginase catalyzes the breakdown of asparagine to aspartic acid and ammonia, denying the cancer cells of this vital amino acid [4]. It is not inconceivable that depletion of this extracellular amino acid may have deleterious effects on non-malignant human cells.\n\nThere is a myriad of adverse effects associated with asparaginase, which include varying severities of hypertriglyceridemia, acute pancreatitis, venous thrombosis, hypersensitivity reactions, neurologic dysfunctions as well as hepatotoxicity and bile duct injury [5-7].\n\nHepatotoxicity due to asparaginase use may present itself as a self-limiting mild elevation of liver enzymes and bilirubin and in rare cases, severe liver injury with associated death [8,9]. Although the complete mechanism of action is not clear, a putative mechanism is the depletion of asparagine and possibly arginine, with resultant impairment in protein synthesis and lipoprotein export, diminished mitochondrial beta-oxidation of fatty acids, and consequent rapid free fatty acid accumulation [10]. The macroscopic effect of this disorder of protein and lipid metabolism is severe hepatic steatosis, found in up to 90% of patients, with associated biliary injury and cholestasis as was seen in our patient [11]. The biopsy specimen revealed significant micro-vesicular and macro-vesicular steatosis with cholestasis and cholangiopathy.\n\nSpontaneous resolution of hepatitis will occur in most cases of asparaginase-induced liver injury, and treatment is largely supportive. However, the use of L-carnitine has been studied in the treatment of liver toxicity due to asparaginase, carbon tetrachloride, valproic acid, and arsenic [12-14]. The combination with vitamin B complex, as was used in our patient, has been documented to accelerate improvement and resolution of hepatitis, especially in severe cases. It is suggested that by acting as mitochondrial beta-oxidation cofactors, they augment fatty acid oxidation and reduce the severity of steatosis [14-16].\n\nAdditionally, our patient had a continued rise in her liver enzymes and bilirubin even after a few days of treatment. This delayed improvement in liver injury has been documented in the literature as well [9].\n\nConclusions\n\nWe believe that our patient sustained liver injury due to PEG-Asparaginase use, and this improved overtime after administration of L-carnitine and vitamin B complex. It is important to note, however, that the beneficial effects of the combination of L-carnitine and vitamin B complex infusions have not been studied in a randomized controlled trial and that this may be a normal course of L-asparaginase induced hepatotoxicity, and therefore the resolution of liver injury cannot be fully ascribed to these medications and can only be inferred. It is nevertheless plausible to commence this combination treatment regimen in patients with severe asparaginase-induced liver injury.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Hepatotoxicity of chemotherapy Semin Oncol Floyd J Mirza I Sachs B Perry MC 50 67 33 2006 16473644\n2 Toxic and antineoplastic effects of L-asparaginase. Study of mice with lymphoma and normal monkeys and report on a child with leukemia Cancer Dolowy WC Henson D Cornet J Sellin H 1813 1819 19 1966 4959138\n3 L-asparaginase in the treatment of patients with acute lymphoblastic leukemia J Pharmacol Pharmacother Egler RA Ahuja SP Matloub Y 62 71 7 2016 27440950\n4 Amino acid requirements in vitro of human leukemic cells Cancer Res Onuma T Waligunda J Holland JF 1640 1644 31 1971 https://cancerres-aacrjournals-org.ezp1.lib.umn.edu/content/canres/31/11/1640.full.pdf 5287343\n5 Managing toxicities with asparaginase-based therapies in adult ALL: summary of an ESMO Open-Cancer Horizons roundtable discussion ESMO Open Burke PW Hoelzer D Park JH Schmiegelow K Douer D 0 5 2020\n6 Tolerability and toxicity of pegaspargase in adults 40 years and older with acute lymphoblastic leukemia Leuk Lymphoma Daley RJ Rajeeve S Kabel CC 176 184 62 2021 32985296\n7 Asparaginase toxicities: identification and management in patients with acute lymphoblastic leukemia Clin J Oncol Nurs Thu Huynh V Bergeron S 0 59 21 2017\n8 Fatal liver failure in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase Digestion Bodmer M Sulz M Stadlmann S Droll A Terracciano L Krähenbühl S 28 32 74 2006 16988508\n9 L-carnitine and vitamin B complex for PEG-L-asparaginase-induced hepatotoxicity ACG Case Rep J Arora S Klair J Bellizzi AM Tanaka T 0 6 2019\n10 Hepatic lipidosis associated with L-asparaginase treatment Proc Soc Exp Biol Med Gross MA Speer RJ Hill JM 733 736 130 1969 5773660\n11 Histopathological features of L-asparaginase-induced liver disease Semin Liver Dis Sahoo S Hart J 295 299 23 2003 14523682\n12 Protective effect of L-carnitine and coenzyme Q10 on CCl₄-induced liver injury in rats Sci Pharm Ali SA Faddah L Abdel-Baky A Bayoumi A 881 896 78 2010 21179323\n13 Acetyl-l-carnitine attenuates arsenic-induced liver injury by abrogation of mitochondrial dysfunction, inflammation, and apoptosis in rats Environ Toxicol Pharmacol Bodaghi-Namileh V Sepand MR Omidi A Aghsami M Seyednejad SA Kasirzadeh S Sabzevari O 11 20 58 2018 29278859\n14 Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: a case report and review of the literature J Oncol Pharm Pract Blackman A Boutin A Shimanovsky A Baker WJ Forcello N 393 397 24 2018 28523950\n15 Successful treatment of pegaspargase-induced acute hepatotoxicity with vitamin B complex and L-carnitine Proc (Bayl Univ Med Cent) Lu G Karur V Herrington JD Walker MG 46 47 29 2016 26722167\n16 Successful treatment of l-asparaginase-induced severe acute hepatotoxicity using mitochondrial cofactors Leuk Lymphoma Al-Nawakil C Willems L Mauprivez C 1670 1674 55 2014 24090500\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(8)", "journal": "Cureus", "keywords": "acute lymphocytic leukemia; asparaginase; cholangiopathy; drug-induced hepatotoxicity; l-carnitine; severe hepatotoxicity; vitamin b", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e16917", "pmc": null, "pmid": "34513489", "pubdate": "2021-08", "publication_types": "D002363:Case Reports", "references": "4959138;28945721;16988508;21179323;24090500;31737724;27440950;33037033;26722167;14523682;28523950;32985296;5287343;16473644;5773660;29278859", "title": "L-Asparaginase-Induced Hepatotoxicity Treated Successfully With L-Carnitine and Vitamin B Infusion.", "title_normalized": "l asparaginase induced hepatotoxicity treated successfully with l carnitine and vitamin b infusion" }

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"patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cholestatic liver injury", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hepatic steatosis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Biliary tract disorder", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "24.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "24.1", "reactionoutcome": "6" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 20210101" } }, "primarysource": { "literaturereference": "Lee C, Leventhal TM, Anugwom CM. L-Asparaginase-Induced Hepatotoxicity Treated Successfully With L-Carnitine and Vitamin B Infusion. Cureus. 2021;13:8", "literaturereference_normalized": "l asparaginase induced hepatotoxicity treated successfully with l carnitine and vitamin b infusion", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20211002", "receivedate": "20211002", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 19909710, "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" } ]

{ "abstract": "BACKGROUND\nSteroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower hypercortisolism in patients with Cushing's syndrome (CS). Cortisol normalization is not reached in all patients taking these medications.\n\n\nOBJECTIVE\nTo test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS.\n\n\nMETHODS\nFifty-four CS patients (46 women; mean [±SD] age, 39.7±12.7; 83% with Cushing's disease [CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms (SNPs) were analysed: rs6410 (CYP11B1 gene), rs1799998 and rs4546 (CYP11B2 gene), and rs6163 (CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated.\n\n\nRESULTS\nNormalization of urinary free cortisol (UFC) was achieved in 50% of patients after 5 months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/AA (OR 0.25 [95%CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range (IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/AC carriers (4 [4.57] months vs 5.2 [6.1] months; P=.026).\n\n\nCONCLUSIONS\nA polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents.", "affiliations": "Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.;Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.;Endocrinology/Medicine Department, Hospital Sant Pau and IIB, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII and Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.", "authors": "Valassi|Elena|E|http://orcid.org/0000-0002-3864-0105;Aulinas|Anna|A|;Glad|Camilla Am|CA|;Johannsson|Gudmundur|G|;Ragnarsson|Oskar|O|;Webb|Susan M|SM|", "chemical_list": "D013256:Steroids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D007654:Ketoconazole; D008797:Metyrapone", "country": "England", "delete": false, "doi": "10.1111/cen.13414", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-0664", "issue": "87(5)", "journal": "Clinical endocrinology", "keywords": "Cushing's syndrome; ketoconazole; metyrapone; polymorphisms", "medline_ta": "Clin Endocrinol (Oxf)", "mesh_terms": "D000328:Adult; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D007654:Ketoconazole; D008297:Male; D008797:Metyrapone; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013254:Steroid 17-alpha-Hydroxylase; D013256:Steroids", "nlm_unique_id": "0346653", "other_id": null, "pages": "433-439", "pmc": null, "pmid": "28665508", "pubdate": "2017-11", "publication_types": "D016428:Journal Article", "references": null, "title": "A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome.", "title_normalized": "a polymorphism in the cyp17a1 gene influences the therapeutic response to steroidogenesis inhibitors in cushing s syndrome" }

[ { "companynumb": "ES-JNJFOC-20171128990", "fulfillexpeditecriteria": "1", "occurcountry": "ES", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "KETOCONAZOLE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "019927", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "48", "drugcumulativedosageunit": "002", "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CUSHING^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "KETOCONAZOLE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METYRAPONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": "120", "drugcumulativedosageunit": "002", "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CUSHING^S SYNDROME", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METYRAPONE" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "INSULIN NOS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNSPECIFIED", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "TYPE 2 DIABETES MELLITUS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INSULIN" } ], "patientagegroup": "5", "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic enzyme increased", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypokalaemia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypertension", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hirsutism", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VALASSI E, AULINAS A, GLAD CA, JOHANNSSON G, RAGNARSSON O, WEBB SM. A POLYMORPHISM IN THE CYP17A1 GENE INFLUENCES THE THERAPEUTIC RESPONSE TO STEROIDOGENESIS INHIBITORS IN CUSHING^S SYNDROME. CLINICAL ENDOCRINOLOGY NOV?2017?87 (5):433?439.", "literaturereference_normalized": "a polymorphism in the cyp17a1 gene influences the therapeutic response to steroidogenesis inhibitors in cushing s syndrome", "qualification": "3", "reportercountry": "ES" }, "primarysourcecountry": "ES", "receiptdate": "20180727", "receivedate": "20180727", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15207133, "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" } ]

{ "abstract": "BACKGROUND\nWilson disease (WD) is an autosomal recessive hereditary disease in which the patient usually has a reduced risk of developing cancer. In particular, with the exception of hepatocellular carcinoma and cholangiocarcinoma, the incidence of cancer is significantly lower in WD patients compared with the general population. This case study presents a rare case of WD complicated with primary breast cancer.\nA 40-year-old woman who was diagnosed with WD at 25 years of age found a lump in her left breast. She has a family history of cancer.\nUltrasound and mammography results were highly suggestive of a malignant lesion. After core needle biopsy, it was confirmed that she had invasive breast cancer.\n\n\nMETHODS\nA modified radical mastectomy was performed for the left breast. As the tumor was defined as a stage IIa triple negative breast cancer, the patient would have been recommended epirubicin/cyclophosphamide + docetaxel for 8 cycles if WD was not a comorbidity. As the patient had cirrhosis and abnormal liver function, she was given paclitaxel weekly for 6 cycles instead.\n\n\nRESULTS\nThe patient showed good tolerance, and has not had a recurrence in 2 years.\n\n\nCONCLUSIONS\nWe reviewed the literature for studies of patients with WD complicated with cancers, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received chemotherapy even with liver dysfunction, which suggests that patients with WD can be safely treated with paclitaxel chemotherapy under close surveillance.", "affiliations": "Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospital.;Department of Anesthesia, Armed Police Corps Hospital in Shanxi Province, Xiaodian District, Taiyuan, Shanxi Province, P. R. China.;Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospital.", "authors": "Li|Dong|D|;Wang|Jun|J|;Gao|Jinnan|J|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000015266", "fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31083157MD-D-18-0748510.1097/MD.0000000000015266152665750Research ArticleClinical Case ReportPrimary breast cancer in a patient with Wilson disease A case reportLi Dong PhD, MDaWang Jun MDbGao Jinnan PhD, MDa∗NA. a Department of Breast Surgery, Shanxi Academy of Medical Scienses Shanxi Dayi Hospitalb Department of Anesthesia, Armed Police Corps Hospital in Shanxi Province, Xiaodian District, Taiyuan, Shanxi Province, P. R. China.∗ Correspondence: Jinnan Gao, Department of Breast Surgery, Shanxi academy of Medical Sciences Shanxi Dayi Hospital, No. 99, Longcheng Street, Taiyuan, Shanxi Province, 030032, P. R. China (e-mail: [email protected]).5 2019 13 5 2019 98 19 e1526629 10 2018 3 3 2019 15 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 License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nWilson disease (WD) is an autosomal recessive hereditary disease in which the patient usually has a reduced risk of developing cancer. In particular, with the exception of hepatocellular carcinoma and cholangiocarcinoma, the incidence of cancer is significantly lower in WD patients compared with the general population. This case study presents a rare case of WD complicated with primary breast cancer.\n\nPatient concerns:\nA 40-year-old woman who was diagnosed with WD at 25 years of age found a lump in her left breast. She has a family history of cancer.\n\nDiagnoses:\nUltrasound and mammography results were highly suggestive of a malignant lesion. After core needle biopsy, it was confirmed that she had invasive breast cancer.\n\nInterventions:\nA modified radical mastectomy was performed for the left breast. As the tumor was defined as a stage IIa triple negative breast cancer, the patient would have been recommended epirubicin/cyclophosphamide + docetaxel for 8 cycles if WD was not a comorbidity. As the patient had cirrhosis and abnormal liver function, she was given paclitaxel weekly for 6 cycles instead.\n\nOutcomes:\nThe patient showed good tolerance, and has not had a recurrence in 2 years.\n\nLessons:\nWe reviewed the literature for studies of patients with WD complicated with cancers, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received chemotherapy even with liver dysfunction, which suggests that patients with WD can be safely treated with paclitaxel chemotherapy under close surveillance.\n\nKeywords\nbreast cancerchemotherapyWilson diseaseOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nWilson disease (WD)[1] is a copper metabolism disorder that is caused by a mutation of the gene encoding the copper-transporting P-type ATPase (ATP7B) protein. The clinical manifestations generally include liver cirrhosis, abnormal liver function, extrapyramidal effects, and corneal ring pigmentation such as Kayser-Fleischer (K-F) rings. The patients have increased levels of urinary copper but decreased levels of serum copper and ceruloplasmin (CER). WD complicated with another malignancy is very rare; in fact, WD patients have a significantly lower incidence rate of liver tumors compared with non-WD patients suffering from the same level of liver cirrhosis.[2] Extrahepatic tumors are even rarer among WD patients; we have found only 1 case of WD complicated with colon cancer[3] and 2 cases of WD complicated with acute lymphoblastic leukemia.[4,5] To date, there has been no report of WD complicated with breast cancer. In this paper, we reported the diagnosis and treatment of a patient with WD complicated with breast cancer.\n\n2 Case presentation\nA woman, aged 40, went to see a doctor because of “a lump felt on the left breast more than half a month ago.” A color Doppler ultrasound revealed: a hypoechoic nodule of about 2.0 × 1.3 cm in the outer upper quadrant of the left breast, with a clear boundary, irregular shape, and visible dotted blood flow signals; and enlarged lymph nodes of 2.3 × 0.8 cm in the left subaxillary region, with poor corticomedullary differentiation. A mammography revealed that both breasts had compact mammary glands, with an irregular and isodense mass of 2.0 × 1.5 cm in the outer upper quadrant of the left breast; the mass had an obscure boundary and inhomogeneous interior echoes with no abnormal calcification found and was classified as BI-RADS 4c. The outpatient clinic carried out a puncture biopsy, and the clinicopathological analysis confirmed that it was an invasive breast cancer. The patient suffered from abdominal distension, swollen legs, glossolalia, and limb jitters 15 years ago, and her CER level was determined to be 0.81 mg/dL; slit-lamp examination revealed the presence of a K-F ring (2+) and abdominal ultrasonography revealed liver cirrhosis. She was diagnosed with WD and received sodium dimercaptosulphonate decoppering treatment (the patient was allergic to penicillamine). With remarkably improved clinical symptoms, she received decoppering treatment on a regular basis thereafter. In 2003, she received a splenectomy due to splenomegaly and hypersplenism. The patient was allergic to penicillin and cephalosporin antibiotics and did not smoke or drink alcohol. She gave birth at the age of 37 without breastfeeding and her menstruation was normal. The patient had a sister who was diagnosed with breast cancer at 42, a maternal aunt who was diagnosed with lung cancer, and a maternal grandmother who was diagnosed with renal carcinoma. No one else in her family was diagnosed with cancer or WD.\n\nPhysical examination on admission showed a blood pressure of 126/88 mmHg and a pulse of 83 times/min. She had clear consciousness, spoke fluently, and both eyeballs moved freely without diplopia or nystagmus in any direction. Her limb muscle strength, muscular tension, and tendon reflex were normal. Both upper limbs had a slight postural tremor. The body skin and sclera did not have any obvious yellow staining. Her abdomen was flat and her liver size was normal; the spleen had been resected, shifting dullness (–) was detected, and both lower limbs were not swollen. A 2.0 cm hard enclosed lump was felt in the outer upper quadrant of left breast, with an unclear boundary and poor mobility. A soft swollen lymph node can be felt in the left subaxillary region. Laboratory examination showed a negative hepatitis virus index, hemoglobin levels of 110.4 g/L, blood albumin levels of 38.2 g/L, prealbumin levels of 183.6 mg/L, total bilirubin of 5.8 μmol/L, aspartate aminotransferase levels of 28.9 IU/L, alanine transaminase levels of 56.9 IU/L, total bile acid of 23.1 μmol/L, normal blood coagulation, urinary copper excretion of 840.5 μg within 24 hours, serum copper, serum zinc, copper/zinc. A modified radical mastectomy for the left breast was performed under general anesthesia and the postoperative pathology showed a left breast invasive ductal carcinoma of grade II (7 points) accompanied by massive necrosis in the central area. The size of the lump was 3 × 2 × 1.5 cm and did not involve vascular nerves. No cancer cells were found in the nipple or the incisal edge of the base. Axillary examination revealed no cancer metastasis in 30 lymph nodes (0/30) and immunohistochemical analysis showed that the carcinoma was ER(–), PR(–), HER-2(–), and showed positive Ki67 staining in 40% of the tumor cells. The patient was ultimately diagnosed with triple negative left breast cancer pT2N0M0, stage IIa. Paclitaxel was offered as a chemotherapy regime after operation (80 mg/m2 weekly), which the patient tolerated well, with just degree II abnormal liver function and degree I to II bone marrow suppression.\n\n3 Discussion and conclusions\nCopper is a trace element essential for the normal metabolism of human cells, acting as an activator for several enzymes as well as an essential component of antioxidant enzymes such as superoxide dismutase and monoamine oxidase. The total copper content in the body of an adult is normally about 50 to 150 mg, of which 5% to 10% exists in the blood. During blood circulation, about 95% of the copper is combined with CER and a small proportion is combined with albumin and histidine.\n\nHepatolenticular degeneration is also called Wilson disease,[1] so named because it was officially established in 1921 by Wilson, an English neuropathist. The incidence rate is estimated to be 1/30,000. WD is a type of autosomal recessive hereditary disease caused by a mutation of the gene encoding the ATP7B protein, which is the main regulator of the hepatic metabolism of copper in the body. Its pathophysiological basis is that the hereditary defect leads to the dysfunction of copper excretion by lysosomes in the liver cells and the decrease of CER synthesized by the liver. As a result, large amounts of copper accumulate in the liver and serum copper is loosely combined with albumin, entering into the systemic circulation. In this way, copper is deposited in the brain, liver, cornea, and other tissues, giving rise to diseases such as liver cirrhosis, liver function abnormalities, vertebral body symptoms, and corneal pigmentation such as K-F rings, as well as increasing levels of urinary copper and decreasing levels of serum copper and CER.\n\nThe relationship between serum copper and malignancies is still unclear. Studies have shown that cancer patients usually have high levels of copper in their serum[6–8] and tissue specimens.[9] Some scholars believe that copper is an inducing factor for malignancies because it can suppress the activity of glutathione peroxidase and make cells vulnerable to attack by free radicals. The overload of copper might raise the incidence rate of malignancies by causing P53 mutations,[10] increasing the possibility of BRAF mutations,[11] and promoting tumor angiogenesis.[12,13] However, others think that the rise of serum copper is not an inducing factor but the result of malignancies with mechanisms that may lead to the rise of serum copper. Under the anaerobic conditions of tumors, several enzymes that rely on copper are suppressed in the body, reflexively prompting the copper in other body parts to be metabolized and released into the blood to maintain the activity of essential enzymes, resulting in an increase in the level of copper in the blood. The increase of sialyltransferases on the surface of tumor cells suppresses CER decomposition and causes the rise of CER and copper in the blood. Currently, many studies have shown that serum copper reduction is used as a strategy to treat cancer. Some studies pointed out that copper chelation with tetrathiomolybdate can lower the chances of cancer recurrence and metastasis,[14–19] possibly due to the reduction of endothelial progenitor cells and inhibition of the generation of tumor microvasculature.\n\nClinically, there is a very low incidence rate of WD complicated with other malignancies. According to previous reports, complicating malignancies of WD mainly include hepatocellular carcinoma and cholangiocarcinoma (the probability of malignant pathological change is remarkably low relative to non-WD patients complicated with the same level of liver cirrhosis[2]) and other types of malignancies are even rarer. Although breast cancer is the most common malignancy in women, there has been no report of WD complicated with breast cancer. To our knowledge, this is the first case report on WD complicated with breast cancer.\n\nIn the report on WD complicated with colon cancer, the authors considered that constant chelation therapy might cause damage to the colonic mucosa, which is a possible factor to precipitate malignant change.[3] However, it is obvious that the incidence of breast cancer has no direct connection to this. We speculate that the decreased level of serum copper and CER in WD patients as well as the adoption of chelation decoppering treatment reduces the incidence rate of cancers and, therefore, the tumor incidence in WD patients is very low. As for the patient featured in our study, she bears many high-risk factors for breast cancer (advanced maternal age, no breastfeeding, history of malignancy in the family, etc.). We believe that she may be subjected to an even higher risk of tumor incidence if she had not contracted WD and accepted decoppering treatment.\n\nThere are scarcely any reports regarding chemotherapy risk assessment in WD patients. We could only find 1 case report about chemotherapy for a WD patient complicated with leukemia, where the authors pointed out that full consideration of serious therapy-related toxicity should be taken when treating WD patients with chemotherapy, which mainly includes hepatotoxicity and bone marrow suppression, and that the chemotherapeutic dosage should be reduced when necessary.[4] Since some researchers noted that the ATP7B mutation might result in drug resistance of tumor cells to platinum-based chemotherapy,[20] we adopted taxanes for chemotherapy. The treatment scheme was weekly therapy with paclitaxel, starting from 50% of the conventional chemotherapeutic dose, which was gradually increased to the standard dose (80 mg/m2 weekly) while keeping a close watch on the patient's liver function. According to clinical observation, the patient had good tolerance, with only degree II abnormal liver function and degree I to II bone marrow suppression (reduced glutathione was used as a liver protection drug during this process).\n\nIn summary, we reported a case of WD complicated with breast cancer, and to our knowledge, this is the first report on WD complicated with breast cancer. The patient received weekly chemotherapy with paclitaxel for 6 cycles after the operation and we will continue to keep a close watch on the patient.\n\nAuthor contributions\nConceptualization: Dong Li.\n\nSupervision: Jinnan Gao.\n\nWriting – original draft: Dong Li.\n\nWriting – review & editing: Jun Wang, Jinnan Gao.\n\nAbbreviations: ATP7B = copper-transporting P-type ATPase, CER = ceruloplasmin, ER = estrogen receptor, HER-2 = human epidermal growth factor receptor 2, K-F ring = Kayser-Fleischer ring, PR = progesterone receptor, WD = Wilson disease.\n\nThe patient has provide informed consent for publication of the case and we could provide this information if requested.\n\nThis paper was supported by a grant from the 136 Startup Project of Shanxi province (2019XY010).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] EASL . Clinical practice guidelines: Wilson's disease . J Hepatol \n2012 ;56 :671–85 .22340672 \n[2] Pfeiffenberger J Mogler C Gotthardt DN \nHepatobiliary malignancies in Wilson disease . Liver Int \n2015 ;35 :1615–22 .25369181 \n[3] Lee SY Kim IH Yoo SH \nA case of colonic adenocarcinoma in a patient with Wilson's disease . Gut liver \n2013 ;7 :500–3 .23898395 \n[4] Maeda S Matsubara H Hiejima E \nAcute lymphoblastic leukemia in a girl with Wilson's disease . Pediatr Int \n2014 ;56 :626–9 .25252055 \n[5] Yuce A Kocak N Yetgin S \nAcute lymphoblastic leukemia in a child with Wilson disease . Turk J Pediatr \n2000 ;42 :256–7 .11105631 \n[6] Gupta SK Shukla VK Vaidya MP \nSerum trace elements and Cu/Zn ratio in breast cancer patients . J Surg Oncol \n1991 ;46 :178–81 .2011029 \n[7] Kuo HW Chen SF Wu CC \nSerum and tissue trace elements in patients with breast cancer in Taiwan . Biol Trace Elem Res \n2002 ;89 :1–1 .12413046 \n[8] Zowczak M Iskra M Torlinski L \nAnalysis of serum copper and zinc concentrations in cancer patients . Biol Trace Elem Res \n2001 ;82 :1–8 .11697759 \n[9] Geraki K Farquharson MJ Bradley DA \nConcentrations of Fe, Cu and Zn in breast tissue: a synchrotron XRF study . Phys Med Biol \n2002 ;47 :2327–39 .12164590 \n[10] Formigari A Gregianin E Irato P \nThe effect of zinc and the role of p53 in copper-induced cellular stress responses . J Appl Toxicol \n2013 ;33 :527–36 .23401182 \n[11] Brady DC Crowe MS Turski ML \nCopper is required for oncogenic BRAF signaling and tumorigenesis . Nature \n2014 ;509 :492–6 .24717435 \n[12] Finney L Vogt S Fukai T \nCopper and angiogenesis: unravelling a relationship key to cancer progression . Clin Exp Pharmacol Physiol \n2009 ;36 :88–94 .18505439 \n[13] Antoniades V Sioga A Dietrich EM \nIs copper chelation an effective anti-angiogenic strategy for cancer treatment? \nMed Hypotheses \n2013 ;81 :1159–63 .24210000 \n[14] Brewer GJ Merajver SD \nCancer therapy with tetrathiomolybdate: antiangiogenesis by lowering body copper--a review . Integr Cancer Ther \n2002 ;1 :327–37 .14664727 \n[15] Khan G Merajver S \nCopper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm . Expert Opin Investig Drugs \n2009 ;18 :541–8 .\n[16] Brewer GJ \nCopper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer . Curr Cancer Drug Targets \n2005 ;5 :195–202 .15892619 \n[17] Chan N Willis A Kornhauser N \nInfluencing the tumor microenvironment: a Phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases . Clin Cancer Res \n2017 ;23 :666–76 .27769988 \n[18] Jain S Cohen J Ward MM \nTetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse . Ann Oncol \n2013 ;24 :1491–8 .23406736 \n[19] Goodman VL Brewer GJ Merajver SD \nControl of copper status for cancer therapy . Curr Cancer Drug Targets \n2005 ;5 :543–9 .16305350 \n[20] Kanzaki A Toi M Neamati N \nCopper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma . Jpn J Cancer Res \n2002 ;93 :70–7 .11802810\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0025-7974", "issue": "98(19)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D003937:Diagnosis, Differential; D005260:Female; D006527:Hepatolenticular Degeneration; D006801:Humans", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e15266", "pmc": null, "pmid": "31083157", "pubdate": "2019-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Primary breast cancer in a patient with Wilson disease: A case report.", "title_normalized": "primary breast cancer in a patient with wilson disease a case report" }

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{ "abstract": "Wilms tumor, or nephroblastoma, is the most common malignant tumor of the urinary tract in children, but is rarely found in adults. Here, we report the first case of a female patient with a Wilms tumor, diagnosed during pregnancy, who underwent radical nephrectomy and adjuvant chemotherapy before and after delivering a healthy child. Generally, treatment should follow the guidelines established for the pediatric setting.", "affiliations": "Department of Urology, Technische Universität München, Klinikum rechts der Isar, Munich, Germany. [email protected]", "authors": "Maurer|T|T|;Zorn|C|C|;Klein|E|E|;Weirich|G|G|;Beer|A J|AJ|;Gschwend|J E|JE|;Zantl|N|N|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000241685", "fulltext": null, "fulltext_license": null, "issn_linking": "0042-1138", "issue": "83(3)", "journal": "Urologia internationalis", "keywords": null, "medline_ta": "Urol Int", "mesh_terms": "D000328:Adult; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D009396:Wilms Tumor", "nlm_unique_id": "0417373", "other_id": null, "pages": "364-7", "pmc": null, "pmid": "19829043", "pubdate": "2009", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Multimodal tumor therapy in a 31-year-old pregnant woman with Wilms tumor.", "title_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor" }

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MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009 OCT?83(3):364-367.", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17537678, "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": "DE-AUROBINDO-AUR-APL-2020-011554", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NEEDED", "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": "6", "activesubstance": { "activesubstancename": "GRANISETRON" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "204238", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, AS NEEDED", "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": "GRANISETRON" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MILLIGRAM/SQ. 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MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009?83(3):364-367", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200310", "receivedate": "20200310", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17519466, "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": "DE-RECORDATI RARE DISEASES-DKLU1060504", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "VINCRISTINE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NEPHROBLASTOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1.5", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VINCRISTINE" }, { "actiondrug": "4", "activesubstance": { "activesubstancename": "DACTINOMYCIN" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": "050682", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "MATERNAL CONDITION AFFECTING FOETUS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "3", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "45", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DACTINOMYCIN" } ], "patientagegroup": "1", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": "2.4", "reaction": [ { "reactionmeddrapt": "Premature baby", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Exposure during pregnancy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "ZANTL N. MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. UROLOGIA INTERNATIONALIS. 2009 OCT?83(3):364-367.", "literaturereference_normalized": "multimodal tumor therapy in a 31 year old pregnant woman with wilms tumor", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "DE", "receiptdate": "20200313", "receivedate": "20200313", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17538962, "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": "DE-MYLANLABS-2020M1029046", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METOCLOPRAMIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK UNK, PRN (UNK, AS NEEDED)", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIEMETIC SUPPORTIVE CARE", "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": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": "064", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.5 MG/M2, WEEKLY (MAXIMUM 2 MG; 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MULTIMODAL TUMOR THERAPY IN A 31-YEAR-OLD PREGNANT WOMAN WITH WILMS TUMOR. 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{ "abstract": "Pyoderma gangrenosum is a sterile inflammatory disease of unknown etiology characterized by recurrent cutaneous ulcers. It can occur in extracutaneous locations, especially at operative sites, and has been reported following gynecologic surgery. This report is the first case of pyoderma gangrenosum as a remote complication of pelvic surgery with associated ureteral stricture. It demonstrates the diagnostic challenge of this rare disease and the importance of broadening the differential diagnosis when apparent infections do not respond to treatment to minimize the morbidity of ineffective antibiotic and surgical interventions.", "affiliations": "Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA.;Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd #3, Atlanta, GA, 30322, USA.;Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA.", "authors": "Walton|Eric|E|;Wolner|Zachary|Z|;Hammett|Jessica|J|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.eucr.2021.101826", "fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00266-7\n10.1016/j.eucr.2021.101826\n101826\nInflammation and Infection\nVaginal cuff pyoderma gangrenosum with associated ureteral stricture: A case report\nWalton Eric [email protected]\na∗\nWolner Zachary b\nHammett Jessica a\na Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA\nb Department of Dermatology, Emory University School of Medicine, 1525 Clifton Rd #3, Atlanta, GA, 30322, USA\n∗ Corresponding author. Department of Urology, Emory University School of Medicine, 1365 Clifton Road NE, Building B, Suite B 1400, Atlanta, GA, 30322, USA. [email protected]\n28 8 2021\n11 2021\n28 8 2021\n39 1018263 8 2021\n24 8 2021\n26 8 2021\n© 2021 The Authors. Published by Elsevier Inc.\n2021\n\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/).\nPyoderma gangrenosum is a sterile inflammatory disease of unknown etiology characterized by recurrent cutaneous ulcers. It can occur in extracutaneous locations, especially at operative sites, and has been reported following gynecologic surgery. This report is the first case of pyoderma gangrenosum as a remote complication of pelvic surgery with associated ureteral stricture. It demonstrates the diagnostic challenge of this rare disease and the importance of broadening the differential diagnosis when apparent infections do not respond to treatment to minimize the morbidity of ineffective antibiotic and surgical interventions.\n\nKeywords\n\nPyoderma gangrenosum\nVaginal cuff\nPelvic surgery\nUreteral stricture\n==== Body\npmc1 Introduction\n\nPyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis characterized by recurrent cutaneous ulceration; it is often associated with inflammatory bowel disease, rhematic disorders, or neoplasms.1 Although rare, there are gynecologic reports of PG.2,3 To the best of our knowledge, this report is the first case of PG arising as a remote complication of pelvic surgery that also involves adjacent urologic organs.\n\n2 Case presentation\n\nA sixty-year-old woman with surgical history pertinent for vaginal hysterectomy twenty years ago and sacrospinous ligament suspension fifteen years ago presented to the urology clinic for evaluation of vaginal discharge associated with right hydronephrosis. Symptoms began ten months prior to presentation when she developed dyspareunia followed by vaginal bleeding and discharge. She then developed low-grade fevers, chills, fatigue, poor appetite, weight loss, and weakness. No dysuria, gross hematuria, flank pain, or suprapubic pain.\n\nA gynecologist performed a pelvic exam and removed a right vaginal suture that appeared infected. She subsequently completed three courses of oral antibiotics without resolution of symptoms. Nine months after symptom onset, vaginal culture grew Bacteroides and MRI was obtained showing new-onset hydronephrosis associated with fluid collection at vaginal cuff (Fig. 1). Renal function was normal. Oral levofloxacin and metronidazole were started and switched to intravenous due to side effects. She then developed scattered skin lesions.Fig. 1 MRI depicting right hydroureteronephrosis associated with right vaginal cuff fluid collection.\n\nFig. 1\n\nMedical history includes hypertension, hyperlipidemia, hypothyroidism, mood disorder, and psoriasis treated with ixekizumab (humanized IgG4 monoclonal antibody specific for interleukin 17A). No personal or family history of inflammatory bowel disease, rheumatoid arthritis, or malignancy. She is a G5P4A1 with all spontaneous vaginal deliveries. She is a non-smoker.\n\nPhysical exam revealed scattered violaceous papules across her face and multiple pustular nodules of the distal extremities concerning for septic emboli (Fig. 2). Dried purulent discharge was noted on otherwise normal genitalia. Pelvic exam revealed an open vaginal cuff with intact perineum and copious purulent material.Fig. 2 Representative lesions on face and distal extremities at time of presentation to urology clinic.\n\nFig. 2\n\nThe patient was admitted with concern for subacute bacterial endocarditis. Vaginal and blood cultures were negative. Finger lesions underwent incision and drainage; wound cultures were negative. Cystoscopy with right retrograde pyelogram showed a draining vaginal cuff fluid collection, bladder inflammation, and right hydroureteronephrosis to the level of the bladder. Three vaginal cuff sutures (appearance most consistent with braided polyester) were removed. Vaginal cuff tissue cultures were negative. Additional soft tissue lesions developed despite broad antibiotic coverage. Echocardiography and autoimmune studies were unremarkable. Dermatology was consulted and expressed high suspicion for PG given history and exhaustive negative infectious work-up. Punch biopsy was performed demonstrating a neutrophilic infiltrate supportive of the diagnosis. The patient was initiated on cyclosporine with rapid response of skin lesions.\n\nOne month later, she had persistent vaginal discharge and right hydronephrosis with normal renal function despite overall good response to cyclosporine. Repeat cystoscopy with right retrograde pyelogram demonstrated vaginal cuff inflammation, severe hydroureteronephrosis, and distal ureteral stricture that was stented (Fig. 3). The patient was transitioned to adalimumab for long-term management. Her ureteral stricture is currently managed with ureteral stent exchanges. When her PG is adequately controlled and her vaginal cuff has healed, she will undergo ureteroneocystostomy.Fig. 3 Right hydroureteronephrosis to the level of the bladder with severe distal ureteral stricture associated with severe vaginal inflammation.\n\nFig. 3\n\n3 Discussion\n\nOnset of PG typically occurs in the third to sixth decade of life with a higher incidence in women. This rare disorder usually presents on the lower extremities as painful pustules that rapidly enlarge into ulcers with violaceous undermined borders, however, it can occur in other cutaneous or extracutaneous location. Etiology of PG is unknown but involves aberrant autoimmune response to unspecified antigen(s). With no definitive diagnostic criteria, it is a diagnosis of exclusion. Differential diagnosis includes vascular occlusive disease, vasculitis, malignancy, infectious diseases, tissue injury, and drug reactions. Diagnosis is supported by response to treatment, typically systemic corticosteroids or cyclosporine.1\n\nGynecologic reports of PG are rare. One report describes chronic ulceration of the vagina following cervical cone biopsy.2 Another case occurred in the vaginal vault as a late complication (post-op day 92) of vaginal hysterectomy.3 More commonly post-operative PG arises at surgical incisions during the immediate post-operative period, with breast and abdomen being the most common sites.4 In post-operative PG, trauma upregulates neutrophils at the site of ulceration. The role of suture material is unknown. It has been theorized that higher reactivity material (eg., silk) with epidermal puncture is more likely to elicit PG, however, no prospective data exists to support this theory and many cases occur after low reactivity absorbable subcuticular sutures are employed.4 Similarly, one case report found no difference in PG lesions created by seven different suture types.5 In this case braided polyester, a low reactivity non-absorbable suture, was identified. Furthermore, post-operative PG has a lower association with system disease (34 vs 50%) compared with classic PG; most patients with post-operative PG receive antibiotics and undergo wound debridement prior to diagnosis.4\n\nThe case presented here demonstrates the challenge of diagnosing PG in extracutaneous locations, especially by clinicians unfamiliar with this rare disease. It highlights the importance of considering alternative etiologies when seemingly infectious problems do not respond to antibiotic therapy. Furthermore, the remote history of pelvic surgery suggests foreign bodies can serve as a source of pathergy in PG beyond the acute peri-operative period. Involvement of adjacent urologic organs in this case add an additional layer of complexity. Ureteral stricture secondary to inflammation from PG has created a treatment conundrum where only additional operative trauma during ureteroneocystostomy can definitively resolve the consequence of the initial disease process.\n\n4 Conclusion\n\nThis case is the first report of PG of the vaginal cuff arising in a patient with a remote history of pelvic surgery; the involvement of adjacent urologic organs is also distinctive. It demonstrates the diagnostic challenge of this rare disease and underlies the importance of maintaining a broad differential diagnosis when apparent surgical infections do not respond to treatment. Early consultation of a dermatologist if concerned for PG can minimize the morbidity of repetitive antibiotic and surgical interventions that do not effectively treat this disease.\n\nConsent\n\nInformed consent was obtained from the patient to include case details in this written report.\n==== Refs\nReferences\n\n1 Wollina U. Pyoderma gangrenosum--a review Orphanet J Rare Dis. Apr 2 2007 19 10.1186/1750-1172-2-19\n2 Lilford R.J. Tindall V.R. Batchelor A.G. Post-surgical pyoderma gangrenosum of the vaginal vault associated with ulcerative colitis and Behçet's disease; a case report Eur J Obstet Gynecol Reprod Biol. Apr 31 1 1989 93 94 10.1016/0028-2243(89)90030-0\n3 Güth U. Wagner S. Huang D.J. Hess T.H. Pyoderma gangrenosum of the vaginal vault after vaginal hysterectomy: only the correct diagnosis of a rare entity can prevent long-term morbidity Arch Gynecol Obstet 288 1 Jul 2013 79 82 10.1007/s00404-012-2692-9 23283595\n4 Tolkachjov S.N. Fahy A.S. Cerci F.B. Wetter D.A. Cha S.S. Camilleri M.J. Postoperative pyoderma gangrenosum: a clinical review of published cases Mayo Clin Proc. 09 91 9 2016 1267 1279 10.1016/j.mayocp.2016.05.001\n5 Kratzsch D. Ziemer M. Milkova L. Wagner J.A. Simon J.C. Kendler M. Facial pyoderma gangrenosum in senescence Case Rep Dermatol 5 3 2013 295 300 10.1159/000356100 24403893\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2214-4420", "issue": "39()", "journal": "Urology case reports", "keywords": "Pelvic surgery; Pyoderma gangrenosum; Ureteral stricture; Vaginal cuff", "medline_ta": "Urol Case Rep", "mesh_terms": null, "nlm_unique_id": "101626357", "other_id": null, "pages": "101826", "pmc": null, "pmid": "34522619", "pubdate": "2021-11", "publication_types": "D002363:Case Reports", "references": "27489052;2714511;17433111;24403893;23283595", "title": "Vaginal cuff pyoderma gangrenosum with associated ureteral stricture: A case report.", "title_normalized": "vaginal cuff pyoderma gangrenosum with associated ureteral stricture a case report" }

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{ "abstract": "Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.", "affiliations": "Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA [email protected].;Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.", "authors": "Below|Samantha|S|http://orcid.org/0000-0001-8707-4800;Bashir|Maaman|M|", "chemical_list": "D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D018271:Signal Recognition Particle; D009173:Mycophenolic Acid; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1136/bcr-2020-237647", "fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-237647\n10.1136/bcr-2020-237647\nCase Report\n1506\n508\n520\n532\n541\nSRP-positive necrotising myopathy: takes more than just the muscles\nhttp://orcid.org/0000-0001-8707-4800Below Samantha 1 Bashir Maaman 2 1 Medicine, Medical College of Wisconsin, Wauwatosa, Wisconsin, USA\n2 Rheumatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA\nCorrespondence to Dr Samantha Below; [email protected]\n2021 \n19 2 2021 \n19 2 2021 \n14 2 e23764710 2 2021 © BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2021http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.\n\nrespiratory medicinelung functionrheumatologymusculoskeletal syndromesspecial-featureunlocked\n==== Body\nBackground\nNecrotising myopathy is a rare autoimmune disease that is thought to primarily affect muscles and commonly presents as weakness; it has been reported that there are associated effects on the heart and lungs. This case describes a middle-aged woman presenting with a chief report of shortness of breath, who was subsequently found to have muscle weakness and respiratory failure due to signal recognition particle (SRP)-positive myopathy. In this case, we evaluate her clinical course, review the literature regarding SRP-positive myopathy and strengthen the case that due to the ubiquitous nature of the SRP autoantibodies; patient presentations can extend beyond proximal muscle weakness.\n\nCase presentation\nA previously independently functioning 52-year-old obese African American woman initially presented to her primary care office with a chief report of unresolving shortness of breath, which seemed to be incited after she tripped over a broom at work. Previous medical history was significant for hyperlipidaemia treated with simvastatin 40 mg for primary prevention from 2013 to 2020, morbid obesity, congestive heart failure and coronary artery disease.\n\nPatient’s primary care doctor sent the patient for a CT angiogram that was significant for pulmonary hypertension and hepatic inflammation. In the following weeks, she was admitted for progressive muscle weakness.\n\nPatient was found to have a creatine kinase (CK) elevation that peaked at 25 295 U/L. MRI of the lumbar spine revealed diffuse oedema of the pelvic muscles. Left quadriceps muscle biopsy was interpreted with ‘rare’ necrotic fibres, ‘occasional’ cytochrome c oxidase-intermediate (COX)-negative fibres, without deposits of complement macrophage antigens (MAC), and major histocompatibility (MHC) class I staining. SRP and -hydroxy-3-methyl-glutaryl-coenzymereductase (HMGCR) antibodies were negative. Antinuclear antibodies (ANA), nuclear ribonucleoprotein (RNP), Sjögren’s syndrome antibody (SSA), double-stranded DNA and myeloperoxidase antibodies were positive. Her home simvastatin was held, she was treated with prednisone and intravenous immunoglobulin. Her CK gradually decreased to the 2000–4000 U/L.\n\nShe continued to experience shortness of breath and was found to have a non-ST elevation myocardial infarction treated with medical management and stent placement for left anterior descending lesion. Further evaluation with an electromyography showed a diffuse, proximal-predominant, irritable myopathy and distal axonal polyneuropathy.\n\nLaboratory workup was consistent with elevated erythrocyte sedimentation rate (ESR) and positive ANA with a homogeneous pattern, which is typically seen in lupus, RNP as well as SSA antibodies as noted at the outside hospital. SRP 54 was now positive. CT C/A/P did not identify any malignancy. Muscle biopsy was significant for highly active and chronic necrotising myopathy with inflammation, mild mitochondrial dysfunction, preferential type 2 atrophy, increased type 2C fibres, occasional rounded atrophic fibres and mild denervation atrophy, indicative of highly active and possibly chronic necrotising myopathy.\n\nTreatment\nPatient was treated with prednisone, IVIG and mycophenolate mofetil.\n\nOutcome and follow-up\nPatient initially failed to improve. Her course was complicated by worsening heart failure, respiratory failure requiring intubation with transition to tracheostomy and dysphagia requiring nasogastric tube for nutrition. She continued to slowly decline and was evaluated for placement at a long-term care facility. After a course at a long-term acute care, the patient returned home with continued needs for assistance with activities of daily living.\n\nDiscussion\nImmune-mediated necrotising myopathy (IMNM) is characterised by minimal infiltration on muscle biopsy and is one of the most severe and progressive myopathies.1 2 In our case, the patient was SRP 54 positive, a subunit of the SRP protein complex, presenting with shortness of breath, followed by weakness, then dysphagia. It is commonly thought that the type of autoantibody will predict the course of the myopathy and the associated extra muscular manifestations. SRP is a ribonuclear protein that regulates translocation of protein across the endoplasmic reticulum. It is not specific to muscle tissue but is ubiquitously found in all protein processing cells.2 Myopathies associated with SRP antibodies were thought to have a similar clinical presentation; however, the literature suggests the presentation of SRP associated myopathy can vary greatly. Anti-SRP-related myopathy is now considered a subset of IMNM, also known as necrotising autoimmune myopathy. Symptoms of anti-SRP myopathy are range from weakness, dysphagia and cardiovascular involvement, with some studies showing lower association with interstitial lung disease (ILD).3 While limb weakness is the most common manifestation of myositis, there are reports of the SRP protein antibodies leading to different presenting symptoms involving the lungs and heart.2 4Involvement of the haematologic system with neutropenia and other alterations in proliferation were also identified.2 5 The ubiquitous nature of the SRP protein leads to multiple different manifestations when attacked by the immune system, from pulmonary, cardiac and haematologic.6 7 Myocardial involvement in anti-SRP myopathy can be severe and is considered a poor prognostic factor. Extramuscular manifestations such as ILD, Raynaud’s and arthralgia have been reported, though these features are typically mild. Some authors have suggested that radiographic suggestion of ILD in these patients may in fact arise from respiratory insufficiency due to musculoskeletal weakness.8\n\nOther autoimmune conditions may have been at play in our patient and her dramatic hospital course. It has been shown that patients positive for ANA in a homogeneous pattern, consistent with SLE, is potentially associated with an overlap syndrome of SLE and necrotising myopathy. While this may have been present in our patient, the likelihood is low as there was no history of SLE in our patient. Furthermore, the overlap between SLE and necrotising myopathy has only been described in one case report to date.9 With this knowledge, clinicians should be aware of the complications of dysphagia, respiratory and cardiac failure and initiate prompt treatment to avoid further complications in the patient’s clinical course.\n\nIn fact, involvement of muscles with a symptom of weakness may not be as prominent as other symptoms such as shortness of breath or dysphagia. This is logical given the ubiquity of SRP and the ability of the antibody to cause dysfunction in different tissues.2\n\nPatient’s perspective\nAs this was during the COVID pandemic, it was extremely difficult for me to adjust to the situation and the loss of the ability to care for myself. I often felt alone and was very scared. As I was in the hospital for over 6 months, I feel that I missed out a lot with my family. We lost my son to a gunshot wound before my sickness and I was also grieving that loss.\n\nLearning points\nNecrotising myopathy is a rare but fatal aetiology in patient’s presenting with weakness and shortness of breath.\n\nPatients can have variable presentations and may initially present with symptoms other than skeletal muscle weakness.\n\nTreatment of the condition should not be delayed while workup is undertaken as it can result in pulmonary hypertension and serious pulmonary and cardiac manifestations.\n\nIt is imperative to know a patient’s functional baseline to set expectations for the clinical course of a myopathy pathology\n\nContributors: MB: served as scientific advisor. SB: wrote and researched case.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Not required.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Ernste \nFC , Reed \nAM \nIdiopathic inflammatory myopathies: current trends in pathogenesis, clinical features, and up-to-date treatment recommendations\n. Mayo Clin Proc \n2013 ;88 :83 –105\n. 10.1016/j.mayocp.2012.10.017 23274022 \n2 Satoh \nM , Tanaka \nS , Ceribelli \nA , et al \nA comprehensive overview on myositis-specific antibodies: new and old biomarkers in idiopathic inflammatory myopathy\n. Clin Rev Allergy Immunol \n2017 ;52 :1 –19\n. 10.1007/s12016-015-8510-y 26424665 \n3 Khan \nMH , Patel \nA , Pendharkar \nS \nAnti-Signal recognition particle necrotizing autoimmune myopathy: an atypical presentation\n. Cureus \n2018 ;10 :e3766. 10.7759/cureus.3766 30820385 \n4 Watanabe \nY , Uruha \nA , Suzuki \nS , et al \nClinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy\n. J Neurol Neurosurg Psychiatry \n2016 ;87 :1038 –44\n. 10.1136/jnnp-2016-313166 27147697 \n5 Basnayake \nSK , Blumbergs \nP , Tan \nJA , et al \nInflammatory myopathy with anti-SRP antibodies: case series of a South Australian cohort\n. Clin Rheumatol \n2015 ;34 :603 –8\n. 10.1007/s10067-014-2512-7 24497174 \n6 Kassardjian \nCD , Lennon \nVA , Alfugham \nNB , et al \nClinical features and treatment outcomes of necrotizing autoimmune myopathy\n. JAMA Neurol \n2015 ;72 :996 –1003\n. 10.1001/jamaneurol.2015.1207 26192196 \n7 Milone \nM \nDiagnosis and management of immune-mediated myopathies\n. Mayo Clin Proc \n2017 ;92 :826 –37\n. 10.1016/j.mayocp.2016.12.025 28473041 \n8 Day \nJA , Limaye \nV \nImmune-Mediated necrotising myopathy: a critical review of current concepts\n. Semin Arthritis Rheum \n2019 ;49 :420 –9\n. 10.1016/j.semarthrit.2019.04.002 31109639 \n9 Cauchi \nJ , Perez-Rosendahl \nM , Mozaffar \nT \nAcute necrotizing myositis in systemic lupus erythematous (4816)\n. Neurology \n2020 .\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1757-790X", "issue": "14(2)", "journal": "BMJ case reports", "keywords": "lung function; musculoskeletal syndromes; respiratory medicine; rheumatology", "medline_ta": "BMJ Case Rep", "mesh_terms": "D001327:Autoimmune Diseases; D004576:Electromyography; D004791:Enzyme Inhibitors; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008875:Middle Aged; D009135:Muscular Diseases; D009173:Mycophenolic Acid; D009336:Necrosis; D011241:Prednisone; D018271:Signal Recognition Particle", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "33608334", "pubdate": "2021-02-19", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "26192196;23274022;30820385;28473041;31109639;26424665;24497174;27147697", "title": "SRP-positive necrotising myopathy: takes more than just the muscles.", "title_normalized": "srp positive necrotising myopathy takes more than just the muscles" }

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{ "abstract": "Coronavirus disease 2019 (COVID-19) has spread to more than 70 countries around the world since its discovery in 2019. More than 2.5 million cases and more than 130,000 deaths have been reported in the United States alone. The common radiological presentation in this disease is noted to be the presence of ground glass opacities and/or consolidations. We report a case of 40-year-old male admitted for COVID-19 and rapidly deteriorated into severe acute respiratory distress syndrome requiring intubation and mechanical ventilation with no prior history of smoking or lung disease. The patient had normal imaging 3 days prior to admission to the hospital and rapidly developed a large pneumatocele with pneumothorax requiring chest tube placement that later on resolved. This is a unique radiologic finding in COVID-19 and likely related to severe inflammation secondary to SARS-CoV-2 infection.", "affiliations": "Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States.;Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, United States.;Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States.;Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States.", "authors": "Sanivarapu|Raghavendra R|RR|;Farraj|Kristen|K|;Sayedy|Najia|N|;Anjum|Fatima|F|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2020.101303", "fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(20)30517-7\n10.1016/j.rmcr.2020.101303\n101303\nCase Report\nRapidly developing large pneumatocele and spontaneous pneumothorax in SARS-CoV-2 infection\nSanivarapu Raghavendra R. MD [email protected]\na∗\nFarraj Kristen MD b\nSayedy Najia MD a\nAnjum Fatima MD a\na Department of Pulmonary & Critical Care Medicine, Nassau University Medical Center, East Meadow, NY, United States\nb Department of Internal Medicine, Nassau University Medical Center, East Meadow, NY, United States\n∗ Corresponding author. [email protected]\n02 12 2020\n2020\n02 12 2020\n31 10130317 9 2020\n18 11 2020\n19 11 2020\n© 2020 The Author(s)\n2020\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nCoronavirus disease 2019 (COVID-19) has spread to more than 70 countries around the world since its discovery in 2019. More than 2.5 million cases and more than 130,000 deaths have been reported in the United States alone. The common radiological presentation in this disease is noted to be the presence of ground glass opacities and/or consolidations. We report a case of 40-year-old male admitted for COVID-19 and rapidly deteriorated into severe acute respiratory distress syndrome requiring intubation and mechanical ventilation with no prior history of smoking or lung disease. The patient had normal imaging 3 days prior to admission to the hospital and rapidly developed a large pneumatocele with pneumothorax requiring chest tube placement that later on resolved. This is a unique radiologic finding in COVID-19 and likely related to severe inflammation secondary to SARS-CoV-2 infection.\n\nKeywords\n\nSARS-CoV-2\nCOVID-19\nPneumatocele\nPneumothorax\nARDS\n==== Body\n1 Background\n\nThe clinical syndrome caused by novel corona virus is termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) and the disease is called as coronavirus disease-19 (COVID-19) [1]. The radiographic findings of COVID-19 patients studied in 69 patients showed about 31% presenting with normal chest x-ray and rest presenting with consolidations or ground glass opacities (GGO) [2]. A systematic review by Bao et al. showed the CT-findings in COVID-19 can present as GGO (83%), GGO with consolidation (58%), pleural thickening (52%), interlobular septal thickening (48%), and air bronchograms (46%) [3]. A retrospective analysis of CT-findings in COVID-19 patients from China by Wu et al. reported presence of pneumatocele in only two cases; however no images are available [4]. Here we present the first case of SARS-CoV-2 infection causing pneumatocele formation and spontaneous pneumothorax in the USA.\n\n1.1 Case presentation\n\nA 40-year-old male with no medical history presented to the emergency room in April of 2020, during the peak of COVID-19 infection in NY with shortness of breath, dry cough, and body aches for 2 weeks duration. On admission, he was hemodynamically stable and afebrile. His chest X-ray showed diffuse reticular markings and bilateral mid-lung field airspace opacities concerning for atypical multifocal pneumonia (Fig. 1). He tested positive for SARS-CoV-2 RNA. He was discharged a day later on hydroxychloroquine. Three days post discharge he got readmitted with acute onset shortness of breath and right-sided chest pain which worsened with inspiration. His vitals were blood pressure: 125/74 mmHg, heart rate: 160 bpm, and was tachypneic at 35 breaths per minute. On physical examination, the patient was in respiratory distress with shallow respirations with decreased breath sounds in bilateral lower lung fields.Fig. 1 Chest X-ray on first admission showing diffuse reticular markings with bilateral airspace opacities.\n\nFig. 1\n\nA repeat chest x-ray showed moderate to large sized right-sided pneumothorax with right middle lobe pneumatocele and worsening bilateral airspace opacities (Fig. 2). A right-sided pig tail catheter was placed. His condition worsened requiring intubation and mechanical ventilation. A CT-thorax was performed showing multifocal bilateral ground-glass opacities with bilateral lower lobe consolidations and a 7.3 × 6.6 cm pneumatocele is noted in mid right posterior hemi thorax (Fig. 3). His hospital course was complicated with acute respiratory distress syndrome requiring proning. The patient received azithromycin, hydroxychloroquine, tocilizumab, steroids, and convalescent plasma as part of COVID-19 treatment.Fig. 2 Chest X-ray on second admission showing moderate to large sized right sided pneumothorax with right middle lobe pneumatocele and worsening bilateral airspace opacities (on left) and expanded lung post pig tail catheter placement (on right).\n\nFig. 2\n\nFig. 3 CT thorax showing multi focal bilateral ground-glass opacities and a 7.3 × 6.6 cm pneumatocele in mid right posterior hemi thorax in axial view (on left) and coronal view (on right).\n\nFig. 3\n\n1.2 Outcome & follow-up\n\nThe patient eventually was transitioned to tracheostomy after prolonged intubation. His repeat chest x-ray 2 months later showed near complete resolution of pneumatocele (Fig. 4). He was finally decannulated and discharged home.Fig. 4 Chest X-ray 3 month from admission showing near complete resolution of pneumatocele.\n\nFig. 4\n\n2 Discussion\n\nSARS-CoV-2 infection is known to cause a cytokine storm causing intense inflammatory reaction [5]. The most common radiological findings in COVID-19 are the presence of ground glass opacities. Pneumatoceles are air-filled, thin-walled cystic lesions in lung that commonly develop after a severe infection like empyema [6]. The common noninfectious etiologies include trauma, positive pressure ventilation and hydrocarbon ingestion. The inflammatory reaction causes obstruction and dilation of bronchi which ruptures causing air-filled cysts [7]. The pneumatocele in some instance can dissect through the pleural membrane and cause pneumothorax [8]. Imaging findings of thin-walled cyst on chest X-ray usually appear 5–6 days after infectious process. CT scan is usually performed and helps to differentiate an abscess. The imaging findings in COVID-19 pneumonia rarely showed the presence of pneumatocele. The treatment is usually focused at controlling the infection, in rare cases of tension pneumatocele a percutaneous drainage is performed [9]. In our case the pneumatocele resorbed once the inflammation subsided and did not require any surgical intervention.\n\nDeclaration of competing interest\n\nAre there any relevant conflicts of interest? NO.\n\nRelevant financial activities outside submitted work: None.\n\nNo other relationships/conditions/circumstances that present a potential conflict of interest.\n\nAll authors read the manuscript and approved for submission.\n==== Refs\nReferences\n\n1 World Health Organization Director-General's remarks at the media briefing on 2019-nCoV on 11 February https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 2020\n2 Wong H.Y.F. Lam H.Y.S. Fong A.H. Frequency and distribution of chest radiographic findings in COVID-19 positive patients [published online ahead of print, 2019 Mar 27] Radiology 2019 201160 10.1148/radiol.2020201160\n3 Bao C. Liu X. Zhang H. Li Y. Liu J. Coronavirus disease 2019 (COVID-19) CT findings: a systematic review and meta-analysis J. Am. Coll. Radiol. 17 6 2020 701 709 10.1016/j.jacr.2020.03.006 32283052\n4 Wu J. Feng L.C. Xian X.Y. [Novel coronavirus pneumonia (COVID-19) CT distribution and sign features]. Zhonghua jie he he hu xi za zhi = Zhonghua Jiehe he Huxi Zazhi Chinese Journal of Tuberculosis and Respiratory Diseases 43 4 2020 Apr 321 326 10.3760/cma.j.cn112147-20200217-00106 32125131\n5 Huang C. Wang Y. Li X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China [published correction appears in Lancet. 2020 Jan 30;:] Lancet 395 10223 2020 497 506 10.1016/S0140-6736(20)30183-5 31986264\n6 Kunyoshi V. Cataneo D.C. Cataneo A.J. Complicated pneumonias with empyema and/or pneumatocele in children Pediatr. Surg. Int. 22 2 2006 186 190 10.1007/s00383-005-1620-5 16362309\n7 Boisset G.F. Subpleural emphysema complicating staphylococcal and other pneumonias J. Pediatr. 81 2 1972 Aug 259 266 4537790\n8 Amitai I. Mogle P. Godfrey S. Aviad I. Pneumatocele in infants and children. Report of 12 cases Clin. Pediatr. 22 6 1983 420 422 10.1177/000992288302200605\n9 Zuhdi M.K. Spear R.M. Worthen H.M. Peterson B.M. Percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children Crit. Care Med. 24 2 1996 Feb 330 333 8605809\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "31()", "journal": "Respiratory medicine case reports", "keywords": "ARDS; COVID-19; Pneumatocele; Pneumothorax; SARS-CoV-2", "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "101303", "pmc": null, "pmid": "33294361", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "4537790;8605809;16362309;31986264;6839622;32125131;32283052", "title": "Rapidly developing large pneumatocele and spontaneous pneumothorax in SARS-CoV-2 infection.", "title_normalized": "rapidly developing large pneumatocele and spontaneous pneumothorax in sars cov 2 infection" }

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{ "abstract": "Human immunodeficiency virus-infected patients are at increased risk of drug reactions because of immune dysregulation and multiple drug intake. Lichenoid drug reactions to isoniazid have been reported previously in the literature. However, for lichenoid drug reaction to isoniazid to be so extensive to present as exfoliative dermatitis is rare. We report here a rare case of lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome.", "affiliations": "Department of Dermatology and STD, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India [email protected].;Department of Dermatology and STD, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India.;Department of Pathology, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India.", "authors": "Thakur|B K|BK|;Verma|S|S|;Mishra|J|J|", "chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid", "country": "England", "delete": false, "doi": "10.1177/0956462414543123", "fulltext": null, "fulltext_license": null, "issn_linking": "0956-4624", "issue": "26(7)", "journal": "International journal of STD & AIDS", "keywords": "AIDS; HIV; adverse drug reaction; antibiotics; antiretroviral therapy; drug rash; exfoliative dermatitis; isoniazid; lichenoid", "medline_ta": "Int J STD AIDS", "mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D000995:Antitubercular Agents; D003873:Dermatitis, Exfoliative; D003875:Drug Eruptions; D015658:HIV Infections; D006801:Humans; D007538:Isoniazid; D017512:Lichenoid Eruptions; D008297:Male; D010328:Patch Tests; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary", "nlm_unique_id": "9007917", "other_id": null, "pages": "512-5", "pmc": null, "pmid": "25013221", "pubdate": "2015-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome.", "title_normalized": "lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome" }

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null, "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, 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"drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080521", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": 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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lichenoid keratosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "4" } ], "summary": null }, "primarysource": { "literaturereference": "THAKUR BK, VERMA S, MISHRA J. LICHENOID DRUG REACTION TO ISONIAZID PRESENTING AS EXFOLIATIVE DERMATITIS IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME. 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INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LAMIVUDINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "RIFAMPIN" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "RIFAMPICIN" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EFAVIRENZ" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "HIV INFECTION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EFAVIRENZ" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISONIAZID" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "008662", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PULMONARY TUBERCULOSIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ISONIAZID." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Papule", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Lichenoid keratosis", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Dermatitis exfoliative", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Exfoliative rash", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Skin exfoliation", "reactionmeddraversionpt": "18.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "THAKUR BK, VERMA S, MISHRA J. LICHENOID DRUG REACTION TO ISONIAZID PRESENTING AS EXFOLIATIVE DERMATITIS IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME. INT-J-STD-AIDS. 2015;26(7):512-15", "literaturereference_normalized": "lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome", "qualification": "3", "reportercountry": "IN" }, "primarysourcecountry": "IN", "receiptdate": "20150714", "receivedate": "20150714", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11271273, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "Propranolol emerged as the first-line therapy for infantile hemangioma (IH). Determinants of interindividual variation in drug response and predictors of rebound growth after drug discontinuation are yet to be firmly established. We aimed to evaluate the outcomes of a relatively large cohort of patients with IH treated by propranolol and to determine predictors of (a) an excellent response to treatment (≥90 improvement) and (b) of rebound growth after drug cessation. A retrospective cohort study was conducted to follow all patients with IH receiving systemic propranolol in a referral center-based specialized clinic. Multivariate logistic regression analysis was performed to identify predictors of excellent response and rebound growth. The study included 206 patients who completed oral propranolol treatment. The mean (SD) age in which the drug was initiated was 4.8 (3.1) months. The average improvement rate was estimated at 85.5 (13.8)%. Initiation of propranolol at the age of 0 to 3 (adjusted odds ratio [OR], 3.43; 95% confidence interval [CI], 1.25-9.40; P = .016) and 3 to 6 (adjusted OR, 3.71; 95% CI, 1.50-9.19; P = .005) months was associated with an increased likelihood of excellent response. Twenty-four (11.7%) patients developed rebound growth following cessation of propranolol. No significant predictors of rebound were identified in the multivariate analysis. Eleven (5.3%) patients experienced mild adverse events, which necessitated drug discontinuation in only two (1.0%) patients. Propranolol is highly effective and safe based on the real-life experience of a referral center for IH. The current study supports early initiation of propranolol.", "affiliations": "Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.;Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.;Department of Dermatology, Rambam Health Care Campus, Haifa, Israel.", "authors": "Pam|Nadav|N|;Kridin|Khalaf|K|0000-0001-9971-9151;Khamaysi|Ziad|Z|", "chemical_list": "D000319:Adrenergic beta-Antagonists; D011433:Propranolol", "country": "United States", "delete": false, "doi": "10.1111/dth.14936", "fulltext": null, "fulltext_license": null, "issn_linking": "1396-0296", "issue": "34(3)", "journal": "Dermatologic therapy", "keywords": "infantile hemangioma; late infancy; post proliferative; propranolol", "medline_ta": "Dermatol Ther", "mesh_terms": "D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists; D015331:Cohort Studies; D006391:Hemangioma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011433:Propranolol; D012017:Referral and Consultation; D012189:Retrospective Studies; D012878:Skin Neoplasms; D016896:Treatment Outcome", "nlm_unique_id": "9700070", "other_id": null, "pages": "e14936", "pmc": null, "pmid": "33704861", "pubdate": "2021-05", "publication_types": "D016428:Journal Article", "references": null, "title": "Propranolol for infantile hemangioma: Evaluating efficacy and predictors of response and rebound growth.", "title_normalized": "propranolol for infantile hemangioma evaluating efficacy and predictors of response and rebound growth" }

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{ "abstract": "BACKGROUND\nTamoxifen is often used as antihormonal therapy in patients with breast cancer. However, it has various side effects, of which pneumonia is a rare occurrence.\n\n\nMETHODS\nA 46-year-old female patient with breast cancer underwent surgical treatment. Tamoxifen was administered as adjuvant therapy on post-operative day 14; 2 days after administration of tamoxifen, the patient developed high fever of more than 39 °C and cough with dyspnea. Based on chest computed tomography findings of ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs, eosinophilic pneumonia was suspected. Tamoxifen was discontinued and methylprednisolone injection was administered; the patient showed improvement of symptoms and radiographic findings.\n\n\nCONCLUSIONS\nTamoxifen was suspected as the cause of eosinophilic pneumonia since the patient developed high-grade fever at the time of tamoxifen administration, which subsided after discontinuation of the treatment. Other factors considered as the cause of pneumonia were examined, but all showed negative results. In order to confirm tamoxifen as the cause of pneumonia, tamoxifen treatment was restarted at follow-up (post-operative day 47); however, after 1 month, regular administration was not possible due to the development of itching symptom and difficulty in obtaining the patient's cooperation.\n\n\nCONCLUSIONS\nThe study highlights that if the patient on tamoxifen develops high fever and cough with dyspnea at 2-3days after the first administration, tamoxifen-induced pneumonia should be suspected.", "affiliations": "Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea.;Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea. Electronic address: [email protected].", "authors": "Kwon|Eiyoung|E|;Kim|Mijin|M|;Choi|Eunhye|E|;Park|Youngsam|Y|;Kim|Cheolseung|C|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.ijscr.2019.02.026", "fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(19)30086-010.1016/j.ijscr.2019.02.026ArticleTamoxifen-induced acute eosinophilic pneumonia in a breast cancer patient Kwon Eiyoung Kim Mijin Choi Eunhye Park Youngsam Kim Cheolseung [email protected]⁎Department of Surgery, Presbyterian Medical Center, Jeon-ju, Republic of Korea⁎ Corresponding author at: Department of Surgery, Presbyterian Medical Center, 365 Seowon-ro, Wansan-gu, Jeon-ju 54987, Republic of Korea. [email protected] 2 2019 2019 27 2 2019 60 186 190 13 12 2018 8 2 2019 13 2 2019 © 2019 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2019This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• If a patient who is taking tamoxifen coughs, be aware of the possibility of pneumonia caused by Tamoxifen.\n\n• Tamoxifen is one of the cause of drug-induced lung injury.\n\n\n\nIntroduction\nTamoxifen is often used as antihormonal therapy in patients with breast cancer. However, it has various side effects, of which pneumonia is a rare occurrence.\n\nPresentation of case\nA 46-year-old female patient with breast cancer underwent surgical treatment. Tamoxifen was administered as adjuvant therapy on post-operative day 14; 2 days after administration of tamoxifen, the patient developed high fever of more than 39 °C and cough with dyspnea. Based on chest computed tomography findings of ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs, eosinophilic pneumonia was suspected. Tamoxifen was discontinued and methylprednisolone injection was administered; the patient showed improvement of symptoms and radiographic findings.\n\nDiscussion\nTamoxifen was suspected as the cause of eosinophilic pneumonia since the patient developed high-grade fever at the time of tamoxifen administration, which subsided after discontinuation of the treatment. Other factors considered as the cause of pneumonia were examined, but all showed negative results. In order to confirm tamoxifen as the cause of pneumonia, tamoxifen treatment was restarted at follow-up (post-operative day 47); however, after 1 month, regular administration was not possible due to the development of itching symptom and difficulty in obtaining the patient’s cooperation.\n\nConclusion\nThe study highlights that if the patient on tamoxifen develops high fever and cough with dyspnea at 2–3days after the first administration, tamoxifen-induced pneumonia should be suspected.\n\nKeywords\nBreast cancerTamoxifenEosinophilic pneumonia\n==== Body\n1 Introduction\nThe incidence of breast cancer in Korea is increasing, and the incidence of estrogen receptor (ER) positive breast cancer increased from 58.2% in 2002 to 73.7% in 2015 [1]. Tamoxifen is a selective estrogen receptor modulator that can be used to increase the treatment effect in hormone receptor (HR) positive breast cancer diagnosed prior to menopause and metastatic or recurrent HR positive breast cancer [1]. Various side effects of tamoxifen such as weight gain, sexual dysfunction, hot flashes, neurocognitive deficits, thrombogenic events, and ocular events have been reported [2]. However, tamoxifen-induced pneumonia is a very rare side effect [3].\n\nHerein, we present a case of acute eosinophilic pneumonia after tamoxifen administration in a patient with ER positive breast cancer patient who underwent mastectomy. This work is reported in line with the SCARE criteria [13].\n\n2 Presentation of case\nA 46-year-old female patient presented to our outpatient clinic for further evaluation of a mass in the left breast that was detected incidentally at a routine health screen in February 2018. She was transferred from the intensive care unit at another center where she was admitted for the treatment of exacerbated epilepsy. Anamnesis revealed a history of mental retardation and medication for epilepsy, but no history of allergy, smoking, and surgery; family history indicated that her sister had received treatment for breast cancer. Ultrasound-guided core needle biopsy performed at our center confirmed a diagnosis of invasive ductal carcinoma. Positron emission tomography–computed tomography and breast ultrasound showed the absence of axillary lymph node involvement, and breast magnetic resonance imaging could not be performed due to the patient’s lack of cooperation. Skin-sparing mastectomy and reconstruction with silicone was performed on April 11, 2018. Histology indicated invasive ductal carcinoma with a mass of 26 × 15 × 15 mm and metastasis in 9 of 10 axillary lymph nodes. The cancer stage was IIIA with T2N2aM0, with ER 8(5 + 3), PR 8(5 + 3), c-erbB2(1+/3), and KI-67(10%).\n\nTreatment with tamoxifen (20 mg/daily) was started on post-operative day 14. On post-operative day 16 (day 3 of tamoxifen treatment), she showed no symptoms other than fever of 39.1 °C. The results of investigation to determine the cause of fever were normal (WBC 6.6 × 103/uL, eosinophil 0.6%) except for mild elevation in the C-reactive protein (CRP) level of 1.13 mg/dL. Culture test for wound infection, using 7 mL of fluid obtained under ultrasound guidance was negative.\n\nSince wound infection could not be completely ruled out as a cause of fever, rifampin (150 mg twice daily) was administered. However, there was persistence of fever of above 39 °C on post-operative day 19 (day 6 of tamoxifen treatment), and absence of redness or pain at the wound site. To rule out antibiotic-related fever, the antibiotic regimen was switched to combined piperacillin and tazobactam, and vancomycin.\n\nOn post-operative day 20 (day 7 of tamoxifen treatment), the patient had cough with profuse sputum production and fever of 40.5 °C. Chest radiograph showed soft haziness at the right middle lung field and blunting of the costophrenic angle with subsegmental atelectasis at the left lower lung field [Fig. 1]. Complete blood count showed a marked increase in the level of eosinophils from 0.2% on day 5 to 3.7% on day 7 of tamoxifen treatment, but WBC was not elevated at 4.8 × 103/uL and the CRP level was increased to 7.94 mg/dL.Fig. 1 Chest x-ray on post-operative Day 20. Soft haziness in the right middle lung field and costophrenic angle blunting with subsegmental atelectasis in left lower lung field are observed.\n\nFig. 1\n\nOn postoperative day 21(day 8 of tamoxifen treatment), chest computed tomography(CT) was performed, which showed ground glass opacity, interlobular septal thickening, and mild pleural effusion in both lungs. Based on these findings, the patient was diagnosed with suspicious eosinophilic pneumonia [Fig. 2]. She complained of severe dyspnea and showed unstable oxygen saturation of 88% and was transferred to the intensive care unit for close monitoring. The laboratory investigations at the time showed WBC 5.2 × 103/uL, eosinophil 3.6%, and a further increase in CRP level to 8.63 mg/dL. Concomitant blood culture was negative.Fig. 2 Chest CT on post-operative Day 21. Ground-glass opacification and interlobular septal thickening, and mild pleural effusion in both lungs.\n\nFig. 2\n\nTamoxifen, administered from post-operative day 14, was considered as the probable cause of eosinophilic pneumonia, and discontinued on post-operative day 21 after chest CT was performed. Methylprednisolone (30 mg twice daily) was administered intravenously and tapered by 10 mg every 3 days. Oral methylprednisolone (24 mg daily) was started from post-operative day 29, and reduced dose of the drug (12 mg daily) was administered from post-operative day 33. After the discontinuation of tamoxifen, there was less fever and recovery to normal temperature at day 3 post-discontinuation of tamoxifen. Oxygen saturation was recovered to normal level, and dyspnea was improved. Chest radiographs acquired daily after discontinuation of tamoxifen showed a decrease in haziness, and sputum and cough were reduced.\n\nMycoplasma pneumonia immunoglobulin M (IgM), Chlamydia pneumonia IgM, pneumonia urinary antigen, Gram stain, and polymerase chain reaction for Mycoplasma tuberculosis performed in the intensive care unit on post-operative day 22 demonstrated negative results. On postoperative day 33 (day 12 post-discontinuation of tamoxifen), the patient showed improvement of symptoms and was discharged.\n\n3 Discussion\nEosinophilic lung disease refers to a condition with an increase in eosinophil count in the peripheral blood or lung tissue [[4], [5], [6]]. Allen and Davis classified eosinophilic pneumonia as an increase in eosinophils in the peripheral blood accompanied by lung infiltration on chest radiography, or eosinophil infiltration through lung histology without an increase in eosinophils in the peripheral blood, or alveolar lavage fluid [4,5]. Eosinophilic lung diseases include simple pulmonary eosinophilia, chronic eosinophilic pneumonia, acute eosinophilic pneumonia, idiopathic hypereosinophilic syndrome, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, parasites, and drugs [4,5]. Acute eosinophilic pneumonia can be defined as fever and respiratory distress with myalgia, chest pain, and hypoxia of 1–5 days’ duration that completely resolve without recurrence spontaneously or after the administration of an adrenal cortex hormone in patient without underlying respiratory disease [4,5].\n\nAcute eosinophilic pneumonia shows the following test results: minute interstitial lung infiltration on the chest radiograph that progresses rapidly within 2 days to mixed alveolar and interstitial infiltration, bilateral ground glass opacity and diffuse, reticular densities on CT [6,7]. Acute eosinophilic pneumonia can be caused by drugs. Drugs known to cause acute eosinophilic pneumonia are listed in Table 1 [5,6].Table 1 Drugs causing eosinophilic lung disease.\n\nTable 1Ampicillin\tMethylphenidate\t\nBeclomethasone dipropionate\tMinocycline\t\nBleomycin\tNaproxen\t\nCarbamazepine\tNickel\t\nChlorpromazine\tNitrofurantoin\t\nClofibrate\tPara-aminosalicylic acid\t\nCocaine(inhaled)\tPenicillin\t\nCromolyn(inhaled)\tPentamidine(inhaled)\t\nDesipramine\tPhenytoin\t\nDiclofenac\tPyrimethamine\t\nFebarbamate\tRapeseed oil\t\nGlafenine\tSulfadimethoxime\t\nGM-CSF\tSulfasalazine\t\nIbuprofen\tSulindac\t\nInterleukin 2&3\tTamoxifen\t\nIodinated contrast media\tTetracycline\t\nl-Tryptophan\tTolazamide\t\nMephenesin carbamate\tTolfenamic acid\t\nMethotrexate\tVaginal sulfonamide cream\t\nAdapted from Allen and Davis [5].\n\nTamoxifen, often used as antihormonal therapy in the treatment of breast cancer, can cause various side effects such as weight gain, sexual dysfunction/loss of libido, hot flashes, neurocognitive deficits, thromboembolic events, ocular events, mood alterations, depression, GI disturbance, bone pain, leg cramps, and insomnia [2]. Pneumonia is a rare side effect of tamoxifen and there are only a few reports of pneumonia in patients who were started on tamoxifen after surgery for breast cancer [[7], [8], [9], [10], [11]].\n\nIn our case, tamoxifen was considered as the cause of eosinophilic pneumonia due to the association between fever onset and time of first tamoxifen administration. The patient developed high-grade fever of over 39 °C from day 3 of tamoxifen administration, which subsided after the discontinuation of tamoxifen [Fig. 3].Fig. 3 Patient’s body temperature and eosinophil count by tamoxifen administration.\n\nFig. 3\n\nTo confirm tamoxifen as the cause of a patient’s pneumonia, tamoxifen should be restarted under patient monitoring for pneumonia recurrence as described in Etori et al. [3]. Previous case reports of tamoxifen-induced pneumonia according to the symptoms, symptom onset-time from medication, and restarting or not are summarized in Table 2.Table 2 Side effects of tamoxifen-induced pneumonia in previous case report.\n\nTable 2\tSymptom onset at post-medication time point\tSymptoms\tRestarting\tSymptoms after restarting\t\nAhmed et al. [10]\t1week\tCough\tNo\tNot reported\t\n\t\tdyspnea\t\t\t\n\t\tintermittent fever\t\t\t\n\t\tmechanical ventilation\t\t\t\nShiiki et al. [12]\t2day\tCough\tYes\tCough\t\n\t\tdyspnea\t\tdyspnea\t\nEtori et al. [3]\t3month\tMild cough\tYes\tCough\t\n\t\t\t\tdyspnea on exertion\t\nKwon et al.a\t3day\tCough\tYes\tItching sense\t\n\t\tdyspnea\t\t\t\n\t\tFever (40.5 °C)\t\t\t\nAll cases had initial and restarting dose of tamoxifen of 20 mg daily.\n\na Current study.\n\n\n\nIn this case, the patient was restarted on tamoxifen 20 mg once daily from May 28, 2018 to confirm tamoxifen as the cause of pneumonia and as choice treatment based on the patient’s age, histology, and pre-menopausal status. Since the patient experienced tamoxifen-related adverse events, alternative therapy with an aromatase inhibitor was considered. Unlike tamoxifen, aromatase inhibitors are only administered after menopause, hence bilateral salpingooophorectomy(BSO) was required in our patient to induce menopause. The option of BSO and aromatase inhibitor was discussed with the patient’s caregiver, and declined based on the concern that the patient’s mental status would prevent her from accepting the consequences of surgery and increase her feelings of loss. Concurrent silicone implantation performed at the time of mastectomy was also due to the caregiver’s concern for the patient’s feeling of loss, though the patient was foreseen to require radiotherapy due to suspicion of axillary lymph node metastasis. However, since the time to natural menopause was too long in our patient, she was administered tamoxifen with methylprednisolone (4 mg twice daily) from May 18, 2018. However, after 1 months’ treatment, regular administration was not possible due to the patients’ symptom of itching and lack of cooperation.\n\n4 Conclusion\nThe current study highlights that in patients undergoing treatment with tamoxifen, if there is development of high-grade fever at 2–3 days after first administration and chest CT shows ground-glass opacification, interlobular septal thickening, and mild pleural effusion, eosinophilic pneumonia due to tamoxifen should be suspected, and tamoxifen should be discontinued. Discontinuation of tamoxifen alone may improve the patient’s symptoms. However, for patients with advanced symptoms, steroid therapy may help to alleviate the symptoms.\n\nConflicts of interest\nThe authors declare that they have no competing interests.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\nIn our institute, ethical approval is exempted, depend on acquired patient consent.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAuthor’s contribution\nKwon EY: writing paper, data collection, table making\n\nKim MJ : data analysis, figure making\n\nChoi EH : data collection, manuscript review\n\nPark YS : manuscript review\n\nKim CS : study design, manuscript review\n\nRegistration of research studies\nWe don’t need to register this work.\n\nGuarantor\nCheolseung Kim.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n==== Refs\nReferences\n1 Korean Breast Cancer Society [Internet], Seoul: Korean Breast Cancer Facts and Figures; c2017 [Cited 10 October 2018]. Available from : http://kbcs.or.kr/journal/file/2017_Breast_Cancer_Facts_and_Figures.pdf.\n2 Pemmaraju N. Munsell M.F. Hortobagyi G.N. Giordano S.H. Retrospective review of male breast cancer patients: analysis of tamoxifen-related side-effects Ann. Oncol. 23 June (6) 2012 1471 1474 22085764 \n3 Etori S. Nakano R. Kamada H. Hosokawa K. Takeda S. Fukuhara M. Tamoxifen induced lung injury Intern. Med. 56 November (21) 2017 2903 2906 28943550 \n4 Choi D.C. Eosinophilic lung disease : diagnosis & treatment Korean J. Intern. Med. 76 3 2009 274 281 \n5 Allen J.N. Davis W.B. Eosinophilic lung disease Am. J. Respir. Crit. Care Med. 150 November (5) 1994 1423 1438 7952571 \n6 Kim Y.K. Lee K.S. Choi D.C. Primack S.L. Im J.G. The spectrum of eosinophilic lung disease J. Comput. Assist. Tomogr. 21 November (6) 1997 920 930 9386285 \n7 Cheon J.E. Lee K.S. Jung G.S. Chung M.H. Cho Y.D. Acute eosinophilic pneumonia: radiographic and CT findings in six patients AJR Am. J. Roentgenol. 167 November (5) 1996 1195 1199 8911179 \n8 Camus P. Fanton A. Bonniaud P. Camus C. Foucher P. Interstitial lung disease induced by drugs and radiation Respiration 71 July (4) 2004 301 326 15316202 \n9 Bentzen S.M. Skoczylas J.Z. Overgaard M. Overgaard J. Radiotherapy-related lung fibrosis enhanced by tamoxifen J. Natl. Cancer Inst. 88 July (13) 1996 918 922 8656444 \n10 Ahmed S. Shahid R.K. Acute interstitial pneumonitis following adjuvant tamoxifen therapy J. Clin. Oncol. 27 15 2009 e11637 \n11 Katayama N. Sato S. Katsui K. Takemoto M. Yoshoida A. Morito T. Analysis of factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia syndrome after breastconserving therapy Int. J. Radiat. Oncol. Biol. Phys. 73 March (4) 2009 1049 1054 18755559 \n12 Shiiki S. A case of drug-induced pneumonia due to tamoxifen Nihon Rinsho Geka Gakkai Zasshi (J. Jpn. Surg. Assoc.) 64 April (12) 2003 3040 3043 \n13 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus surgical case report (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279\n\n", "fulltext_license": "CC BY", "issn_linking": "2210-2612", "issue": "60()", "journal": "International journal of surgery case reports", "keywords": "Breast cancer; Eosinophilic pneumonia; Tamoxifen", "medline_ta": "Int J Surg Case Rep", "mesh_terms": null, "nlm_unique_id": "101529872", "other_id": null, "pages": "186-190", "pmc": null, "pmid": "31229774", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "8656444;30342279;28943550;18755559;9386285;7952571;8911179;15316202;22085764", "title": "Tamoxifen-induced acute eosinophilic pneumonia in a breast cancer patient.", "title_normalized": "tamoxifen induced acute eosinophilic pneumonia in a breast cancer patient" }

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{ "abstract": "OBJECTIVE\nCiprofloxacin is considered to be a safe and effective treatment for acute infectious colitis. However, this drug may cause drug-induced pancreatitis, albeit rarely.\n\n\nMETHODS\nFrom March 2007 to February 2012, we studied 227 patients who were hospitalized for infectious colitis at St. Mary's Hospital. All of the patients received ciprofloxacin therapy for the treatment of infectious colitis. We observed a few cases of rare adverse events, including ciprofloxacin-induced acute pancreatitis diagnosed based on the Naranjo algorithm.\n\n\nRESULTS\nDuring ciprofloxacin therapy, seven of 227 patients (3.1%) developed rare pancreatitis as defined by the Naranjo algorithm; pancreatic enzyme activity was sporadically elevated with ciprofloxacin use. After ciprofloxacin administration, the average interval until the development of pancreatitis was 5.5 days (range, 4 to 7 days). On abdominal computed tomography, pancreatic swelling and homogenous enhancement was noted in three of seven patients. Complicating acute pancreatitis was gradually but completely resolved after cessation of ciprofloxacin administration. The mean recovery time was 11.3 days (range, 8 to 15 days).\n\n\nCONCLUSIONS\nWe observed that ciprofloxacin-induced pancreatitis may occur with an incidence of approximately 3%. Ciprofloxacin-induced pancreatitis presents a short latency, suggesting an idiosyncratic hypersensitivity reaction. Practitioners should be aware that drug-induced pancreatitis can occur during ciprofloxacin therapy.", "affiliations": "Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.;Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.", "authors": "Sung|Hye Young|HY|;Kim|Jin Il|JI|;Lee|Hyun Jeong|HJ|;Cho|Hyung Jun|HJ|;Cheung|Dae Young|DY|;Kim|Sung Soo|SS|;Cho|Se Hyun|SH|;Kim|Jae Kwang|JK|", "chemical_list": "D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004952:Esters; D006146:Guanidines; C034532:camostat; D016670:Gabexate; D002939:Ciprofloxacin", "country": "Korea (South)", "delete": false, "doi": "10.5009/gnl.2014.8.3.265", "fulltext": "\n==== Front\nGut LiverGut LiverGNLGut and Liver1976-22832005-1212The Korean Society of Gastroenterology; the Korean Society of Gastrointestinal Endoscopy; the Korean Association for the Study of the Liver; the Korean Society of Neurogastroenterology and Motility; Korean Association for the Study of Intestinal Diseases; Korean College of Helicobacter and Upper Gastrointestinal Research; Korean Pancreatobiliary Association; Korean Society of Gastrointestinal Cancer 2482762210.5009/gnl.2014.8.3.265Original ArticleAlimentary TractAcute Pancreatitis Secondary to Ciprofloxacin Therapy in Patients with Infectious Colitis Sung Hye Young aKim Jin Il Lee Hyun Jeong Cho Hyung Jun Cheung Dae Young Kim Sung Soo Cho Se Hyun Kim Jae Kwang Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea.\nCorrespondence to: Jin Il Kim. Division of Gastroenterology, Department of Internal Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea College of Medicine, 10 63-ro, Yeongdeungpo-gu, Seoul 150-713, Korea. Tel: +82-2-3779-1519, Fax: +82-2-3779-1331, [email protected] affiliation: Department of Internal Medicine, Wonkwang University Sanbon Hospital, Gunpo, Korea.\n\n5 2014 24 12 2013 8 3 265 270 25 3 2013 03 6 2013 03 6 2013 Copyright © 2014 by the Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association for the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nCiprofloxacin is considered to be a safe and effective treatment for acute infectious colitis. However, this drug may cause drug-induced pancreatitis, albeit rarely.\n\nMethods\nFrom March 2007 to February 2012, we studied 227 patients who were hospitalized for infectious colitis at St. Mary's Hospital. All of the patients received ciprofloxacin therapy for the treatment of infectious colitis. We observed a few cases of rare adverse events, including ciprofloxacin-induced acute pancreatitis diagnosed based on the Naranjo algorithm.\n\nResults\nDuring ciprofloxacin therapy, seven of 227 patients (3.1%) developed rare pancreatitis as defined by the Naranjo algorithm; pancreatic enzyme activity was sporadically elevated with ciprofloxacin use. After ciprofloxacin administration, the average interval until the development of pancreatitis was 5.5 days (range, 4 to 7 days). On abdominal computed tomography, pancreatic swelling and homogenous enhancement was noted in three of seven patients. Complicating acute pancreatitis was gradually but completely resolved after cessation of ciprofloxacin administration. The mean recovery time was 11.3 days (range, 8 to 15 days).\n\nConclusions\nWe observed that ciprofloxacin-induced pancreatitis may occur with an incidence of approximately 3%. Ciprofloxacin-induced pancreatitis presents a short latency, suggesting an idiosyncratic hypersensitivity reaction. Practitioners should be aware that drug-induced pancreatitis can occur during ciprofloxacin therapy.\n\nAnti-bacterial agentsPancreatitisDrug toxicityInfectious colitis\n==== Body\nINTRODUCTION\nCiprofloxacin, a synthetic 4-quinolone derivative, is a widely used, broad-spectrum antibiotic.1 Generally, it is considered to be a safe and effective treatment of acute infectious colitis.2,3 Additionally, it is a widely used empirical therapy for travelers' diarrhea.4 However, ciprofloxacin can, in rare cases, cause drug-induced pancreatitis. Until now, there has only been one case report associated with ciprofloxacin in the literature.5 In March 2007, we observed ciprofloxacin-induced pancreatitis in a patient with infectious colitis during therapeutic use. Since 2007, we have been aware that drug-induced pancreatitis can occur during ciprofloxacin therapy. And we have continued monitoring chemical profiles during ciprofloxacin use in patients with infectious colitis. As a result, here we describe seven patients who developed acute pancreatitis after receiving ciprofloxacin to treat infectious colitis. The patients with infectious colitis were kept nil per os (NPO; keeping off ingestion) other than ciprofloxacin during treatment of infection colitis, so other drug effects can be excluded completely. As a result, we think that hospitalized patients with infectious colitis are a good cohort to discriminate side effects of ciprofloxacin. The study's aim was to identify the clinical features and natural course of drug-induced pancreatitis by ciprofloxacin during therapeutic use.\n\nMATERIALS AND METHODS\n1. Patients\nBetween March 2007 and February 2012, 227 patients were hospitalized for moderate to severe infectious colitis at St. Mary's Hospital, Seoul, Korea. Infectious colitis was diagnosed according to clinical history with colonoscopy finding. After admission, they were enrolled in the infectious colitis registry. At initial admission, all patients received ciprofloxacin therapy while keeping NPO for bowel rest. During ciprofloxacin therapy, rare adverse events suggesting drug-induced pancreatitis were recorded in a few patients. In these cases, we stopped ciprofloxacin and recorded their clinical features while administering conservative treatment. We excluded the patients who had acute pancreatitis at initial admission or who had gallstones or common bile stones from this registry.\n\n2. Clinical assessment and management in patients with infectious colitis\nThe patients visited our emergency department because of severe abdominal pain, diarrhea, and/or vomiting for several days. At initial admission, all patients were assessed via colonoscopy and blood chemical profiles such as hemoglobin, white blood cell, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase (γ-GTP), amylase, and lipase. Initially, abdominal computed tomography was performed to exclude vascular insufficiency or other diseases. After admission, patients were started on intravenous ciprofloxacin therapy (400 mg of intravenous ciprofloxacin two times daily for 3 days to 4 days). They were kept NPO for a bowel rest with parenteral nutritional support. If their abdominal pain and diarrhea were improved, they receive a soft diet and oral ciprofloxacin therapy (500 mg of oral ciprofloxacin two times daily for 3 days to 5 days). Chemical profiles were monitored regularly, once every 3 days. If an adverse event was recorded on chemical profiles during ciprofloxacin therapy, the therapy was ceased, and clinical feature were observed while conservative treatment was administered. All patients were monitored using the Naranjo algorithm for assessing probability of an adverse drug reaction.6\n\n3. Statistical analysis\nWe assessed whether initial demographic variables were associated with drug-induced pancreatitis by ciprofloxacin. All statistical analyses were performed using the SPSS version 12.0 (SPSS Inc., Chicago, IL, USA). Pearson chi-square test was used for comparison of the categorical variables. Statistical comparisons of the symptom score between the normal and abnormal test group was performed using an independent-samples t-test. For all tests, the significance level was established at a value of p<0.05.\n\n4. Ethical considerations\nThis study was approved by the Institutional Review Board (IRB) at the St. Mary's Hospital of The Catholic University of Korea College of Medicine (IRB number, SC11RISI0065). The study was carried out in accordance with the recommendations of the Declaration of Helsinki.\n\nRESULTS\n1. Demographic characteristics\nBetween March 2007 and February 2012, 227 patients were hospitalized and enrolled in an infectious colitis registry at St. Mary's Hospital (113 males and 114 females with a mean age of 50.5±21.8 years; range, 14 to 92 years). Mean hospital stay was 5.1±5.3 days. After admission, all patients received intravenous ciprofloxacin and nutritional support. Ciprofloxacin was a safe and effective drug for the treatment of infectious colitis in 220 of 227 (96.9%) patients. These patients successfully recovered from infectious colitis. However, seven of 227 patients (3.1%) experienced an adverse event (four males and three females with a mean age of 46.9±17.4 years; range, 24 to 71 years). Clinical characteristics are summarized at Table 1. The development of drug-induced pancreatitis had no relation with age or sex (p=0.33, p=0.36, respectively). The total duration of hospital stay was much longer in patients with drug-induced pancreatitis (5.1±5.3 vs 19.0±6.8, p=0.002).\n\n2. Diagnosis of drug-induced pancreatitis\nSeven patients showed abnormal pancreatic enzymes; amylase and lipase levels were elevated. Pancreatitis was diagnosed by the concurrence of at least two of the following findings:7 1) newly onset epigastric abdominal pain during admission; 2) elevated serum amylase and lipase levels at three times the upper level of the normal range; and 3) imaging evidence of pancreatic inflammation on radiologic study. In all seven cases described, other causes of pancreatitis were completely ruled out. None of the patients had significant alcohol use, nor were there family histories of pancreatitis. Cholelithiasis was not present, and triglyceride levels were normal. Furthermore, all the seven patients were not receiving any medications except for ciprofloxacin. They were kept NPO after admission with infectious colitis for bowel rest. Having probable pancreatitis was considered secondary to ciprofloxacin by the Naranjo algorithm.6 After ciprofloxacin administration, the average time interval until development of pancreatitis was 5.5 days (range, 4 to 7 days) (Table 1, Fig. 1). This short time frame of latency suggests a hypersensitivity reaction. Abdominal imaging was performed to exclude other possible causes of pancreatitis and to assess the severity of pancreatitis. Abdominal imaging did not show gallstones or gallbladder wall thickening in any of these patients. Pancreas swelling and homogenous enhancement were noted in three of seven patients (42.9%) (Figs 2 and 3).\n\n3. Treatment option for drug-induced pancreatitis and therapeutic efficiency after conservative care\nIn cases of adverse reactions, we immediately stopped ciprofloxacin administration. These patients were kept NPO with parenteral nutritional support. The treatment was targeted to pancreatic enzyme intravenous Gabexate Mesilate (Foy inj®, 200 mg/day; Dong-A ST Co., Seoul, Korea) was given for several days for acute pancreatitis. If the pancreatic enzyme was declined, treatment was changed to per oral Camostat Mesilate (Foipan®, 300 mg/day; Ilsung Co., Seoul, Korea) until the chemical profile returned to normal. Complicating acute pancreatitis was completely resolved gradually after the removal of ciprofloxacin. Mean recovery time for drug-induced pancreatitis was 11.3 days (range, 8 to 15 days) (Table 1, Fig. 1). The patients had no further abdominal pain episodes and remained stable for the remainder of the hospital day. All the patients have been doing well and denied any gastrointestinal symptoms. After discharge, an outpatient follow-up of blood chemistries demonstrated that the pancreatic enzyme stayed in the normal range.\n\nDISCUSSION\nCiprofloxacin is now widely used for a number of conditions and, in particular, is thought to be appropriate for early self-treatment of moderate to severe travelers' diarrhea in adults.4 Additionally, it is considered to be a safe and effective treatment for acute infectious colitis.2,3 Its lack of serious adverse effects has been an important factor in its use for what is usually a benign, self-limiting condition. Of 63,059 patients given oral ciprofloxacin, adverse effects occurred in 5.8% of patients, with 3.4% being of a gastrointestinal nature.7 The U.K. Medicine Control Agency received 635 reports of serious reactions per 1 million prescriptions of ciprofloxacin since the drug launch in 1987 through 1995.7 Common gastrointestinal side effects include diarrhea, Clostridium difficile enterocolitis, and abnormalities of liver biochemistry. The drug is generally associated with mild, reversible elevation of liver enzymes and bilirubin in approximately 2% to 3% of patients.2 In the pancreatic field, ciprofloxacin can be a useful tool as an empirical therapy in necrotizing pancreatitis to prevent secondary bacterial infection,8,9,10,11 because ciprofloxacin penetrates the human pancreas very well.12,13 However, ironically, it is claimed that the ciprofloxacin can, in rare cases, cause drug-induced pancreatitis. Until now, there has only been one case report associated with ciprofloxacin in the literature.5 Since March 2007, we observed seven cases of ciprofloxacin-induced pancreatitis in patients with infectious colitis during therapeutic use. In the prior report, the first episode of pain was undiagnosed, the clinical features were compatible with acute pancreatitis and on rechallenge with the same drug 18 months later, a similar episode of pain was confirmed as acute pancreatitis.5 Drug-induced pancreatitis is a rare cause of acute pancreatitis, accounting for approximately 2% to 5% of all cases of pancreatitis.2,3,4,14 In our hospital, total number of acute pancreatitis patients during the study was 251. Out of 251 acute pancreatitis patients reported during the study, 11 cases were found to be drug-induced, accounting for 4.4% (11/251). Possible drugs that may have caused the acute pancreatitis include ciprofloxacin which is suspected to be responsible for seven cases, augmentin for one, anticancer drug tacrolimus for one, anti-inflammatory caridase for one, diuretics for one. However, these speculations were not rechallenged by retrospective studies, and thus not confirmed.\n\nDrug-induced pancreatitis is not a negligible disease, but it is hard to diagnose. The most frequently implicated medications are metronidazole, tetracycline, azathioprine, furosemide, thiazide diuretics, angiotensin converting enzyme inhibitors, didanosine, aspirin, valproic acid, and codeine.1,15,16 The pathogenetic mechanism of drug-induced pancreatic injury remains unclear. The pathophysiology is likely an idiosyncratic hypersensitivity reaction that differs among the aforementioned medications depending on their chemical structures. A positive rechallenge is considered when the drug is stopped after a patient is found to have acute pancreatitis and after resolution of the pancreatitis, when the drug is restarted, acute pancreatitis develops again. However, due to the character of the disease and ethical considerations, rechallenge is usually unintended. Despite the lack of a rechallenge, a drug may also be strongly suspected if there is a consistent latency among the case reports between initiating the drug and the onset of acute pancreatitis. A consistent latency may be a sign that the drug has a common mechanism of action.17 In our cases, ciprofloxacin had a latency from drug administration to the development of acute pancreatitis of 4 to 7 days. This short time frame suggests a hypersensitivity reaction.17 In our observations, drug-induced pancreatitis caused by ciprofloxacin occurs at a low incidence of less than 3%. In most cases, the patient was not aware of typical symptoms of acute pancreatitis. The prognosis of drug-induced pancreatitis by ciprofloxacin is good. We had the patients fast and quit the drug suspected of inducing acute pancreatitis meanwhile continuously intravenous administrating gabexate mesilate. Elevated enzyme levels of amylase and lipase improved dramatically within a week after stopping drug administration. Ciprofloxacin is a broad spectrum antibiotic and is widely used to treat a number of conditions. However, the question of why ciprofloxacin-inducing pancreatitis is rarely observed remains. The answer to this is quite simple: routine screening of the chemical profile has been overlooked, despite the risk of an adverse event. It is important that practitioners be aware that this potential adverse effect may be occurring. We advise more caution in recommending this antibiotic for therapeutic use or empirical use. Close monitoring for an adverse event may be necessary. During ciprofloxacin use, regular screening of chemical profiles including amylase, lipase, liver enzyme, and creatinine is warranted. We consider it necessary that larger, prospective studies aimed at drug-induced pancreatitis caused by ciprofloxacin be conducted.\n\nWe described seven cases of ciprofloxacin-induced acute pancreatitis; the patients' pancreatic enzymes were at a normal range at initial admission. Pancreatic enzyme was sporadically elevated with ciprofloxacin use. We observed that ciprofloxacin-induced pancreatitis may occur with an incidence of approximately 3%. Drug-induced pancreatitis by ciprofloxacin displays a short latency, suggesting an idiosyncratic hypersensitivity reaction. If pancreatitis was detected early, the prognosis was very good, and all of our patients fully recovered within 3 weeks. Although the exact mechanism for this reaction remains a mystery, ciprofloxacin use may be considered a rare risk factor for the development of acute pancreatitis.\n\nACKNOWLEDGEMENTS\nWe appreciate Ka Young Kim from Cornell University who provided great support in data analysis and English proofreading as well as secretory assistance.\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Laboratory findings of drug-induced pancreatitis by ciprofloxacin. Among 227 patients who received ciprofloxacin, seven (3.1%) demonstrated an adverse reaction; the pancreatic enzyme levels spiked after ciprofloxacin injection. Ciprofloxacin has a latency of 4 to 7 days from the beginning of drug infusion to the development of acute pancreatitis. This short time frame suggests a hypersensitivity reaction.\n\nFig. 2 A 58-year-old Korean male presented to the emergency department of our institution with a 4-day history of lower abdominal pain with diarrhea and fever. He was diagnosed with infectious colitis. The results of an initial chemical profile were within the normal ranges. He received 400 mg of intravenous ciprofloxacin twice daily for 2 days while remaining nil per os for bowel rest. On the third day of treatment, he complained of severe abdominal pain. At this time, his serum amylase and lipase activities were elevated to 677 U/L (reference range, 45 to 160 IU/L) and 1,405 U/L (reference range, 42 to 168 mg/dL), respectively. (A, B) Abdominal computed tomography demonstrated swelling of the pancreatic head and peripancreatic inflammation. (A) Mild swelling of the duodenal second and third loops was noted. The patient was diagnosed with probable drug-induced pancreatitis secondary to ciprofloxacin using the Naranjo algorithm for assessing the probability of an adverse drug reaction.11\n\nFig. 3 A 71-year-old male presented to the emergency department of our institution with nausea, vomiting, and watery diarrhea over the previous 3 days. Amylase and lipase levels were normal at 130 U/L (reference range, 45 to 160 IU/L) and 51 U/L (reference range, 13 to 60 U/L), respectively. The patient was given 400 mg of intravenous ciprofloxacin twice daily for 2 days. Subsequently, he was given 500 mg of oral ciprofloxacin twice daily for 3 days. On the sixth day of treatment, follow-up laboratory parameters worsened; the serum amylase and lipase activities were elevated to 246 and 566 U/L, respectively. (A, B) Seven days after admission, abdominal computed tomography demonstrated swelling and homogeneous enhancement of the pancreas head and body. The patient was managed conservatively and had an uneventful recovery, and has remained well since discharge. He was diagnosed with probable drug-induced pancreatitis secondary to ciprofloxacin based on the Naranjo algorithm.11\n\nTable 1 Demography and Clinical Characteristics of Drug-Induced Pancreatitis Secondary to Ciprofloxacin Use\n\nM, male; F, female; IV, intravenous; PO, per oral.\n\n*Normal range of amylase, 45 to 160 IU/L; †Normal range of lipase, 13 to 60 U/L.\n==== Refs\n1 Vinklerová I Procházka M Procházka V Urbánek K Incidence, severity, and etiology of drug-induced acute pancreatitis Dig Dis Sci 2010 55 2977 2981 20499176 \n2 Wolfson JS Hooper DC Overview of fluoroquinolone safety Am J Med 1991 91 153S 161S 1767803 \n3 Ericsson CD Johnson PC Dupont HL Morgan DR Bitsura JA de la Cabada FJ Ciprofloxacin or trimethoprim-sulfamethoxazole as initial therapy for travelers' diarrhea: a placebo-controlled, randomized trial Ann Intern Med 1987 106 216 220 3541724 \n4 Nathwani D Wood MJ The management of travellers' diarrhoea J Antimicrob Chemother 1993 31 623 626 8335493 \n5 Mann S Thillainayagam A Is ciprofloxacin a new cause of acute pancreatitis? J Clin Gastroenterol 2000 31 336 11129278 \n6 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 245 7249508 \n7 Ball P Tillotson G Tolerability of fluoroquinolone antibiotics: past, present and future Drug Saf 1995 13 343 358 8652079 \n8 Cinar E Ateskan U Baysan A Is late antibiotic prophylaxis effective in the prevention of secondary pancreatic infection? Pancreatology 2003 3 383 388 14526147 \n9 Mithöfer K Fernández-del Castillo C Ferraro MJ Lewandrowski K Rattner DW Warshaw AL Antibiotic treatment improves survival in experimental acute necrotizing pancreatitis Gastroenterology 1996 110 232 240 8536862 \n10 Isenmann R Rünzi M Kron M Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial Gastroenterology 2004 126 997 1004 15057739 \n11 García-Barrasa A Borobia FG Pallares R A double-blind, placebo-controlled trial of ciprofloxacin prophylaxis in patients with acute necrotizing pancreatitis J Gastrointest Surg 2009 13 768 774 19082671 \n12 Isenmann R Friess H Schlegel P Fleischer K Büchler MW Penetration of ciprofloxacin into the human pancreas Infection 1994 22 343 346 7843813 \n13 Adam U Herms S Werner U The penetration of ciprofloxacin into human pancreatic and peripancreatic necroses in acute necrotizing pancreatitis Infection 2001 29 326 331 11787833 \n14 Norrby SR Lietman PS Safety and tolerability of fluoroquinolones Drugs 1993 45 Suppl 3 59 64 7689453 \n15 Trivedi CD Pitchumoni CS Drug-induced pancreatitis: an update J Clin Gastroenterol 2005 39 709 716 16082282 \n16 Lankisch PG Dröge M Gottesleben F Drug induced acute pancreatitis: incidence and severity Gut 1995 37 565 567 7489946 \n17 Tenner S Drug-induced acute pancreatitis: underdiagnosis and overdiagnosis Dig Dis Sci 2010 55 2706 2708 20686844\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1976-2283", "issue": "8(3)", "journal": "Gut and liver", "keywords": "Anti-bacterial agents; Drug toxicity; Infectious colitis; Pancreatitis", "medline_ta": "Gut Liver", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D002939:Ciprofloxacin; D003092:Colitis; D004791:Enzyme Inhibitors; D004952:Esters; D005260:Female; D016670:Gabexate; D006146:Guanidines; D006801:Humans; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis; D055815:Young Adult", "nlm_unique_id": "101316452", "other_id": null, "pages": "265-70", "pmc": null, "pmid": "24827622", "pubdate": "2014-05", "publication_types": "D016428:Journal Article", "references": "7249508;20499176;8652079;15057739;3541724;11787833;19082671;7689453;1767803;16082282;8335493;14526147;7843813;11129278;8536862;20686844;7489946", "title": "Acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis.", "title_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis" }

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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080814, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2014-01800", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "200563", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "24", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis acute", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KIM J, SUNG H, LEE H, CHO H, KIM S, CHO S, KIM J, CHEUNG D. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080818, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00006", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "31", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. 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ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080873, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" }, { "companynumb": "KR-OTONOMY INC.-2016OTO00005", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CIPROFLOXACIN" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": "207986", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "800 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "INFECTIOUS COLITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "800", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CIPROFLOXACIN." } ], "patientagegroup": null, "patientonsetage": "51", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pancreatitis", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "LEE S, KIM J. ACUTE PANCREATITIS SECONDARY TO CIPROFLOXACIN THERAPY IN PATIENTS WITH INFECTIOUS COLITIS. J GASTROENTEROL HEPATOL. 2015?30(SUPPL 4):148", "literaturereference_normalized": "acute pancreatitis secondary to ciprofloxacin therapy in patients with infectious colitis", "qualification": "3", "reportercountry": "KR" }, "primarysourcecountry": "KR", "receiptdate": "20160216", "receivedate": "20160216", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12080813, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160526" } ]

{ "abstract": "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a serious autoimmune disorder characterized by psychiatric symptoms, seizures and movement disorder. Predisposing factors have been reported since the time it was described, and its pathophysiology has been tried to be clarified over the years. Although overlap with other demyelinating diseases had been reported, such an association between Multiple Sclerosis (MS) anti ANTİ-NMDAR encephalitis is limited to only a few case reports. In this article, a patient diagnosed with relapsing remitting multiple sclerosis (RRMS) for ten years who then developed NMDA-R encephalitis while on disease modifying treatment will be presented and possible common pathophysiology with previously reported literature will be discussed.", "affiliations": "Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul. Electronic address: [email protected].;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Anesthesiology and Reanimation, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Anesthesiology and Reanimation, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Nuclear Medicine, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Istanbul School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.;Neurology, Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Istanbul.", "authors": "Gulec|Bade|B|;Kurucu|Hatice|H|;Bozbay|Suha|S|;Dikmen|Yalım|Y|;Sayman|Haluk|H|;Tuzun|Erdem|E|;Tutuncu|Melih|M|;Uygunoglu|Ugur|U|;Yalcinkaya|Cengiz|C|;Saip|Sabahattin|S|;Siva|Aksel|A|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2020.102075", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "42()", "journal": "Multiple sclerosis and related disorders", "keywords": "Multiple sclerosis; NMDAR encephalitis; Overlapping demyelinating syndromes", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": "D000328:Adult; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis; D015897:Comorbidity; D005260:Female; D006801:Humans; D020529:Multiple Sclerosis, Relapsing-Remitting", "nlm_unique_id": "101580247", "other_id": null, "pages": "102075", "pmc": null, "pmid": "32388459", "pubdate": "2020-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Co-existence of multiple sclerosis and anti-NMDA receptor encephalitis: A case report and review of literature.", "title_normalized": "co existence of multiple sclerosis and anti nmda receptor encephalitis a case report and review of literature" }

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"drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NATALIZUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Sleep disorder", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Agitation", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Encephalitis autoimmune", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, auditory", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Status epilepticus", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Memory impairment", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Autonomic nervous system imbalance", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Optic neuritis", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Sinus node dysfunction", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Hallucination, visual", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Generalised tonic-clonic seizure", "reactionmeddraversionpt": "23.0", "reactionoutcome": "1" } ], "summary": { "narrativeincludeclinical": "CASE EVENT DATE: 201704" } }, "primarysource": { "literaturereference": "GULECA B, KURUCU H, BOZBAY S, DIKMENB Y, SAYMANC H, TUZUND E, ET AL.. CO-EXISTENCE OF MULTIPLE SCLEROSIS AND ANTI-NMDA RECEPTOR ENCEPHALITIS: A CASE REPORT AND REVIEW OF LITERATURE. MULTIPLE SCLEROSIS AND RELATED DISORDERS. 2020?42:102075", "literaturereference_normalized": "co existence of multiple sclerosis and anti nmda receptor encephalitis a case report and review of literature", "qualification": "3", "reportercountry": "TR" }, "primarysourcecountry": "TR", "receiptdate": "20200625", "receivedate": "20200625", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17939909, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200714" } ]

{ "abstract": "Long-term survival of liver transplant recipients is endangered by tumorigenesis at different sites. Little is known about primary de novo tumors developing in the graft.\nWe analyzed the follow-up data of 2731 liver recipients that were transplanted between 1988 and 2019 at our institution (Charité - Universitätsmedizin Berlin, Department of Surgery). All cases with new intrahepatic tumors during follow-up were identified.\nA total of nine patients were diagnosed at a median of 16 years (range, 2-24 years) after surgery. Eight patients presented with hepatocellular carcinoma (HCC), and one patient presented with epithelioid hemangioendothelioma (EHE). All eight HCC patients had a recurrence of the initial disease that had caused liver failure before transplantation. This was associated with viral reinfection with either HCV or HBV in seven cases. Of the nine patients, three underwent surgical resection and only one patient was alive at data abstraction.\nIntrahepatic de novo neoplasms in the liver graft need to be considered in the long-term follow-up of liver recipients and were strongly associated with recurrent viral hepatitis in our study. Although prognosis of this rare complication is generally poor, patients may benefit from surgical resection of localized disease.", "affiliations": "Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Radiology (including Pediatric Radiology), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.;Department of Surgery, Campus Charité Mitte | Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany.", "authors": "Pflüger|Michael J|MJ|;Maurer|Max M|MM|;Hillebrandt|Karl H|KH|;Andreou|Andreas|A|;Geisel|Dominik|D|;Schmelzle|Moritz|M|;Pratschke|Johann|J|;Eurich|Dennis|D|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1016/j.jceh.2020.11.003", "fulltext": null, "fulltext_license": null, "issn_linking": "0973-6883", "issue": "11(4)", "journal": "Journal of clinical and experimental hepatology", "keywords": "AFP, alpha-fetoprotein; ALF, acute liver failure; CA 19-9, carbohydrate antigen 19-9; CCA, cholangiocarcinoma; CEA, carcinoembryonic antigen; DCV, daclatasvir; EHE, epithelioid hemangioendothelioma; ESLD, end-stage liver disease; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; IS, immunosuppressive therapy; LT, liver transplantation; NUCs, nucleos(t)ide analogues; PSC, primary sclerosing cholangitis; PTLD, post-transplantation lymphoproliferative disorder; PegIFN, pegylated interferon; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained viral response; epithelioid hemangioendothelioma; hepatocellular carcinoma; liver transplant; long-term survival; surgical resection", "medline_ta": "J Clin Exp Hepatol", "mesh_terms": null, "nlm_unique_id": "101574137", "other_id": null, "pages": "435-442", "pmc": null, "pmid": "34276150", "pubdate": "2021", "publication_types": "D016428:Journal Article", "references": "28039946;26597456;15048797;17404871;19766646;28590598;28364823;17008365;9873096;12037793;29359020;16967310;8188183;19659806;15964379;17060864;21989430;26405713;14702536;23915066;26807385;17019735;19460546;26269665;8594428;18813102;20602682;19737373;19857941;12752322;24106037", "title": "Intrahepatic De Novo Tumors in Liver Recipients are Highly Associated With Recurrent Viral Hepatitis.", "title_normalized": "intrahepatic de novo tumors in liver recipients are highly associated with recurrent viral hepatitis" }

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Intrahepatic De Novo Tumors in Liver Recipients are Highly Associated With Recurrent Viral Hepatitis. 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INTRAHEPATIC DE NOVO TUMORS IN LIVER RECIPIENTS ARE HIGHLY ASSOCIATED WITH RECURRENT VIRAL HEPATITIS. JOURNAL OF CLINICAL + EXPERIMENTAL HEPATOLOGY. 2021?11:435?442. DOI:HTTPS://DOI.ORG/10.1016/J.JCEH.2020.11.003", "literaturereference_normalized": "intrahepatic de novo tumors in liver recipients are highly associated with recurrent viral hepatitis", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210728", "receivedate": "20210728", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19624429, "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": "DE-AUROBINDO-AUR-APL-2021-034719", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TENOFOVIR DISOPROXIL" }, 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"drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LAMIVUDINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN HEPATITIS B VIRUS IMMUNE GLOBULIN" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "HEPATITIS B IMMUNE GLOBULIN" } ], "patientagegroup": null, "patientonsetage": "73", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Viraemia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "24.0", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "PFLUGER, MJ, ET AL. INTRAHEPATIC DE NOVO TUMORS IN LIVER RECIPIENTS ARE HIGHLY ASSOCIATED WITH RECURRENT VIRAL HEPATITIS.. JOURNAL OF CLINICAL + EXPERIMENTAL HEPATOLOGY. 2021?11:435?442", "literaturereference_normalized": "intrahepatic de novo tumors in liver recipients are highly associated with recurrent viral hepatitis", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20210811", "receivedate": "20210811", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 19682649, "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": "Second-line chemotherapy is not a standard of care in patients with malignant pleural mesothelioma (MPM) that progresses after first-line treatment with cisplatin and pemetrexed. In pre-clinical models, the combination of gemcitabine (GEM) and imatinib mesylate (IM), compared with GEM alone, led to a further tumor growth inhibition and improved survival. This phase II study evaluates the antitumor activity of a combination of IM and GEM in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by immunohistochemistry (IHC).\n\n\n\nGEM (1000 mg/m2) was given on days 3 and 10; IM (400 mg) was taken orally on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was the 3-month progression-free survival (PFS) rate. The study follows the optimal two-stage design of Simon. A 3-month PFS target of 75 % was required. With a probability error α = 10 % and a power of 80 %, the calculated sample size was 22 patients. In particular, in the first step, six out of nine patients and globally 14/22 patients free from progressive disease at 3 months were required. Secondary endpoints included response rate, duration of response, toxicity and overall survival (OS).\n\n\n\nIn total, 23 patients were enrolled (ECOG PS 0-1/2: 9/13; one previous line/≥two previous lines: 10/13). Partial response was achieved in four patients (17.4 %) and stable disease in 11 (47.8 %) with a disease control rate of 65.3 %. After a median follow-up of 34.5 months, median PFS and OS were 2.8 and 5.7 months, respectively. The 3-month PFS rate was 39.1 % (9/23 patients). All-grade drug-related adverse events occurred in 17 (73.9 %) patients. Grade 3 treatment-related adverse events were observed in four (17 %) patients.\n\n\n\nThe combination of IM and GEM is well tolerated in platinum-pemetrexed-pretreated MPM patients expressing PDGFR-β and/or cKIT by IHC, but it does not show a significant PFS benefit.", "affiliations": "Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Biostatistic Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].;Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. Electronic address: [email protected].", "authors": "Zucali|Paolo Andrea|PA|;Perrino|Matteo|M|;De Vincenzo|Fabio|F|;Giordano|Laura|L|;Cordua|Nadia|N|;D'Antonio|Federica|F|;Santoro|Armando|A|", "chemical_list": "D000068437:Pemetrexed; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; C056507:gemcitabine", "country": "Ireland", "delete": false, "doi": "10.1016/j.lungcan.2020.02.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0169-5002", "issue": "142()", "journal": "Lung cancer (Amsterdam, Netherlands)", "keywords": "Combination therapy; Gemcitabine; Imatinib; Mesothelioma", "medline_ta": "Lung Cancer", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D000086002:Mesothelioma, Malignant; D000068437:Pemetrexed; D010997:Pleural Neoplasms; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate", "nlm_unique_id": "8800805", "other_id": null, "pages": "132-137", "pmc": null, "pmid": "32102735", "pubdate": "2020-04", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma.", "title_normalized": "a phase ii study of the combination of gemcitabine and imatinib mesylate in pemetrexed pretreated patients with malignant pleural mesothelioma" }

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{ "abstract": "Kaposi sarcoma is a mesenchymal tumor associated to a human herpes virus-8. It often occurs in human immunodeficiency virus-positive subjects. Colorectal localization is rare. We report the case of a colorectal Kaposi sarcoma complicating a refractory ulcerative colitis treated with surgery after the failure of immunomodulator therapy in a human immunodeficiency virus-negative heterosexual man.", "affiliations": "Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Histopathology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;General surgery department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Histopathology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;General surgery department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.;Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia.", "authors": "Hamzaoui|Lamine|L|;Kilani|Houda|H|;Bouassida|Mahdi|M|;Mahmoudi|Moufida|M|;Chalbi|Emna|E|;Siai|Karima|K|;Ezzine|Heykel|H|;Touinsi|Hassen|H|;Azzouz|Mohamed M'saddak|MM|;Sassi|Sadok|S|", "chemical_list": "D000911:Antibodies, Monoclonal; D013256:Steroids; D000069285:Infliximab; D001379:Azathioprine", "country": "Uganda", "delete": false, "doi": "10.11604/pamj.2013.15.154.2988", "fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-15-15410.11604/pamj.2013.15.154.2988Case ReportIatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient Hamzaoui Lamine 1Kilani Houda 2Bouassida Mahdi 3&Mahmoudi Moufida 1Chalbi Emna 2Siai Karima 1Ezzine Heykel 1Touinsi Hassen 3Azzouz Mohamed M'Saddak 1Sassi Sadok 11 Gastroenterology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia2 Histopathology department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia3 General surgery department, Mohamed Tahar Maamouri Hospital, Nabeul, Tunisia& Corresponding author: Mahdi Bouassida, MD, Department of Surgery, Mohamed Tahar Maamouri Hospital, 8000 Mrazga, Nabeul, Tunisia29 8 2013 2013 15 15418 6 2013 23 8 2013 © Mahdi Bouassida et al.2013The Pan African Medical Journal - ISSN 1937-8688. 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.Kaposi sarcoma is a mesenchymal tumor associated to a human herpes virus-8. It often occurs in human immunodeficiency virus-positive subjects. Colorectal localization is rare. We report the case of a colorectal Kaposi sarcoma complicating a refractory ulcerative colitis treated with surgery after the failure of immunomodulator therapy in a human immunodeficiency virus-negative heterosexual man.\n\nKaposi's Sarcomaulcerative colitisHuman Herpes Virus-8Infliximabimmunosuppression\n==== Body\nIntroduction\nKaposi's sarcoma (KS) is a mesenchymal tumor, arising predominantly in the skin but which can affect any organ system. It's associated to human herpes virus-8 (HHV8) [1, 2]. Patients with inflammatory bowel disease, in particular ulcerative colitis (UC), are often treated with immunosuppressive therapy and can develop colorectal KS [3]. We report the case of a human immunodeficiency negative-virus (HIV) man, with a severe refractory UC, who was treated with steroids, azathioprine and infliximab (IFX). Failure of medical treatment indicated surgery. Histological examination of the colon revealed KS.\n\nPatient and observation\nA 30-year-old heterosexual man, without familial and personal history, was diagnosed with rectosigmoid ulcerative colitis since 2010 revealed by chronic bloody diarrhea with abdominal pain and weight loss. He had a 3 pack-year history of smoking (stopped 3 years ago). He was initially treated with oral and local mesalamine with a good response. In 2011, he was treated 3 times with steroids (1mg/kg/day of prednisone) for a moderately active disease without a complete relief of diarrhea. In December 2011, at physical exam, his body mass index was 17kg/m2. Abdominal exam was normal. There was no skin lesion. Iron deficiency anemia (11g/dL) and signs of inflammation: erythrocyte sedimentation rate (ESR) of 37mm and C - reactive protein (CRP) of 74mg/L were noted. Albumin level was 25g/L. Ileocolonoscopy showed large superficial ulcerations, spontaneous bleeding and pseudo-polyps. Lesions were mainly located in the rectosigmoid colon and the colitis was extended to the hepatic flexure. Histology found clear signs of active UC with no signs of malignancy. Oral corticosteroids were prescribed with a good initial response. At week 4 of corticosteroid therapy, we noted a relapse of bloody diarrhea, inflammation and aggravation of anemia (7,3g/dL). A left-sided colonoscopy didn't show severe endoscopic signs. Copro-parasitological examinations were negative. Cytomegalovirus testing was negative too. Detection of Clostridium difficile toxins was not done. Intravenous corticosteroids and parenteral nutrition were prescribed during 1week. At week 5 of corticosteroid therapy, another relapse occurred (7 to 8 stools daily, anemia 6g/dL, ESR 40mm, albumin 17g/L) and we had considered that it was a refractory severe UC. As the patient was reticent to surgery, medical treatment with immunomodulators was indicated. Assessment before immunosuppressive therapy was normal. He received blood transfusion, albumin infusion, parenteral nutrition and intravenous corticosteroids (with progressive decreasing doses). After improvement in health status, anemia (9g/dL) and albumin concentration (37g/L), azathioprine (2,5mg/kg/day, total of 3 months of treatment) and IFX (induction regimen with 5mg/kg, weeks 0, 2 and 6) were prescribed with unchanged disease activity. Drug failure led to a surgical treatment. A subtotal colectomy with double stomy of the ileum and of the sigmoid colon was performed. Colon macroscopic examination revealed multiple polypoid red lesions associated with large ulcerations. Histologic examination of polypoid lesions showed fusocellular spindle cells proliferation with a slit like vascular channels and extravased red blood cells consistent with the diagnosis of KS, associated with typical features of UC (Figure 1). Immunolabelling for HHV8 stained the nuclei of the spindle cells (Figure 2, Figure 3). Involvement in 1 of the 25 perivisceral lymph nodes isolated was demonstrated. The patient underwent mucosal proctectomy and ileoanal anastomosis.\n\nFigure 1 Histology (H and E stain x 40): Spindle cell proliferation with vascular channels infiltrating a colonic mucosa\n\nFigure 2 HHV8 immunohistochemical stain: strong nuclear positivity in spindle tumor cells x200\n\nFigure 3 Fig CD31 immunohistochemical stain: positivity in vascular channels x40\n\nDiscussion\nThere are four clinical variants of KS with distinct clinical and epidemiological characteristics: classic, endemic, acquired immunodeficiency syndrome and iatrogenic [4]. Iatrogenic KS has been described in kidney and liver transplant recipients and also auto-immune diseases [5, 6]. KS of gastrointestinal tract is rarely seen in the developed countries. Involvement by KS has been noted in 80% of patients with visceral disease in endemic areas [7]. Case studies have reported colorectal KS associated with inflammatory bowel disease in HIV-negative patients (since until now 11 observations). Most of cases were refractory UC on immunosuppressive therapy [8]. Our patient has received a triple immunosuppression (steroids, azathioprine and infliximab). It's the second case occurring into IFX. The diagnosis is difficult to establish in the absence of skin lesions, as in our patient. Nodular and polypoid lesions are observed in endoscopy and biopsies may fail to sample diagnostic tissue before tumor infiltration of the mucosa [8]. Intraluminal polyps are red or blue, due to high vascular and conjunctive tissue proliferation. Distinction from pseudo-polyps is difficult [9]. Seven months before diagnosis, the colonoscopy showed polypoid lesions, considered as inflammatory pseudo-polyps by the histologist. Immunohistochemistry of HHV-8 is helpful in the histological assessment of the lesions and may demonstrate infiltration of the mucosa by KS [8]. HHV-8 was positive in our case. Proctocolectomy associated to immunosuppressor withdrawal is usually effective to treat both UC and KS. After subtotal colectomy and confirmation of KS associated to UC, the patient will undergo proctectomy.\n\nConclusion\nAlthough it is rare, it is important to consider a concomitant KS in patients with refractory severe ulcerative colitis, on immunosuppressor therapy, independently of HIV status.\n\nCompeting interests\nThere authors declare no competing interest.\n\nAuthors’ contributions\nAll authors contributed in this work in ways that conform to ICMJE authorship criteria. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1 Chang Y Cesarman E Pessin MS Identification of herpesvirus-like DNA sequences in AIDSassociated Kasposi's sarcoma Science. 1994 266 5192 1865 9 7997879 \n2 Antman K Chang Y Kaposi's sarcoma N Engl J Med. 2000 342 14 1027 38 10749966 \n3 Meltzer SJ Rotterdam HZ Korelitz BI Kaposi's sarcoma in association with ulcerative colitis Am J Gastroenterol. 1987 82 4 378 81 3565348 \n4 Martin RW III Hood AF Farmer ER Kaposi sarcoma Medicine. 1993 72 4 245 61 8341141 \n5 García-Astudillo LA Leyva-Cobián F Human herpesvirus-8 infection and Kaposi′s sarcoma after liver and kidney transplantation in different geographical areas of Spain Transpl Immunol. 2006 17 1 86 9 \n6 Klein MB Pereira FA Kantor I Kaposi sarcoma complicating systemic lupus erythematosus treated with immunosuppression Arch Dermatol. 1974 110 4 602 4 4414026 \n7 Taylor FJ Templeton AC Vogel CL Kaposi's sarcoma in Uganda: a clinicopathological study Int J Cancer. 1971 8 1 122 35 5118203 \n8 Girelli CM Serio G Rocca E Rocca F Refractory ulcerative colitis and iatrogenic colorectal Kaposi's sarcoma Dig Liver Dis. 2009 41 2 170 4 18054849 \n9 Tavassolie H Mir-Madjlessi SH Sadr-Ameli MA The endoscopic demonstration of Kaposi's sarcoma of the colon Gastrointest Endosc. 1983 29 4 331 332 6642174\n\n", "fulltext_license": "CC BY", "issn_linking": null, "issue": "15()", "journal": "The Pan African medical journal", "keywords": "Human Herpes Virus-8; Infliximab; Kaposi's Sarcoma; immunosuppression; ulcerative colitis", "medline_ta": "Pan Afr Med J", "mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D001379:Azathioprine; D003093:Colitis, Ulcerative; D015179:Colorectal Neoplasms; D018023:HIV Seronegativity; D006801:Humans; D007049:Iatrogenic Disease; D000069285:Infliximab; D008297:Male; D012514:Sarcoma, Kaposi; D013256:Steroids; D017211:Treatment Failure", "nlm_unique_id": "101517926", "other_id": null, "pages": "154", "pmc": null, "pmid": "24396560", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "10749966;3565348;5118203;17157220;18054849;8341141;7997879;4414026;6642174", "title": "Iatrogenic colorectal Kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative-virus patient.", "title_normalized": "iatrogenic colorectal kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative virus patient" }

[ { "companynumb": "TN-WATSON-2014-16636", "fulfillexpeditecriteria": "1", "occurcountry": "TN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PREDNISONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "080356", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "1 MG/KG, DAILY, THREE TIMES", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": "2011", "drugstartdateformat": "602", "drugstructuredosagenumb": "1", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISONE (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "AZATHIOPRINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "Unk", "drugdosagetext": "2.5 MG/KG, DAILY", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AZATHIOPRINE (UNKNOWN)" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INDUCTION REGIMEN OF 5 MG/KG WEEKS 0, 2 AND 6", "drugenddate": null, "drugenddateformat": null, "drugindication": "COLITIS ULCERATIVE", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "INFLIXIMAB" } ], "patientagegroup": null, "patientonsetage": "30", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Kaposi^s sarcoma", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "17.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HAMZAOUI L, KILANI H, BOUASSIDA M, MAHMOUDI M, CHALBI E, SIAI K. ET AL. IATROGENIC COLORECTAL KAPOSI SARCOMA COMPLICATING A REFRACTORY ULCERATIVE COLITIS IN A HUMAN IMMUNODEFICIENCY NEGATIVE-VIRUS PATIENT. PAN AFR MED J. 2013;15:154", "literaturereference_normalized": "iatrogenic colorectal kaposi sarcoma complicating a refractory ulcerative colitis in a human immunodeficiency negative virus patient", "qualification": "3", "reportercountry": "TN" }, "primarysourcecountry": "TN", "receiptdate": "20140806", "receivedate": "20140806", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10366245, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150326" } ]

{ "abstract": "Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation.\n\n\n\nBetween 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation.\n\n\n\nIn the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3.\n\n\n\nPatients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.", "affiliations": "Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Pneumology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Pneumology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.;Department of Radiation Oncology, Paracelsus Medical University, SALK, Salzburg, Austria.", "authors": "Grambozov|Brane|B|0000-0003-2454-7425;Wass|Romana|R|;Stana|Markus|M|;Gerum|Sabine|S|;Karner|Josef|J|;Fastner|Gerd|G|;Studnicka|Michael|M|;Sedlmayer|Felix|F|;Zehentmayr|Franz|F|0000-0001-5931-3907", "chemical_list": null, "country": "Singapore", "delete": false, "doi": "10.1111/1759-7714.13884", "fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n33586228\n10.1111/1759-7714.13884\nTCA13884\nOriginal Article\nOriginal Articles\nImpact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single‐center retrospective analysis\nGrambozov et al.\nGrambozov Brane https://orcid.org/0000-0003-2454-7425\n1 [email protected]\n\nWass Romana 2 3\nStana Markus 1\nGerum Sabine 1\nKarner Josef 1\nFastner Gerd 1\nStudnicka Michael 2\nSedlmayer Felix 1 4\nZehentmayr Franz https://orcid.org/0000-0001-5931-3907\n1 4\n1 Department of Radiation Oncology Paracelsus Medical University, SALK Salzburg Austria\n2 Department of Pneumology Paracelsus Medical University, SALK Salzburg Austria\n3 Department of Pulmonology Kepler University Hospital Linz Austria\n4 radART – Institute for Research and Development on Advanced Radiation Technologies Paracelsus Medical University Salzburg Austria\n* Correspondence\nBrane Grambozov, Radiation Oncology, Salzburg University Clinic, Müllner Hauptstraße 48, A‐5020 Salzburg, Austria.\nEmail: [email protected]\n\n14 2 2021\n4 2021\n12 8 10.1111/tca.v12.8 11621170\n26 1 2021\n21 12 2020\n26 1 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nGiven the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high‐dose reirradiation.\n\nMaterials and methods\n\nBetween 2013 and 2019, 47 consecutive patients with in‐field tumor recurrence underwent high‐dose thoracic reirradiation at our institute. Twenty patients (43%) received high‐dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work‐up included a mandatory fluorodeoxyglucose‐positron emission tomography‐computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation.\n\nResults\n\nIn the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5–21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8–25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log‐rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3.\n\nConclusion\n\nPatients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.\n\nThe aim of our retrospective study was to investigate whether reccurrent lung patients would benefit in terms of overall survival by adding immunotherapy to high‐dose reirradiation. Between 2013 and 2019, 47 consecutive patients with in‐field tumor recurrence underwent high‐dose thoracic reirradiation at our institute. Twenty patients (43%) received high dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.\n\nimmunotherapy\nlocal recurrence\nlung cancer\noverall survival and toxicity\nreirradiation\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:14.04.2021\nGrambozov B , Wass R , Stana M , et al. Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single‐center retrospective analysis. Thorac Cancer. 2021;12 :1162–1170. 10.1111/1759-7714.13884\n==== Body\nAbbreviations\n\nCCI Charlson co‐morbidity index\n\nCTCAE common toxicity criteria for adverse events\n\nDART dose‐differentiated accelerated radiotherapy\n\nECOG Eastern cooperative oncology group\n\nEQD2 biologically equivalent dose in 2 Gy fractions\n\nFDG‐PET‐CT fluorodeoxyglucose‐positron emission tomography\n\nIMRT intensity modulated radiotherapy\n\nmOS median overall survival\n\nNSCLC nonsmall cell lung cancer\n\nOS overall survival\n\nRT radiotherapy\n\nSABR stereotactic ablative body therapy\n\nSCLC small‐cell lung cancer\n\nTNM tumor, node, metastasis\n\nVMAT volumetric intensity modulated arc therapy\n\nINTRODUCTION\n\nImmunotherapy has led to revolutionary advancements in cancer treatment 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 and has given new hope to the large number of patients who die from lung cancer each year. 9 Immunotherapy is now a standard first‐ and second‐line therapy for patients with advanced lung cancer. 1 , 2 , 3 , 4 , 6 , 8\n\nWith the aim of improving the options available for the treatment of lung cancer patients and based on the potential synergistic effect of radiation therapy and immunotherapy in terms of both local and systemic antitumor response as already described in preclinical models, 10 , 11 , 12 the interest of the oncological community in combining these therapeutic modalities in a clinical setting has increased. 1 , 2 , 13 , 14 As a result, clinical studies have shown remarkable benefits in terms of both progression‐free and overall survival (OS) in lung cancer patients with acceptable toxicity, 1 , 2 , 13 which may be attributed to the synergistic antitumor effect mentioned above. In contrast, numerous publications have suggested that the very complex interaction between the irradiated cells, tissue, and the immune system could enhance the effect of immunotherapy. 1 , 2 , 5 , 7 , 12 , 15 , 16 , 17\n\nIn light of this, the potential for antitumor immune activation by irradiation could play an important role for radiotherapy in systemic disease, especially since the presence of immunosuppressive mediators in the tumor microenvironment could limit the number of patients who experience the therapeutic benefits of immunotherapy. 12 , 18 Despite progress in all related clinical disciplines, there is a need to improve clinical outcomes in patients at all tumor, node, metastasis (TNM) stages, including those with recurrent lung cancer for whom curative treatment is already limited. 5 , 19 , 20 Hence, combining therapeutic modalities such as radiotherapy, chemotherapy, and immunotherapy in the hope of overcoming their therapeutic limitations and achieving a synergistic effect seems plausible. 1 , 2 With respect to the combination of reirradiation for loco‐regional relapse and immunotherapy, there is currently one review extant. 5 Additionally, the results of an ongoing study are pending (ClinicalTrials.gov identifier NCT03087760), which—as opposed to our study—uses proton reirradiation rather than photons.\n\nThe aim of our retrospective analysis was to investigate whether patients with recurrent lung cancer would benefit from adding immunotherapy to ablative reirradiation in terms of OS, taking into account toxicity. Local control after reirradiation and dose to organs at risk are the subject of another paper that is currently under review.\n\nMETHODS\n\nPatients\n\nBetween 2013 and 2019, 47 consecutive patients who underwent high‐dose thoracic reirradiation were included in a prospective observational database. While 20 patients were reirradiated only, 27 received systemic therapy in addition to high‐dose reirradiation. In this subgroup, immunotherapy was administered alone or with chemotherapy in 21/27 patients (78%). Six out of 27 patients (22%) received chemotherapy alone. The inclusion criteria were as follows: (1) all patients had to be classified as inoperable and in all patients both the primary and the secondary tumor had to be located in the lungs; (2) if possible, patients should have received two courses of curatively intended radiation therapy with a time interval of 9 months or more between them (an exception was made in only one patient who was reirradiated 5 months after the first radiation therapy treatment); (3) the tumor was histologically verified and categorized according to the 8th edition of the TNM classification; (4) fluorodeoxyglucose‐positron emission tomography‐computed tomography (18F‐FDG‐PET‐CT) was required in the diagnostic work‐up; (5) the performance status had to be ≤2 according to the Eastern Cooperative Oncology Group (ECOG). Patients who received palliative radiation treatment, postoperative radiotherapy (RT), or those with chest wall tumors and/or out‐of‐field tumor recurrences were excluded. All patients were discussed in a multidisciplinary tumor board with pneumologists, medical oncologists, radiologists, thoracic surgeons, pathologists, and radiation oncologists. This study was reviewed and approved by the ethics committee of the Federal Province of Salzburg (No. 1070/2020).\n\nRadiation and systemic therapy\n\nPatients were reirradiated using intensity modulated radiotherapy (IMRT/VMAT) or stereotactic body radiotherapy (SABR). A planning computed tomography (CT) scan with an acquisition time of 3 s was performed prior to IMRT/VMAT. Additionally, four‐dimensional computed tomography (4D‐CT) was performed in SABR patients. Patients were immobilized using a vacuum cradle and WingSTEP. Subsequently, the planning CT was registered with 18F‐FDG‐PET‐CT. For SABR patients, the internal target volume (ITV) was created by contouring the gross tumor volume (GTV) on three breathing phases (expiration, inspiration, and average) and their subsequent union (ITV = CTV‐clinical target volume). The planning target volume (PTV) was created by adding a symmetric margin of 5 mm to the ITV and an additional 4 mm margin in the cranio‐caudal direction. In IMRT/VMAT patients, the GTV was contoured on a so called “slow CT” with an acquisition time of 4 s. This GTV actually constitutes an ITV/CTV as it includes the respiration‐dependent movement of the tumor. The PTV was defined by adding a symmetric margin of 7 mm to GTV. IMRT/VMAT was delivered in three fractionation regimens: dose‐differentiated accelerated RT in twice daily fractions of 1,8 Gy (dose‐differentiated accelerated radiotherapy [DART]‐bid) as described in two previous publications, 21 , 22 conventionally with 2 Gy per fraction, and hypofractionated RT (one fraction of 3 Gy per day). SABR included two different schemes: eight fractions of 8 Gy (65% isodose) delivered daily for central tumors (i.e. within 2 cm of the proximal bronchial tree) and three fractions of 15.4 Gy in (65% isodose) every other day for peripheral tumors. Since various fractionation regimens were used, total radiation doses were compared by biologically equivalent dose in 2 Gy fractions (EQD2). Organs at risk (OAR), such as esophagus, central vessels and airways, spinal cord, lungs, and heart were routinely contoured and dose volume histograms of both initial and reirradiation plans were used to determine the cumulative radiation dose of each critical organ.\n\nPrior to reirradiation, patients with nonsmall cell lung cancer (NSCLC) received two cycles of either cisplatin (75 mg/m2/d) combined with pemetrexed (500 mg/m2/d) or gemcitabine (1000 mg/m2/d), while small‐cell lung cancer (SCLC) patients received four cycles of cisplatin (75 mg/m2/d) together with etoposide (120 mg/m2 days 1 to 3). In the case of renal dysfunction carboplatin at an area under the curve (AUC) of 5 on day 1 (absolute maximum dose 1100 mg) was applied instead of cisplatin. Depending on the tumor histology, patients received one of the following immunotherapeutic agents after the second ablative radiation therapy: atezolizumab, durvalumab, nivolumab, or pembrolizumab.\n\nToxicity\n\nThe Common Terminology Criteria for Adverse Events version (CTCAE) 5.0 were used to report toxicity. Grade 1 toxicities were not considered as clinically relevant and have therefore not been assessed in this study. A cutoff of 90 days after completion of reirradiation was used to distinguish between acute and late toxicities, with the exception of pneumonitis, which was still considered acute if it occurred within 180 days of the end of RT.\n\nFollow up\n\nPatients were seen 6 weeks after completion of radiotherapy, then every 3 months for the first 2 years and twice a year thereafter. Clinical examinations, contrast‐enhanced CTs, and pulmonary function tests were performed at every follow‐up. If local recurrences or new lung lesions were suspected on the chest CT, 18F‐FDG‐PET‐CT was performed. Local relapse was defined as tumor growth within the reirradiated volume covered by the 95% or 65% isodose after IMRT/VMAT or SABR, respectively.\n\nStatistics\n\nThe primary endpoint was OS, which was calculated using the Kaplan–Meier method. We defined OS as the time between the end of reirradiation and death or latest follow‐up. Although the subgroup of 27 patients was of interest for our analysis, a total of 47 patients—20 of whom were only reirradiated—were also analyzed. With the aim of retaining as much potential information regarding the effects of the three therapy modalities on OS as possible, the threshold for first‐order errors (α) was set at 0.2, which is a more permissible limit usually used in exploratory studies. 23 , 24 For intergroup comparisons the log‐rank test was used.\n\nRESULTS\n\nPatients\n\nOf the 47 patients in the whole cohort, 29 (62%) were men and 18 (38%) were women. The median age at the start of the reirradiation was 66 years (range 52–83 years) in both the entire cohort and the subgroup. Based on histological findings at initial diagnosis, 35/47 (75%) patients had NSCLC and 10/47 (21%) patients had SCLC across the cohort. No pathological confirmation could be obtained in two patients (4%). For details, see Table 1.\n\nTABLE 1 Patient‐ and treatment‐related parameters in the cohort (N = 47)\n\nPatients N = 47\t\nPatient parameters\tAge (years)\tMedian\t66,3\t\nRange\t52–83\t\nSex\tMale\t29\t\nFemale\t18\t\nWeight loss (%)\t>5%\t22\t\n<5%\t25\t\nECOG\t0–1\t40\t\n2\t7\t\nHistology\tSCLC\t10\t\nNSCLC\t35\t\nUnknown\t2\t\nT stage\tx\t3\t\n1\t9\t\n2\t21\t\n3\t9\t\n4\t5\t\nN stage\t0\t11\t\n1\t7\t\n2\t22\t\n3\t7\t\nM stage\t0\t40\t\n1\t7\t\nUICC stage\tI\t7\t\nII\t8\t\nIII\t25\t\nIV\t7\t\nFEV1 (%)\tMedian\t71\t\nRange\t35–100\t\nCOPD grade\t0\t17\t\n1\t3\t\n2\t9\t\n3\t10\t\n4\t6\t\nUnknown\t2\t\nCharison Comorbidity Index\tMedian\t5\t\nRange\t2‐10\t\nTreatment‐related parameters\tReirradiation volume (ml)\tMedian\t47\t\nRange\t4–541\t\nTumor location (n)\tPeripheral\t22\t\nCentral\t25\t\nCumulative EQD2 (Gy)\tMedian\t131\t\nRange\t77‐339\t\nSystemic therapy (n)\tYes\t27\t\nNo\t20\t\nInterval between radiation courses (months)\tMedian\t20\t\nRange\t5–145\t\nRadiation technique\tAccelerated\t23\t\nSTX\t13\t\nConventional (= 2 Gy/d)\t6\t\nHypofractionated\t5\t\nNote: Tx‐means that the tumor was not able to be evaluated\n\nAbbreviations: COPD, chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control.\n\nThe subgroup included 27 patients, of whom 17 (63%) were men and 10 (37%) were women. All tumors were histologically verified at initial diagnosis, according to which 21/27 patients (78%) had NSCLC and 6/27 patients (22%) had SCLC. The vast majority of patients (25/27, 92.5%) had an ECOG performance score ≤1 with a mean Charlson co‐morbidity index (CCI) of 6 (range 3–10). More than half of the patients (16/27, 60%) had stage III disease. Four patients (15%) were classified as oligometastic at reirradiation. Further details are shown in Table 2.\n\nTABLE 2 Patient‐ and treatment‐related parameters in the systemic therapy subgroup (N = 27)\n\nPatients N = 27\t\nPatient parameters\tAge (years)\tMedian\t66,3\t\nRange\t52–83\t\nSex\tMale\t17\t\nFemale\t10\t\nWeightless (%)\t>5%\t13\t\n<5%\t14\t\nECOG\t0–1\t25\t\n2\t2\t\nHistology\tSCLC\t6\t\nNSCLC\t21\t\nT stage\tx\t2\t\n1\t6\t\n2\t11\t\n3\t4\t\n4\t4\t\nN stage\t0\t5\t\n1\t4\t\n2\t13\t\n3\t5\t\nM stage\t0\t23\t\n1\t4\t\nUICC stage\tI\t2\t\nII\t5\t\nIII\t16\t\nIV\t4\t\nFEV1 (%)\tMedian\t71,1\t\nRange\t36–100\t\nCOPD grade\t0\t13\t\n1\t1\t\n2\t4\t\n3\t6\t\n4\t2\t\nUnknown\t1\t\nCharison comorbidity index\tMedian\t6\t\nRange\t3–10\t\nTreatment‐related parameters N = 27\tReirradiation volume (ml)\tMedian\t48.8\t\nRange\t4.5–217\t\nTumor location (n)\tPeripheral\t14\t\nCentral\t13\t\nCumulative EQD2 (Gy)\tMedian\t132,8\t\nRange\t79–211\t\nSystemic therapy\tChemotherapy\t6\t\nImmunotherapy with/without Chemotherapy\t21\t\nInterval between radiation courses (months)\tMedian\t14\t\nRange\t5–80\t\nRadiation technique\tAccelerated\t13\t\nSTX\t6\t\nConventional (= 2 Gy/d)\t5\t\nHypofractionated\t3\t\nAbbreviations: COPD,chronic obstructive pulmonary disease; ECOG, Eastern cooperative oncology group; EQD2, biologically equivalent dose in 2 Gy fractions; FEV1, forced expiratory volume during the first second; N stage, lymph nodes; NSCLC, nonsmall cell lung cancer; M stage, metastasis; SCLC, small cell lung cancer; STX, stereotactic body irradiation; T stage, tumor; UICC, Union for International Cancer Control.\n\nReirradiation and systemic therapy\n\nWhile 20 of the 47 patients were only reirradiated (43%), 27/47 (57%) received systemic therapy in addition to reirradiation. In this subgroup of interest, the tumor was located peripherally in 14/27 (52%) patients and centrally in 13/27 (48%) patients. Almost half of the patients (13/27, 48%, median EQD2 128 Gy, range 89–150.5 Gy) were reirradiated with DART‐bid, while 6/27 (22%, median EQD2 191 Gy, range 148–211 Gy) received SABR; in 5/27 patients (19%, median EQD2 122 Gy, range 79–134 Gy) conventional radiation therapy was applied and in 3/27 (11%, median EQD2 99 Gy, range 94–135.5 Gy) a hypofractionated schedule was used. The median reirradiation PTV was 48.8 ml (range 4.5–217 ml) and the median cumulative radiation dose EQD2 delivered in both treatments was 132.8 Gy (range 79–211 Gy). The median interval between the first and second treatment courses was 14 months (range 5–80 months). Twenty‐one patients (78%) received immunotherapy with or without chemotherapy (Table 2). The immunotherapeutic agents were administered after reirradiation over a median treatment time of 6 months (range 0.5–24 months). Six patients (22%) received chemotherapy alone prior to reirradiation.\n\nOverall survival\n\nThe median follow‐up across the cohort was 11.7 months (range 0.3–64.4 months). Of the 47 patients, 21 are still alive (45%). The median OS (mOS) after reirradiation was 18.9 months (95% CI 16.5–21.3 months; Figure 1(a)). The difference in OS between the three treatment modalities in the whole cohort, i.e. reirradiation only vs. reirradiation plus chemotherapy vs. reirradiation plus immunotherapy with/without chemotherapy was in favor of the third group (log‐rank p value = 0.132; Figure 1(b)).\n\nFIGURE 1 (a) The median overall survival (mOS) in the whole cohort of 47 patients was 18.9 months (95% confidence interval [CI] 16.5–21.3 months). (b) The 47 patients in the whole cohort were stratified according to the type of systemic therapy received together with reirradiation: immunotherapy or immunochemotherapy (orange), reirradiation alone without systemic treatment (blue), chemotherapy (green). Of these, the first group had the longest survival (mOS 23.7 months, 95% CI 20.3–27.1 months, overall log‐rank p value = 0.132)\n\nIn the immunotherapy subgroup, the mOS after the second radiation course was 21.8 months (95% CI 17.8–25.8 months; Figure 2(a)). Patients were followed up for a median of 18.4 months (range 1.4–60.9 months), and of these 12 (44%) are still alive, while 14 (52%) patients died from cancer‐related conditions. One patient (4%) died from peritonitis caused by bacterial infection. The median local progression‐free survival was 7.9 months (95% CI 6.7–9 months). The difference in OS was in favor of the immunotherapy subgroup (log‐rank p value = 0.063; Figure 2(b)).\n\nFIGURE 2 (a) The median OS (mOS) in the systemic therapy subgroup was 21.8 months (95% confidence interval [CI] 17.8–25.8 months). (b) Patients who received immunotherapy or chemo‐immunotherapy together with reirradiation lived longer than patients who underwent reirradiation with chemotherapy alone (mOS 23.7 months, 95% CI 20.3–27.1 months, log‐rank p value = 0.063)\n\nToxicity\n\nOf the 47 patients, eight (17%) experienced acute side effects greater than or equal to grade 2 and 1/47 (2%) patients had late ≥grade 2 toxicity. A grade 5 acute heart failure 1 week after the end of reirradiation was reported in 1/47 (2%) patients with no history of cardiac disease. In this patient, the cumulative maximum EQD2 delivered in both radiation courses was 110 Gy, which was below the 115 Gy classified as tolerable in the literature. 25 The 43% total V20 lung (volume receiving ≥20 Gy) met the above limitation while the 45% V25 (volume receiving ≥25 Gy) heart did not because the tumor was in the central upper lobe including the left hilum and upper segments of the lower lobe. Since a therapeutic cause of death, although unlikely, could not be entirely excluded this patient was scored as having grade 5 toxicity (Table 3).\n\nTABLE 3 Treatment‐related toxicity in the whole cohort\n\nToxicity (N = 47)\t\nType of toxicity\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tGrade 5\t\nAcute\tEsophagitis\tna\t4\t2\t0\t0\t\nPneumonitis\tna\t1\t0\t0\t0\t\nHeart\tna\t0\t0\t0\t1\t\nLate\tEsophagitis\tna\t0\t0\t0\t0\t\nPneumonitis\tna\t0\t0\t0\t0\t\nHemorrhage\tna\t0\t1\t0\t0\t\nChest wall pain\tna\t0\t0\t0\t0\t\nAbbreviation: na, not assessed.\n\nIn contrast, there were no grade 4 or 5 toxicities in the immunotherapy subgroup. Acute toxicities occurred as grade 2 in three patients (11%). Two of these patients had acute esophagitis and one reported acute pneumonitis. A late grade 3 hemorrhage occurred in one patient (4%, Table 4).\n\nTABLE 4 Treatment‐related toxicity in the subgroup\n\nToxicity (N = 27)\t\nType of toxicity\tGrade 1\tGrade 2\tGrade 3\tGrade 4\tGrade 5\t\nAcute\tEsophagitis\tna\t2\t0\t0\t0\t\nPneumonitis\tna\t1\t0\t0\t0\t\nHeart\tna\t0\t0\t0\t0\t\nLate\tEsophagitis\tna\t0\t0\t0\t0\t\nPneumonitis\tna\t0\t0\t0\t0\t\nHemorrhage\tna\t0\t1\t0\t0\t\nChest wall pain\tna\t0\t0\t0\t0\t\nAbbreviation: na, not assessed.\n\nDISCUSSION\n\nIn this analysis we could show that in patients with locoregional relapse of lung cancer a second course of irradiation together with immunotherapy leads to better OS than a combination with chemotherapy (log‐rank p value = 0.063; Figure 2(b)).\n\nOur finding is consistent with a concept published in a review by Evans 5 intended for recurrent lung cancer patients who already have limited chances of successful curative treatment. 5 , 19 , 26 , 27 According to Evans, 5 the combination of the two therapy modalities would have a synergistic effect in terms of both local and systemic disease control, given the high potential for local and systemic failure, possibly due to radiation resistance and the aggressiveness of the disease in recurrent lung cancer patients. 5 Immunotherapy could potentially play an important role in enhancing the effectiveness of reirradiation and vice versa, which could hypothetically explain the prolonged survival of the subgroup who received reirradiation followed by immunotherapy in our study.\n\nIn the absence of published studies on reirradiation with immunotherapy, this consideration relies on data from patients receiving first‐time irradiation, assuming that outcome and toxicity would be similar in the reirradiation setting. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 15 , 16 , 20 , 28 , 29 , 30 In this context, there is data already available on the combination of RT and immunotherapy with primarily curative intent, indicating the potential clinical benefit in lung cancer patients. 1 , 2 This could be attributed to the potential synergistic effect of radioimmunotherapy, resulting in a local and systemic anti‐tumor response, which is currently attracting great academic interest and generating many hypotheses about the exact trigger and interaction mechanism behind it. 5 , 7 , 12 , 17 , 18 , 29 In this regard, a recently published review 17 highlighted the possible synergistic benefits of combining chemotherapy, radiation therapy, and immunotherapy such as the increase of cytotoxicity, the enhancement of immunogenic cell death and tumor necrosis as well as increased tumor‐derived and neoantigen generation, all of which could lead to a potentially enhanced antitumor effect.\n\nThe details of the complex mechanism of immunotherapy and radiation, as well as the interaction between the two, are described elsewhere. 5 , 7 , 16 , 17 , 29 , 30 Briefly summarized, tumor cells evade the immune response by up‐regulating specific proteins such as programmed cell death 1 ligand 1 (PDL‐1) on their surface. These immune checkpoint ligands interact with the programmed cell death protein 1 (PD‐1) surface receptors of activated cytotoxic T cells, thereby inhibiting them. By inhibiting the PD‐1/PDL‐1 signaling pathway with inhibitors such as nivolumab, pembrolizumab, durvalumab, and atezolizumab, which were administered in our immunotherapy subgroup, the T cells can recognize the tumor cells as pathogens and eliminate them. 1 , 2 , 5 , 7 , 20 Relatedly, radiation‐induced antitumor activity is immune‐mediated by the T cells. 11 Radiation stimulates tumor antigen presentation on the surface of dendritic cells to T cells, which is to prime the T cells in the lymph nodes to respond effectively against tumor cells. 15 , 18 , 31\n\nThe sequence in which RT and immunotherapy would be applied is still under investigation, 13 , 32 however available data showed clinical benefit with acceptable toxicity when immunotherapy was administered after radiation treatment, 12 , 14 which corresponds to the toxicity results obtained in our study. Accordingly, in our study, considering the side effects of immunotherapy, particularly with regard to pneumonitis 33 and the severe systemic 7 and local side effects that could be caused by the reirradiation treatment, immunotherapy was given after reirradiation. This treatment sequence was well tolerated. Eleven percent of the patients experienced grade 2 toxicity, with esophagitis and pneumonitis being the only radiogenic side effects, and 4% reported grade 3 toxicity. No grade 4 or 5 toxicity events were reported.\n\nAn obvious weakness of our analysis is the rather permissive threshold for first‐order errors (α). However, this is not unusual in exploratory studies with the aim of extracting as much potentially important information as possible. 23 , 34 Despite the small cohort and the retrospective nature, our data may gain additional significance given the fact that prospective studies on the combination of reirradiation combined with immunotherapy are lacking.\n\nCONCLUSION\n\nThe combination of reirradiation with immunotherapy could potentially prolong survival with acceptable toxicity. Although prospective studies are warranted, we believe that this combined treatment approach can transform the way patients with recurrent lung cancer are treated.\n\nCONFLICT OF INTEREST\n\nAll authors declare that they have no conflict of interest.\n==== Refs\nREFERENCES\n\n1 Antonia SJ , Villegas A , Daniel D , Vicente D , Murakami S , Hui R , et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379 (24 ):2342–50.30280658\n2 Antonia SJ , Villegas A , Daniel D , Vicente D , Murakami S , Hui R , et al. Durvalumab after chemoradiotherapy in stage III non‐small‐cell lung cancer. N Engl J Med. 2017;377 (20 ):1919–29.28885881\n3 Brahmer J , Reckamp KL , Baas P , Crinò L , Eberhardt WEE , Poddubskaya E , et al. Nivolumab versus docetaxel in advanced squamous‐cell non‐small‐cell lung cancer. N Engl J Med. 2015;373 (2 ):123–35.26028407\n4 Horn L , Mansfield AS , Szczęsna A , Havel L , Krzakowski M , Hochmair MJ , et al. First‐line Atezolizumab plus chemotherapy in extensive‐stage small‐cell lung cancer. N Engl J Med. 2018;379 (23 ):2220–9.30280641\n5 Evans T , Ciunci C , Hertan L , Gomez D . Special topics in immunotherapy and radiation therapy: reirradiation and palliation. Transl Lung Cancer Res. 2017;6 (2 ):119–30.28529895\n6 Horn L , Spigel DR , Vokes EE , Holgado E , Ready N , Steins M , et al. Nivolumab versus docetaxel in previously treated patients with advanced non‐small‐cell lung cancer: two‐year outcomes from two randomized, open‐label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017;35 (35 ):3924–33.29023213\n7 Wirsdorfer F , de Leve S , Jendrossek V . Combining radiotherapy and immunotherapy in lung cancer: can we expect limitations due to altered Normal tissue toxicity? Int J Mol Sci. 2018;20 (1 ):24.\n8 Reck M , Rodríguez‐Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , et al. Pembrolizumab versus chemotherapy for PD‐L1‐positive non‐small‐cell lung cancer. N Engl J Med. 2016;375 (19 ):1823–33.27718847\n9 Malvezzi M , Carioli G , Bertuccio P , Boffetta P , Levi F , la Vecchia C , et al. European cancer mortality predictions for the year 2019 with focus on breast cancer. Ann Oncol. 2019;30 (5 ):781–7.30887043\n10 Deng LF et al. Irradiation and anti‐PD‐L1 treatment synergistically promote antitumor immunity in mice. J Clin Investig. 2014;124 (2 ):687–95.24382348\n11 Demaria S , Pilones KA , Vanpouille‐Box C , Golden EB , Formenti SC . The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat Res. 2014;182 (2 ):170–81.24937779\n12 Ko EC , Raben D , Formenti SC . The integration of radiotherapy with immunotherapy for the treatment of non‐small cell lung cancer. Clin Cancer Res. 2018;24 (23 ):5792–806.29945993\n13 Peters S , Felip E , Dafni U , Belka C , Guckenberger M , Irigoyen A , et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo‐radiotherapy regimen in stage III non‐small cell lung cancer‐the ETOP NICOLAS trial. Lung Cancer. 2019;133 :83–7.31200833\n14 Shaverdian N , Lisberg AE , Bornazyan K , Veruttipong D , Goldman JW , Formenti SC , et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non‐small‐cell lung cancer: a secondary analysis of the KEYNOTE‐001 phase 1 trial. Lancet Oncol. 2017;18 (7 ):895–903.28551359\n15 Grass GD , Krishna N , Kim S . The immune mechanisms of abscopal effect in radiation therapy. Curr Probl Cancer. 2016;40 (1 ):10–24.26612692\n16 Ko EC , Formenti SC . Radiotherapy and checkpoint inhibitors: a winning new combination? Ther Adv Med Oncol. 2018;10 :1758835918768240.29662550\n17 Kasmann L et al. Chemoradioimmunotherapy of inoperable stage III non‐small cell lung cancer: immunological rationale and current clinical trials establishing a novel multimodal strategy. Radiat Oncol. 2020;15 (1 ):167.32646443\n18 Lugade AA , Moran JP , Gerber SA , Rose RC , Frelinger JG , Lord EM . Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen‐specific effector cells that traffic to the tumor. J Immunol. 2005;174 (12 ):7516–23.15944250\n19 De Ruysscher D et al. High‐dose re‐irradiation following radical radiotherapy for non‐small‐cell lung cancer. Lancet Oncol. 2014;15 (13 ):e620–4.25456380\n20 Antonia SJ , López‐Martin JA , Bendell J , Ott PA , Taylor M , Eder JP , et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small‐cell lung cancer (CheckMate 032): a multicentre, open‐label, phase 1/2 trial. Lancet Oncol. 2016;17 (7 ):883–95.27269741\n21 Wurstbauer K , Deutschmann H , Dagn K , Kopp P , Zehentmayr F , Lamprecht B , et al. DART‐bid (dose‐differentiated accelerated radiation therapy, 1.8 Gy twice daily): a novel approach for non‐resected NSCLC: final results of a prospective study, correlating radiation dose to tumor volume. Radiat Oncol. 2013;8 :49.23497555\n22 Grambozov B et al. Pulmonary function decreases moderately after accelerated high‐dose irradiation for stage III non‐small cell lung cancer. Thoracic Cancer. 2019;11 (2 ):369–78.31855325\n23 Palma DA , Olson R , Harrow S , Gaede S , Louie AV , Haasbeek C , et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR‐COMET): a randomised, phase 2, open‐label trial. Lancet. 2019;393 (10185 ):2051–8.30982687\n24 Rubinstein LV , Korn EL , Freidlin B , Hunsberger S , Ivy SP , Smith MA . Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 2005;23 (28 ):7199–206.16192604\n25 Meijneke TR , Petit SF , Wentzler D , Hoogeman M , Nuyttens JJ . Reirradiation and stereotactic radiotherapy for tumors in the lung: dose summation and toxicity. Radiother Oncol. 2013;107 (3 ):423–7.23647748\n26 Nieder C , Mannsåker B , Yobuta R , Haukland E . Provider decision regret‐a useful method for analysis of palliative thoracic re‐irradiation for lung cancer? Strahlenther Onkol. 2020;196 (4 ):315–24.32002566\n27 Schlampp I , Rieber J , Adeberg S , Bozorgmehr F , Heußel CP , Steins M , et al. Re‐irradiation in locally recurrent lung cancer patients. Strahlenther Onkol. 2019;195 (8 ):725–33.30937509\n28 Abuodeh Y , Venkat P , Kim S . Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016;40 (1 ):25–37.26582738\n29 Kalbasi A , June CH , Haas N , Vapiwala N . Radiation and immunotherapy: a synergistic combination. J Clin Invest. 2013;123 (7 ):2756–63.23863633\n30 Brix N , Tiefenthaller A , Anders H , Belka C , Lauber K . Abscopal, immunological effects of radiotherapy: narrowing the gap between clinical and preclinical experiences. Immunol Rev. 2017;280 (1 ):249–79.29027221\n31 Burnette BC , Liang H , Lee Y , Chlewicki L , Khodarev NN , Weichselbaum RR , et al. The efficacy of radiotherapy relies upon induction of type i interferon‐dependent innate and adaptive immunity. Cancer Res. 2011;71 (7 ):2488–96.21300764\n32 Lin SH , Lin Y , Yao L , Kalhor N , Carter BW , Altan M , et al. Phase II trial of concurrent atezolizumab with chemoradiation for unresectable NSCLC. J Thorac Oncol. 2020;15 (2 ):248–57.31778797\n33 Topalian SL , Hodi FS , Brahmer JR , Gettinger SN , Smith DC , McDermott DF , et al. Safety, activity, and immune correlates of anti‐PD‐1 antibody in cancer. N Engl J Med. 2012;366 (26 ):2443–54.22658127\n34 Dhawan A , Scott JG , Harris AL , Buffa FM . Pan‐cancer characterisation of microRNA across cancer hallmarks reveals microRNA‐mediated downregulation of tumour suppressors. Nat Commun. 2018;9 :5228.30531873\n\n", "fulltext_license": "CC BY", "issn_linking": "1759-7706", "issue": "12(8)", "journal": "Thoracic cancer", "keywords": "immunotherapy; local recurrence; lung cancer; overall survival and toxicity; reirradiation", "medline_ta": "Thorac Cancer", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011879:Radiotherapy Dosage; D000069475:Re-Irradiation; D012189:Retrospective Studies; D016019:Survival Analysis", "nlm_unique_id": "101531441", "other_id": null, "pages": "1162-1170", "pmc": null, "pmid": "33586228", "pubdate": "2021-04", "publication_types": "D016428:Journal Article", "references": "24937779;33586228;22658127;26612692;30280658;30577587;32646443;30531873;30280641;26028407;25456380;31778797;29023213;16192604;28885881;27269741;23863633;30887043;30937509;27718847;23497555;21300764;24382348;29945993;31855325;30982687;29662550;28551359;28529895;32002566;26582738;23647748;15944250;31200833;29027221", "title": "Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single-center retrospective analysis.", "title_normalized": "impact of reirradiation chemotherapy and immunotherapy on survival of patients with recurrent lung cancer a single center retrospective analysis" }

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{ "abstract": "Malignant pleural mesothelioma (MPM) is an asbestos-related tumor arising in the pleural cavity. Symptoms reflect extension of disease and include shortness of breath and chest pain. Unexplained pleural effusion and pleural pain in patients exposed to asbestos should raise the suspicion of MPM. The most common radiologic presentation is ipsilateral pleural effusion with or without pleural thickening or a mass. Thoracoscopic biopsy remains the most appropriate procedure for definitive diagnosis of mesothelioma. Despite advancement in diagnostic procedures and biomolecular research, this tumor nevertheless has poor prognosis. Mesothelioma remains a diagnostic and therapeutic challenge and is likely to remain one in the years to come. Here we present the first reported case of steroid treatment responsive pleural effusion in a 72 year-old-male that initially was misdiagnosed as rheumatoid related effusion. However, Pleuroscopy with biopsy revealed mesothelioma.", "affiliations": "Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.;Department of Pulmonary and Critical Care Medicine, Veterans Administration Medical Center, Huntington, WV 25701, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.;Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA.", "authors": "Shehata|Mena|M|;Zaid|Fouad|F|;Ottaviano|Peter|P|;Shweihat|Yousef|Y|;Munn|Nancy|N|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/j.rmcr.2018.12.006", "fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(18)30324-110.1016/j.rmcr.2018.12.006Case ReportCase report: Steroid responsive mesothelioma-related pleural effusion Shehata Mena [email protected]∗Zaid Fouad bcOttaviano Peter cShweihat Yousef bMunn Nancy bca Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USAb Department of Pulmonary Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USAc Department of Pulmonary and Critical Care Medicine, Veterans Administration Medical Center, Huntington, WV 25701, USA∗ Corresponding author. [email protected] 12 2018 2019 19 12 2018 26 131 135 19 10 2018 11 12 2018 11 12 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Malignant pleural mesothelioma (MPM) is an asbestos-related tumor arising in the pleural cavity. Symptoms reflect extension of disease and include shortness of breath and chest pain. Unexplained pleural effusion and pleural pain in patients exposed to asbestos should raise the suspicion of MPM. The most common radiologic presentation is ipsilateral pleural effusion with or without pleural thickening or a mass. Thoracoscopic biopsy remains the most appropriate procedure for definitive diagnosis of mesothelioma. Despite advancement in diagnostic procedures and biomolecular research, this tumor nevertheless has poor prognosis. Mesothelioma remains a diagnostic and therapeutic challenge and is likely to remain one in the years to come.\n\nHere we present the first reported case of steroid treatment responsive pleural effusion in a 72 year-old-male that initially was misdiagnosed as rheumatoid related effusion. However, Pleuroscopy with biopsy revealed mesothelioma.\n==== Body\n1 Introduction\nMalignant mesothelioma is a tumor arising from the mesothelial cells or sub-mesothelial cells of the pleura, peritoneum or pericardium, with more than 80% originate in the pleura [1]. The most common cause of diffuse malignant mesothelioma in the United States is inhalation of asbestos [2]. The latency from the time of exposure to the development of malignant mesothelioma is several decades [3]. Low-level exposures, as well as bystander are risk factors for the mesothelioma. No threshold of asbestos exposure has been established for the development of malignant mesothelioma [4]. Despite the fact that industrial use of asbestos was forbidden many years ago, new cases of mesothelioma continue to appear because of the long latency of the disease [5].\n\nHere, we report a case of 72-years-old male with multiple admissions for pleuritic chest pain associated with recurrent exudative pleural effusions with dramatic response to steroids, initially misdiagnosed as connective tissue disease related pleural effusion. Yet it was found to be mesothelioma.\n\n2 Case presentation\nHerein a 72-year-old male patient with no significant past medical history apart from hyperlipidemia. He is a retired plumber and former Veteran. He quit smoking 38 years ago. He presented to the Emergency department (ED) with complain of worsening chest pain for few days that increased with deep inspiration. Pain was piercing in nature affecting his right side, sometimes associated with cough but no concomitant shortness of breath. His vital signs at that time were within normal and his cardiopulmonary exam was unremarkable. Acute coronary syndrome was ruled out through negative troponin series and a normal EKG. Patient was diagnosed with pleurisy and was released home from ED with a NSAID along with short steroid taper.\n\nTwo weeks later the patient presented again with the same complain. Physical exam was unremarkable and initial laboratory results were significant for mild leukocytosis. Chest x-ray showed new right sided effusion with infiltrate versus consolidation (Fig. 1). Computed tomography of the chest with intravenous contrast ruled out pulmonary embolism yet it has showed a small right-sided pleural effusion as well as right lower lobe infiltration versus consolidation. Patient also had right hilar small lymphadenopathy on imaging and minimal pericardial effusion (Fig. 2, Fig. 3, Fig. 4).Fig. 1 Admission Plain radiograph with small pleural effusion.\n\nFig. 1Fig. 2 CT mediastinal view of the chest with lymphadenopathy.\n\nFig. 2Fig. 3 Pleural effusion on the right.\n\nFig. 3Fig. 4 Right lower lobe infiltrate.\n\nFig. 4\n\nPatient then was admitted to the hospital and was treated as community acquired pneumonia with intravenous ceftriaxone and Azithromycin. Patient was also started on intravenous methylprednisolone every six hours and ibuprofen as needed for pain control. The white-cell count on subsequent days has increased from 14.5 × 103 to 30.5 × 103/μL on day 3. Antibiotics were escalated to intravenous vancomycin, Piperacillin and tazobactam. Pulmonary service was consulted for worsening leukocytosis in setting of pneumonia and parapneumonic pleural effusion. At that time patient symptoms had improved and there was no indication for aspiration because of minimal effusion and subjective improvement. The pulmonologist has recommended repeat chest scan in 8–12 weeks to reassess adenopathy and confirm resolution. His white count was attributed to steroid administration. He was discharged on oral antibiotics along with a prednisone taper upon improvement of his symptoms and labs.\n\nTwo weeks later the patient represented to ED with recurrence of his symptoms few days after he had finished his steroid course. Physical exam was significant for tachycardia 111 bpm and tachypnea, laboratory testing was Significant for leukocytosis of 19.6 × 103/μL. EKG showed sinus tachycardia. Plain chest radiograph showed recurrence of pleural effusion in the right side (Fig. 5a). Repeat Chest CT showed worsening right pleural effusion along with progressive consolidative changes in the right lower lobe (Fig. 5, Fig. 6, Fig. 7). Patient was admitted and was started on intravenous vancomycin, Piperacillin, tazobactam as well as methylprednisolone for presumed worsening pneumonia. Echocardiogram demonstrated normal biventricular function.Fig. 5 Worsening pleural effusion (a and b).\n\nFig. 5Fig. 6 Right middle lobe infiltrate.\n\nFig. 6Fig. 7 Worsening right lower lobe infiltrate.\n\nFig. 7\n\nPulmonary service was re-consulted who did bedside ultrasound on the next day showed very small right sided pleural effusion that is unsafe to tap. The dramatic improvement of pleural fluid after steroid treatment increased the suspicion of possible connective tissue disease as a cause. Connective tissue diseases work-up was done, revealed positive rheumatoid factor along with strongly positive Anti-cyclic citrullinated peptide (level > 70). Erythrocyte sedimentation rate C-reactive protein were both elevated 61 mm/hr and 260.4, respectively. ANA, ANCA profile and anti SCL-70 were negative. Before being discharged the pleural effusion as resolved (Fig. 8). He was discharged on prednisone 40 mg daily for two weeks until seen by pulmonary clinic for follow up.Fig. 8 Dramatic improvement of right-side pleural effusion at hospital (a) and then at the clinic (b).\n\nFig. 8\n\nPatient stopped the treatment as a repeat x-ray done in his primary care physician office after following up hospital visit showed complete resolution of his effusion (Fig. 8b).\n\nFew days later, patient was due for his pulmonary clinic follow up and he complained of return of his pleurisy symptoms when he tapered steroid. At that time, he was restarted on a prolonged steroid taper starting at 60 mg of prednisone per day. Repeat chest scan for follow up on the hilar lymphadenopathy showed near normalization of the size of the lymph nodes and trace residual right pleural effusion (Fig. 8a and b). Also, right lower lobe infiltrate showed resolution compared to prior imaging. At that time the patient was still on steroid taper and was asymptomatic (see Fig. 9).Fig. 9 CT scan showed regression of lymphadenopathy and near complete resolution of pleural effusion.\n\nFig. 9\n\nOne month later the patient was seen in the pulmonary clinic for follow-up. Chest plain radiograph was normal and prednisone dose was further reduced to 10 mg. Yet few days later the patient developed pleuritic type chest pain and chest x ray showed re-accumulation of his pleural effusion at the emergency department (Fig. 10).Fig. 10 Plain radiograph with recurrent moderate pleural effusion.\n\nFig. 10\n\nPatient refused admission and Video-Consult to pulmonary was done and patient was advised to restart on prednisone 40 mg until future appointment in the pulmonary clinic for thoracentesis. Due to the prolonged steroid course the patient was also started on Trimethoprim/Sulfamethoxazole for prophylaxis against pneumocystis. And patient returned to the pulmonary clinic one week later, and a repeat CXR showed decreased pleural effusion responding to steroid (Fig. 11). At that time, he was thought of as rheumatoid induced pleural effusion steroid responsive, yet no tapping has been done.Fig. 11 Plain radiograph with decreasing right pleural effusion.\n\nFig. 11\n\nAbout one month later (4 months since initial presentation) while the patient was still taking 30 mg prednisone, his pleural effusion recurred, and first-time thoracentesis was done at the pulmonary clinic with inconclusive fluid studies. Gram stain was negative and culture later on had no growth. Patient was discharged on same treatment.\n\nPatient developed atrial fibrillation with rapid ventricular rhythm and was admitted through another facility and chest x ray still had pleural effusion. Repeat thoracentesis results were exudative, Serum protein 6.7 g/dl, Serum LDH 149 (87-241 IU/L), Fluid LDH 851 IU/L, Negative microbiology, Fluid glucose 137 mg/dl, Fluid protein 3.2 g/dl, WBC 206 × 103/μL (16 neutrophils, 12 monocytes, 60 lymphocytes), Cytology results came back with atypical cells present on both thoracentesis. Patient again was readmitted for therapeutic and diagnostic purposes from effusion recurrence. Third time thoracentesis done week later was same on analysis. Patient was referred for pleuroscopy with biopsy.\n\nPleuroscopy showed lots of loculations as well as adhesions. The parietal pleural was infiltrated with what seemed to be inflammatory tissue and had some areas of nodularity. Multiple biopsies were obtained from the parietal pleura. The entire surface of the parietal pleura including some of the diaphragmatic pleura was involved. Visceral pleura was noted to be unaffected by gross exam. For his recurrent pleural effusion, a Pleurx catheter was left for drainage and symptomatic relief.\n\nPathological exam report was positive for a tumor consistent with mesothelioma (epithelioid type). Immunohistochemical stains performed. Results were of cells positive for Calretinin, CK5/6, CK7, and WT-1 but negative for Napsin-A, CK20, and TTF-1.\n\nPET scan results revealed diffuse abnormal right pleural uptake consistent with history of mesothelioma with no evidence of disease elsewhere (Fig. 12).Fig. 12 Pet scan results with disease limited to pleura on the right side.\n\nFig. 12\n\nPatient disease was classified as stage 1 as per the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) [6].Patient was referred to a specialized cancer center for management.\n\n3 Discussion\nDespite the presence of some clinical and laboratory findings on review of the case, these can be as misleading if not carefully assessed. The differential diagnosis of this unexplained pleuropulmonary process includes collagen vascular disease, thromboembolic disease, and malignant tumors. The recurrent effusion that occurred in the absence of evidence of infection, as well as recurrent worsening chest pain that was reported by the patient on admissions in lieu of dramatic response to steroid on multiple occasions plus inability to do thoracentesis early made the diagnosis of the case challenging.\n\nPneumonia can be a cause of exudative pleural effusions especially if partially treated. Parapneumonic pleural effusion refers to pleural effusion associated with bacterial pneumonia, a pulmonary abscess or infected bronchiectasis [7]. This is less likely to be the case here since the patient symptoms didn't fit with this diagnosis. Also, his very rapid response to steroid treatment with marked regression of the effusion is less likely to happen with a parapneumonic effusion.\n\nPatients with collagen vascular disease can initially present with recurrent pleural effusions [8]. Rheumatoid effusions are well described in the literature with pleural involvement is the most common thoracic manifestation of rheumatoid disease [9], yet the absolute incidence of rheumatoid pleural effusion is low. Especially with the presence of anti-rheumatoid factor and anti-Citrullinated peptide antibodies, rheumatoid disease is a high suspicion. Despite these suspicions the patient had no history of a rheumatoid disease. Additionally, in rheumatoid induced pleural effusion, one would see numerous polymorphonuclear leukocytes at the time of presentation and as the effusion matures a lymphocytic predominance can be appreciated [10]. Rheumatoid effusion is also characterized by low pleural fluid glucose level, usually less than 30 mg/dl [11]. His pleural effusion analysis was atypical of rheumatoid induced pleural effusion.\n\nMalignant pleural effusion can result from primary malignancies of the pleura or with intrathoracic and extra-thoracic malignancies that reach the pleural space by hematogenous, lymphatic, or contiguous spread [9]. Lung carcinoma is the most common cause of chest pain and pleural effusions in this age group [8] These effusions are known as paraneoplastic or paramalignant pleural effusions [9]. Malignant mesothelioma is a tumor arising from the mesothelial cells or sub-mesothelial cells of the pleura, peritoneum or pericardium, with more than 80% originate in the pleura [1]. The most common radiographical presentation is unilateral pleural effusion with or without ipsilateral pleural thickening or mass [12]. Only a small number of patients are asymptomatic at diagnosis, having an incidental detection of abnormality on imaging undertaken for a different reason [13]. Dyspnea is the first symptom of pleural mesothelioma cases [14,15]. Pleural mesothelioma can cause pain by irritating intercostal nerves or by infiltrating into the chest wall. Rarer manifestations include phrenic nerve palsy, irritative cough, para-neoplastic phenomena, and spontaneous pneumothorax [16]. Malignant pleural effusion is often one of the primary manifestation of mesothelioma and can be found in about 90% of patients at diagnosis [17]. Effusion sampling obtained by thoracentesis and cytological examination is the most informative laboratory test for diagnosis. In patients who do not appear to have a history of asbestos exposure, mesothelioma should not be ruled out if other symptoms and signs of the disease are present. Unfortunately establishing the diagnosis of mesothelioma can be difficult. In malignant mesothelioma of the pleura, cytology displays a low sensitivity and is not an accurate assay in differentiating malignant cells from reactive mesothelial cells or lung cancer cells [18,19]. When nodular pleural thickening is present, a fine-needle biopsy can be performed to establish the diagnosis, but there is only a 25% chance that the biopsy will yield a diagnosis in the presence of a no diagnostic effusion. Video-assisted thoracoscopic surgery (VATS) is the diagnostic procedure of choice; it yields a diagnosis in more than 90% of cases.\n\nUpon careful review of literature and to the best of our knowledge, we were unable to find any case report describing steroid responsive pleural effusion secondary to mesothelioma.\n\nDeclaration of conflicting interests\nThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 Kim J. Bhagwandin S. Labow D.M. Malignant peritoneal mesothelioma : a review 5 11 2017 1 11 \n2 L. S. Welch, “Asbestos Exposure Causes Mesothelioma, But Not This Asbestos Exposure:,” no. 133178, pp. 318–327.\n3 Iwatsubo Y. Pairon J. De Beaune C.A. Bignon J. Brochard P. Pleural Mesothelioma : a Descriptive Analysis Based on a Case-Control Study and Mortality Data in Ile de 88 1994 77 88 \n4 Craighead J.E. Epidemiology of Mesothelioma and Historical Background 2011 \n5 Delgermaa V. Takahashi K. Park E. Le V. Sorahan T. Global Mesothelioma Deaths Reported to the World Health Organization between 1994 and 2008,” No. January 2011 716 724 \n6 Amin MB S. Edge S.B. Greene F.L. AJCC (American Joint Committee on Cancer) Cancer Staging Manual eighth ed. 2017 \n7 Yu H. Management of pleural effusion, empyema, and lung abscess 1 212 2011 75 86 \n8 Kradin R.L. Fidias P. Case 17-2014 : a 64-year-old Man with Chest Pain and a Pleural Effusion 2014 \n9 Press D. Pleural effusion: diagnosis, treatment, and management 2012 31 52 \n10 Avnon L.S. Abu-Shakra M. Flusser D. Heimer D. Sion-Vardy N. Pleural effusion associated with rheumatoid arthritis: what cell predominance to anticipate? Rheumatol. Int. 27 10 2007 Aug 1 919 925 17294192 \n11 Article R. Differential diagnosis of pleural effusions 49 9 2006 315 319 \n12 Fayed H.E. Woodcock V.K. Grayez J. Simultaneous bilateral spontaneous hydropneumothorax : a rare presentation of bilateral malignant pleural mesothelioma 2013 1 3 \n13 Bianco A. Valente T. De Rimini M.L. Sica G. Fiorelli A. Clinical diagnosis of malignant pleural mesothelioma 10 7 2018 253 261 \n14 Scherpereel A. Guidelines of the european respiratory society and the european society of thoracic surgeons for the management of malignant pleural mesothelioma 35 3 2010 479 495 \n15 Health O. Neumann V. Löseke S. Nowak D. Herth F.J.F. Tannapfel A. Malignant pleural mesothelioma 110 2013 18 \n16 Article O. Malignant Mesothelioma ± German Mesothelioma Register 1987±1999 2001 383 395 \n17 Franceschini M.C. Mesothelin in Serum and pleural effusion in the diagnosis of malignant pleural mesothelioma with non-positive cytology 7430 2014 7425 7429 May 2013 \n18 A. A. Renshaw, B. R. Dean, and K. H. Antman, “The role of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma *,” Chest, vol. 111, no. 1, pp. 106–109.\n19 Rakha E.A. The sensitivity of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma 38 2010 12\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2213-0071", "issue": "26()", "journal": "Respiratory medicine case reports", "keywords": null, "medline_ta": "Respir Med Case Rep", "mesh_terms": null, "nlm_unique_id": "101604463", "other_id": null, "pages": "131-135", "pmc": null, "pmid": "30603603", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "11563601;17294192;17915546;19717482;20049969;21479893;22084509;22379278;23682089;23720698;24869724;25503183;29507793;8074126;8996002", "title": "Case report: Steroid responsive mesothelioma-related pleural effusion.", "title_normalized": "case report steroid responsive mesothelioma related pleural effusion" }

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"2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PAIN MANAGEMENT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IBUPROFEN." } ], "patientagegroup": null, "patientonsetage": "72", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Leukocytosis", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product use in unapproved indication", "reactionmeddraversionpt": "21.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { 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CASE REPORT: STEROID RESPONSIVE MESOTHELIOMA-RELATED PLEURAL EFFUSION. RESPIRATORY MEDICINE CASE REPORTS. 2019?26:131-5", "literaturereference_normalized": "case report steroid responsive mesothelioma related pleural effusion", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20190204", "receivedate": "20190204", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 15906192, "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": "A seven years old girl presented with history of sudden onset of generalized body weakness to an extent that she was not able to move any body part. On thorough history it was revealed that she was given intramuscular injection lincomycin at private clinic which lead to neuromuscular paralysis of whole body. This antibiotic is currently not being used in humans and being only used as veterinary medication.", "affiliations": null, "authors": "Shah|Syed Sajid Hussain|SS|;Saleem|Munaza|M|;Mehood|Tahir|T|", "chemical_list": "D000900:Anti-Bacterial Agents; D008034:Lincomycin", "country": "Pakistan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1025-9589", "issue": "26(3)", "journal": "Journal of Ayub Medical College, Abbottabad : JAMC", "keywords": null, "medline_ta": "J Ayub Med Coll Abbottabad", "mesh_terms": "D000900:Anti-Bacterial Agents; D002648:Child; D005260:Female; D006801:Humans; D008034:Lincomycin; D010243:Paralysis", "nlm_unique_id": "8910750", "other_id": null, "pages": "406-7", "pmc": null, "pmid": "25671960", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Neuromuscular paralysis by a single injection of lincomycin.", "title_normalized": "neuromuscular paralysis by a single injection of lincomycin" }

[ { "companynumb": "PK-PFIZER INC-2015109394", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LINCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "050317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RASH GENERALISED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINCOMYCIN HCL" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LINCOMYCIN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "050317", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PRURITUS GENERALISED", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINCOMYCIN HCL" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paralysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH SS. NEUROMUSCULAR PARALYSIS BY A SINGLE INJECTION OF LINCOMYCIN. JOURNAL OF AYUB MEDICAL COLLEGE, ABBOTTABAD: JAMC. 2014;26(3):406-407", "literaturereference_normalized": "neuromuscular paralysis by a single injection of lincomycin", "qualification": "3", "reportercountry": "PK" }, "primarysourcecountry": "PK", "receiptdate": "20150402", "receivedate": "20150402", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 10979347, "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" }, { "companynumb": "PK-WATSON-2015-08347", "fulfillexpeditecriteria": "1", "occurcountry": "PK", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "LINCOMYCIN" }, "drugadditional": null, "drugadministrationroute": "030", "drugauthorizationnumb": "063180", "drugbatchnumb": "UNCONFIRMED", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNK", "drugdosagetext": "UNK, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "URTICARIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LINCOMYCIN (UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "7", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Paralysis", "reactionmeddraversionpt": "18.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH SS, SALEEM M, MEHOOD T. NEUROMUSCULAR PARALYSIS BY A SINGLE INJECTION OF LINCOMYCIN. J AYUB MED COLL ABBOTTABAD. 2014;26(3):406-7", "literaturereference_normalized": "neuromuscular paralysis by a single injection of lincomycin", "qualification": "3", "reportercountry": "PK" }, "primarysourcecountry": "PK", "receiptdate": "20150428", "receivedate": "20150428", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11072248, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20150821" } ]

{ "abstract": "OBJECTIVE\nTo describe the long-term outcomes of intravitreal bevacizumab (IVB) for the treatment of pediatric retinal and choroidal diseases.\n\n\nMETHODS\nThis was a multicenter, retrospective, consecutive case series of patients <18 years of age treated with IVB from 2005 to 2013. Primary outcome measures included visual acuity and central macular thickness at 12 months' follow-up.\n\n\nRESULTS\nA total of 95 eyes of 90 patients (average age, 8.7 years [range, 0.33-17 years]) were included, in which 352 injections (average, 3.7/eye) were administered for choroidal neovascular membrane (CNVM, n = 35), Coats disease (n = 35), familial exudative vitreoretinopathy (FEVR, n = 13), cystoid macular edema (CME, n = 6), and other (n = 6). Mean follow-up was 679 ± 581 days. IVB was used as monotherapy in 27 eyes and as part of combination therapy in 68. Mean Snellen equivalent visual acuity improved from 20/224 at baseline to 20/120 at 6 months (P = 0.034) and 20/108 at 12 months (P = 0.005). Mean central macular thickness improved from 426 μm to 349 μm at 6 months (P = 0.025) and 340 μm at 12 months (P = 0.002). Statistically significant visual acuity gains at 12 months were achieved in patients with CNVM (P = 0.009) but not in eyes with CME (P = 0.06), Coats disease (P = 0.15), or FEVR (P = 0.93). Adverse effects included ocular hypertension in 8 eyes and worsening tractional retinal detachment in 3 eyes.\n\n\nCONCLUSIONS\nPatients receiving IVB as part of the treatment for pediatric retinal and choroidal diseases experienced significant visual acuity gains and reductions in central macular thickness. IVB was generally well tolerated, although safety concerns persist.", "affiliations": "Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida. Electronic address: [email protected].;Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.;Murray Ocular Oncology and Retina, Miami, Florida.;Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.", "authors": "Henry|Christopher R|CR|;Sisk|Robert A|RA|;Tzu|Jonathan H|JH|;Albini|Thomas A|TA|;Davis|Janet L|JL|;Murray|Timothy G|TG|;Berrocal|Audina M|AM|", "chemical_list": "D020533:Angiogenesis Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1091-8531", "issue": "19(6)", "journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus", "keywords": null, "medline_ta": "J AAPOS", "mesh_terms": "D000293:Adolescent; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D002648:Child; D002675:Child, Preschool; D015862:Choroid Diseases; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D008297:Male; D012164:Retinal Diseases; D012189:Retrospective Studies; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity", "nlm_unique_id": "9710011", "other_id": null, "pages": "541-8", "pmc": null, "pmid": "26691034", "pubdate": "2015-12", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Long-term follow-up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases.", "title_normalized": "long term follow up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases" }

[ { "companynumb": "US-ROCHE-1399195", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "CHOROIDITIS", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 MG/0.05 ML VIA THE PARS PLANA USING A 30- OR 32-GAUGE HALF-INCH NEEDLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Retinal detachment", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Ocular hypertension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", SISK R, TZU J, ALBINI T, DAVIS J, MURRAY T AND BERROCAL A. LONG-TERM FOLLOW-UP OF INTRAVITREAL BEVACIZUMAB FOR THE TREATMENT OF PEDIATRIC RETINAL AND CHOROIDAL DISEASES. JOURNAL OF AAPOS 2015;19 (6):541-548.", "literaturereference_normalized": "long term follow up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170606", "receivedate": "20140516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10175509, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170829" }, { "companynumb": "US-ROCHE-1400958", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": null, "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINOPATHY CONGENITAL", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": "3", "drugadministrationroute": "050", "drugauthorizationnumb": "125085", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1.25 MG/0.05 ML OF BEVACIZUMAB", "drugenddate": null, "drugenddateformat": null, "drugindication": "RETINAL DISORDER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB" } ], "patientagegroup": null, "patientonsetage": "16", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Idiopathic intracranial hypertension", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": ", SISK R, TZU J, ALBINI T, DAVIS J, MURRAY T AND BERROCAL A. LONG-TERM FOLLOW-UP OF INTRAVITREAL BEVACIZUMAB FOR THE TREATMENT OF PEDIATRIC RETINAL AND CHOROIDAL DISEASES. JOURNAL OF AAPOS 2015;19 (6):541-548.", "literaturereference_normalized": "long term follow up of intravitreal bevacizumab for the treatment of pediatric retinal and choroidal diseases", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170606", "receivedate": "20140516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10175505, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170829" } ]

{ "abstract": "Data from clinical trials do not always provide adequate information to judge the impact of new treatments when used in a real-world setting. The aim of our study was to analyze adverse events (AEs) associated with enzalutamide (ENZ) and abiraterone (ABI) using real-life data from the EudraVigilance (EV) database.\n\n\n\nThe EV database is the system for managing and analyzing information on suspected adverse reactions to medicines, which have been authorized or are being studied in clinical trials in the European Economic Area. We recorded the number of AEs for ABI and ENZ per category and severity from January 2013 to January 2019. In addition, we recorded AEs per age group. A meta-analysis of AEs reported in registrational phase III studies (AFFIRM, PREVAIL, COU-AA) was performed.\n\n\n\nThe number of individual cases identified in EV database was 13,562 for ABI and 40,599 for ENZ. Over 90% of the reported AEs were defined as serious for both drugs. Older patients (>85 years and 65-85 years) treated with ABI or ENZ are at increased risk of cardiac, infectious, metabolic, and respiratory disorders when compared with younger patients (<65). According to registrational phase III studies, the most frequent AEs in patients treated with ABI are hepatobiliary disorders, while the most frequent AEs in patients treated with ENZ are psychiatric and vascular disorders. Several AEs present in the EV database are not reported in the registrational phase III studies. It is important to note that we have no information on the number of patients under treatment in the EV database.\n\n\n\nThe EV database highlights several AEs that are not reported in registrational phase III studies as well as different AEs profiles according to age. Clinicians should consider these data when treating patients with castration-resistant prostate cancer with ABI or ENZ.", "affiliations": "Department of Urology, Ospedale Sant'Andrea, Rome, Italy. [email protected].;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.;Oncologia Medica, Fondazione Policlinico Universitario \"A. Gemelli\" IRCCS, Rome, Italy.;Department of Urology, Azienda Ospedaliera di Terni, Terni, Italy.;Department of Urology, Ospedale Sant'Andrea, Rome, Italy.", "authors": "De Nunzio|Cosimo|C|;Lombardo|Riccardo|R|;Tema|Giorgia|G|;Voglino|Olivia|O|;Sica|Angela|A|;Baldassarri|Valeria|V|;Nacchia|Antonio|A|;Iacovelli|Roberto|R|;Bracarda|Sergio|S|;Tubaro|Andrea|A|", "chemical_list": "D000736:Androstenes; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone", "country": "England", "delete": false, "doi": "10.1038/s41391-019-0182-x", "fulltext": null, "fulltext_license": null, "issn_linking": "1365-7852", "issue": "23(2)", "journal": "Prostate cancer and prostatic diseases", "keywords": null, "medline_ta": "Prostate Cancer Prostatic Dis", "mesh_terms": "D000736:Androstenes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D017326:Clinical Trials, Phase III as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin; D011379:Prognosis; D011471:Prostatic Neoplasms; D012189:Retrospective Studies", "nlm_unique_id": "9815755", "other_id": null, "pages": "199-206", "pmc": null, "pmid": "31685981", "pubdate": "2020-06", "publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review", "references": null, "title": "Adverse events related to abiraterone and enzalutamide treatment: analysis of the EudraVigilance database and meta-analysis of registrational phase III studies.", "title_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies" }

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"activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Cardiac disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Mediastinal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Connective tissue disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Product quality issue", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Lymphatic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hepatobiliary disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Breast disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Eye disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Angiopathy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Respiratory disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Abdominal pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infestation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Neoplasm", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Malnutrition", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Gastrointestinal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Urinary tract disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Inner ear disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Mental disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Metabolic disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Laboratory test abnormal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Reproductive tract disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Disability", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Blood disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Adverse event", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Constipation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Endocrine disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Surgery", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Immune system disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Skin disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Musculoskeletal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Injury", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Social problem", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Pregnancy of partner", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" } ], "summary": null }, "primarysource": { "literaturereference": "TUBARO A, LOMBARDO R, TEMA G, VOGLINO O, SICA A, BALDASSARRI V, NACCHIA A, IACOVELLI R, BRACARDA S, NUNZIO C. ADVERSE EVENTS RELATED TO ABIRATERONE AND ENZALUTAMIDE TREATMENT: ANALYSIS OF THE EUDRAVIGILANCE DATABASE AND META?ANALYSIS OF REGISTRATIONAL PHASE III STUDIES. PROSTATE CANCER AND PROSTATIC DISEASES. 2019 NOV 04?.", "literaturereference_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200820", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17970418, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": 1, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" }, { "companynumb": "IT-JNJFOC-20200641345", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neonatal disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "3" }, { "reactionmeddrapt": "Paternal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "COSIMO D, RICCARDO L, GIORGIA T, OLIVIA V, ANGELA S, VALERIA B, ANTONIO N, ROBERTO I, SERGIO B, ANDREA T. ADVERSE EVENTS RELATED TO ABIRATERONE AND ENZALUTAMIDE TREATMENT: ANALYSIS OF THE EUDRAVIGILANCE DATABASE AND META?ANALYSIS OF REGISTRATIONAL PHASE III STUDIES. PROSTATE CANCER AND PROSTATIC DISEASES. 2019 NOV 04?.", "literaturereference_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200701", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17967796, "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": "IT-JNJFOC-20200641205", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ABIRATERONE ACETATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "202379", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "TABLET", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "PROSTATE CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ABIRATERONE ACETATE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Foetal exposure during pregnancy", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Congenital anomaly", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "COSIMO D. ADVERSE EVENTS RELATED TO ABIRATERONE AND ENZALUTAMIDE TREATMENT: ANALYSIS OF THE EUDRAVIGILANCE DATABASE AND META?ANALYSIS OF REGISTRATIONAL PHASE III STUDIES. PROSTATE CANCER AND PROSTATIC DISEASES. 2019 NOV 04?.", "literaturereference_normalized": "adverse events related to abiraterone and enzalutamide treatment analysis of the eudravigilance database and meta analysis of registrational phase iii studies", "qualification": "3", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20200701", "receivedate": "20200701", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 17967811, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Anticoagulants are commonly prescribed in medical practices and could be of significant harm in the case of medication errors. We conducted a retrospective observational study to determine the frequency and consequences of the therapeutic duplication of anticoagulants (TDA). As a secondary objective, we aimed to determine the characteristics of the population in which TDA occurs.\nWe conducted a retrospective observational study among admitted patients who concomitantly received at least two anticoagulants from August 2017 to August 2018.\nA total of 107 patients with TDA are included in the research. The patients with TDA have a mean age of 73. The TDA population has a high rate of associated comorbidities with 69% of patients having arterial hypertonia, 40% with chronic kidney disease, 26% with a history of malignancy, and 20.5% with a history of stroke. More than 65% of patients were under anticoagulation before admission, mostly due to atrial fibrillation. The TDA occurred in more than 95% of cases in the first week or the last week of hospitalization. Patients had a high risk of bleeding prior to the TDA-event with about 62.5% of TDA patients having a HAS-BLED score at least 3. A total of 8 patients showed a significant Hemoglobin (Hb)-drop of at least 10 g/L within 24 h after TDA-event. Two patients had a new or worsened hematuria following TDA-event.\nTDA occurred in 0.8% of patients who were under anticoagulation and in 6.7% of patients who received direct oral anticoagulants (DOACs). TDA led in about 7.4% of cases to hemoglobin-relevant bleeding. The old patients with significant comorbidities and a high HAS-BLED score were mainly affected. The female gender and presence of anemia independently predicted the occurrence of bleeding following TDA.", "affiliations": "Faculty of Medicine, University of Basel, Basel, Switzerland.;Hospital Pharmacy, Kantonsspital Aarau, Aarau, Switzerland.;Hospital Pharmacy, Kantonsspital Aarau, Aarau, Switzerland.;Faculty of Medicine, University of Basel, Basel, Switzerland.;Department of Internal Medicine, Kantonsspital Aarau, 5000 Aarau, Switzerland.", "authors": "Rahmanzade|Ramin|R|;Cabrera Diaz|Francisco|F|;Zaugg|Claudia|C|;Schuetz|Philipp|P|;Salili|Ali Reza|AR|0000-0003-2488-646X", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12959-020-00227-w", "fulltext": "\n==== Front\nThromb J\nThromb J\nThrombosis Journal\n1477-9560 BioMed Central London \n\n227\n10.1186/s12959-020-00227-w\nResearch\nTherapeutic duplication of anticoagulants: a retrospective study of frequency and consequences in a tertiary referral hospital\nRahmanzade Ramin 12 Cabrera Diaz Francisco 3 Zaugg Claudia 3 Schuetz Philipp 14 http://orcid.org/0000-0003-2488-646XSalili Ali Reza [email protected] 45 1 grid.6612.30000 0004 1937 0642Faculty of Medicine, University of Basel, Basel, Switzerland \n2 grid.410567.1Biomedical Research and Training, University Hospital Basel, Basel, Switzerland \n3 grid.413357.70000 0000 8704 3732Hospital Pharmacy, Kantonsspital Aarau, Aarau, Switzerland \n4 grid.413357.70000 0000 8704 3732Department of Internal Medicine, Kantonsspital Aarau, 5000 Aarau, Switzerland \n5 Department of Internal Medicine, Clinical Pharmacology, Kantonsspital Aarau, Tellstrasse 51, CH-5001 Aarau, Switzerland \n3 8 2020 \n3 8 2020 \n2020 \n18 1430 3 2020 18 6 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\nAnticoagulants are commonly prescribed in medical practices and could be of significant harm in the case of medication errors. We conducted a retrospective observational study to determine the frequency and consequences of the therapeutic duplication of anticoagulants (TDA). As a secondary objective, we aimed to determine the characteristics of the population in which TDA occurs.\n\nMethods\nWe conducted a retrospective observational study among admitted patients who concomitantly received at least two anticoagulants from August 2017 to August 2018.\n\nResults\nA total of 107 patients with TDA are included in the research. The patients with TDA have a mean age of 73. The TDA population has a high rate of associated comorbidities with 69% of patients having arterial hypertonia, 40% with chronic kidney disease, 26% with a history of malignancy, and 20.5% with a history of stroke. More than 65% of patients were under anticoagulation before admission, mostly due to atrial fibrillation. The TDA occurred in more than 95% of cases in the first week or the last week of hospitalization. Patients had a high risk of bleeding prior to the TDA-event with about 62.5% of TDA patients having a HAS-BLED score at least 3. A total of 8 patients showed a significant Hemoglobin (Hb)-drop of at least 10 g/L within 24 h after TDA-event. Two patients had a new or worsened hematuria following TDA-event.\n\nConclusion\nTDA occurred in 0.8% of patients who were under anticoagulation and in 6.7% of patients who received direct oral anticoagulants (DOACs). TDA led in about 7.4% of cases to hemoglobin-relevant bleeding. The old patients with significant comorbidities and a high HAS-BLED score were mainly affected. The female gender and presence of anemia independently predicted the occurrence of bleeding following TDA.\n\nKeywords\nAnticoagulantsTherapeutic duplicationMedication errorDirect Oral anticoagulantsHAS-BLED scoreissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAccording to the Institute for Safe Medication Practice (ISMP), anticoagulants (AC) are among the high-alert-medications leading to serious complications in the case of medication errors [1]. Anticoagulants are involved in about 8.3% of all medication errors in admitted patients [2]. In a 5-year retrospective study, the investigators showed that medication errors are the cause by about 48.8% of all AC-associated adverse drug events [3]. The AC-related medication errors have been mainly classified according to the phase of medication process in which the error occurred into the following types: prescribing, transcribing, dispensing, administering, and monitoring errors. A cross-sectional study on the nation-wide drug safety system of the Netherland showed that the anticoagulant-related medication errors occurred mainly in the prescribing phase and in about 56% of errors low-molecular-weight heparins (LMWH) were involved [2, 4]. Consistently, a similar descriptive study on the Danish patient safety database reported that the adverse medication incidents occurred mainly in the prescribing phase, and in about 80% of incidents the errors occurred at the time of sector changes (at the admission, at the discharge or ward changes) [5]. Among different error subtypes occurring in the prescribing phase, the wrong dosage and drug omission have been repeatedly found as the most common subtype [3, 6, 7]. The affected patients are usually polymorbid patients in advanced ages having already high risk of bleeding [8]. Accordingly, the AC-related errors occur in about 78% of cases in adults older than 60 and in about one third in patients older than 80 years old [9]. The studies reporting the frequency and complications of AK-related medication errors have been mostly done based on data reported to in-house or nation-wide drug safety systems [2, 3, 5–10]. As many of these errors could not be detected or have not been reported by medical staff, the studies based on them could not reliably show the incidence of errors, the affected population and the rate of consequences. For different categories of ACs, the rates of adverse complications, especially the minor and major bleeding rates, have been well studied and reported [11–15].\n\nTherapeutic duplication is defined a concomitant prescription of two medications of the same class. Except for a few indications, the therapeutic duplication of anticoagulants is contraindicated. The therapeutic duplication of anticoagulants (TDA) as a medication error occurring in the prescribing phase was rarely studied [15–17]. As the primary objective, we aimed to comprehensively investigate the incidence, affected population, and complications of TDA in patients admitted to our tertiary referral hospital from 21.08.2017 to 20.08.2018.\n\nMaterial & Methods\nPatient population\nThis study is a retrospective observational study conducted at Kantonsspital Aarau (KSA), a 450-bed tertiary care facility providing medical and surgical care in all general and specialized medical disciplines. The hospital utilizes an electronic health care system (KISIM) gathering all medical and personal data of patients who received medical care, either in the in-patient or out-patient settings. For the present study, we retrospectively collected data of admitted patients who received AC, using a computerized export from KISIM. From this population, all patients admitted to our in-patient wards, from 21.08.2017–20.08.2018, who concomitantly received at least two ACs were included in the study. Subsequently, the following patients have been excluded: [1] patients who received the anticoagulants separately, no overlapping prescription [2] patients treated with the combination of heparin/ heparin analogs and vitamin-K antagonists (VKA) [3] patients receiving heparin/ heparin analogs based on a weekly schedule such as patients with hemodialysis [4] patients receiving low-dose alteplase (= < 4 mg) as a catheter locking solution [5] patients treated with the combination of VKA and direct oral anticoagulants (DOACs) during bridging from DOACs to VKA [6] patients who explicitly refused participation in research.\n\nData collection and data analysis\nAn export (in CSV format) from the data storage system of our hospital (KISIM) has been done. The mentioned export includes all patients who received at least one anticoagulant during their admission from 21.08.2017–20.08.2018 and contains the following patient data: Patient number, admission number, sex, date of birth, dates of admission and discharge, the name of prescribed anticoagulants and the dates of prescriptions.\n\nAccording to the inclusion and exclusion criteria, the patients with a contraindicated combination of at least two AK have finally been separated. Then, the corresponding demographic, biochemical and clinical parameters, listed ahead were extracted from KISIM: The para-clinical data including pre-error and post-error Hb (Hemoglobin of patient before and after TDA), pre-error and post-error urine analysis, the indication of anticoagulant therapy, the presence of underlying diseases predisposing, the patients to develop complications under TDA: arterial hypertension, renal insufficiency and its stage according to glomerular filtration rate (GFR), hepatic failure, active gastrointestinal ulcers, concomitant therapy with NSAIDs or thrombocyte-aggregation inhibitors, documented bleeding diathesis (abnormal post-operative bleeding, hematoma or bleeding under anticoagulant therapy in therapeutic dosage, known hemorrhagic disorders, etc.), prior anticoagulant therapy, history of recent trauma or upcoming surgery and finally the HAS-BLED score prior to the error. Subsequently, all demographic, biochemical and, clinical data of patients included in the study have been analyzed statistically. The variables have consequently been analyzed descriptively. A Hemoglobin-drop of more than 10 g/L within 24 h has been considered as significant Hb-drop. The patients have been divided into two groups with and without significant Hb-drop. Then, unpaired T-test and chi-square have been done for continuous and binary variables, respectively, to study whether there is a significant difference in variables between two patients groups. Finally, to determine the effect of different risk factors on the bleeding following TDA, we performed univariate and multivariate logistic regression.\n\nResults\nAmong 14,812 patients who received at least one anticoagulant, a total of 1663 patients met the inclusion criteria and have been treated with at least two anticoagulants during the one-year period. Among them, a total of 1542 patients met the first five exclusion criteria. Then, a total of 121 patients with a contraindicated combinative therapy of at least two anticoagulants (TDA) have been found. Out of them, 14 patients refused to participate and the rest 107 patients were included in the study (Fig. 1).\nFig. 1 Diagram of patient recruitment\n\n\n\nCharacteristics of the patient population\nAge and sex\nFrom 107 patients included in the study, 72 patients (67.3%) were male and 35 patients (32.7%) were female. The minimum and maximum of age were 35 and 97 years, respectively. The mean age of patients was 73.67 (95% CI, 71.2–76.1) and 78.5% of the population was older than 65 years.\n\nDuration of hospitalization\nThe minimum and maximum of the hospitalization duration were 2 and 72, respectively. The mean duration of hospitalization was 11.52 (CI 95%: 9.69–13.3).\n\nHAS-BLED score related comorbidities\nTable 1 shows the HAS-BLED score related parameters and comorbidities. Out of 107 patients, 74 patients (69.1%) had long-term arterial hypertension. Among them, 38 patients had uncontrolled arterial hypertension with systolic blood pressure higher than 160 mmHg. A high proportion of patients (40.1%) had a known chronic kidney disease prior to admission. Among them, 69.7% had stage 3 or higher. Abnormal liver function has been found in 7 patients; 2 with liver cirrhosis and 5 others with hepathopaties. 20.5% of patients had a history of stroke. A relevant co-medication with other drugs (aspirin, clopidogrel, NSAIDs etc.) or alcohol consumption predisposing patients to bleed has been found in 28 Out of 107 patients (26%). Seventeen patients were known to have a bleeding diathesis or a history of major bleeding (See Table 1).\nTable 1 A summary of the HAS-BLED score, the modified score and the related parameters\n\nCharacteristics\tTDA-patients (whole population)\tPatients with Hb-relevant bleeding\tPatients without Hb-relevant bleeding\t\nNumber\t107\t8\t99\t\nHypertension\t38\t4\t34\t\nAbnormal liver function\t7\t1\t6\t\nAbnormal renal function\t43\t3\t40\t\nStroke\t22\t3\t19\t\nLabile INR\t15\t2\t13\t\nBleeding diathesis\t17\t2\t15\t\nAge > 65 years\t84\t7\t77\t\nDrug/alcohol concomitantly\t28\t2\t26\t\nPrior anticoagulation\t71\t7\t64\t\nHAS-BLED score\t2.37 (CI95% 2.14–2.60)\t3.00 (CI95% 2.26–3.74)\t2.32 (CI95% 2.08–2.55)\t\nModified HAS-BLED score\t3.04 (CI95% 2.8–3.28)\t3.87 (CI95% 3.09–4.66)\t2.97 (CI95% 2.72–3.22)\t\n\n\nHAS-BLED score of the patient population\nThe minimum and maximum values of the HAS-BLED scores were 0 and 7, respectively. The mean HAS-BLED score was 2.37 (CI95% 2.14–2.60) with a median value of 3.\n\nFurther bleeding-related parameters and comorbidities\nTable 2 shows further bleeding-related comorbidities, which have not been considered by the HAS-BLED score. Most of the patients with TDA (66.3%) were on anticoagulation prior to admission. Diabetes mellitus has been found in 24 patients (22.4%). A high proportion of patients had a history of malignancy (26.1%). Out of 107 included patients, 22 (20.5%) and 13 (12.1%) patients had ischemic and congestive heart disease, respectively. A fresh fracture or traumatic brain injury has been found in 12 patients (11.2%) at admission. A total of 13 patients had a documented thrombocytopenia prior to the medication error and 8 patients had a known falling tendency. The higher proportion of patients with falling tendency, ischemic heart disease or with a history of a recent fracture or brain injury in the group of patients with Hb-relevant bleeding may put this population at increased risk of complications following TDA. Although it was suggested that anemia might contribute to the major bleeding under rivaroxaban therapy [18], our study showed a lower proportion of anemia in patients with Hb-relevant bleeding. However, the risk of bleeding may also be affected by other contributing factors. It has been demonstrated that AC therapy in patients with deep vein thrombosis leads more frequently to bleeding complications compared to those with atrial fibrillation [19, 20]. While 50% of patients with Hb-relevant bleeding were under anticoagulation due to AF, this was 68% for patients without Hb-relevant bleeding.\nTable 2 Comparison of bleeding-relevant characteristics of TDA-patients with and without significant Hb-drop\n\nParameters\tTDA-patients (whole population)\tPatients with Hb-relevant bleeding\tPatients without Hb-relevant bleeding\t\nPre-error anemia\t63.5%\t37.5%\t65.6%\t\nPre-error thrombocytopenia\t12.1%\t12.5%\t12.1%\t\nHistory of malignancy\t26.1%\t0%\t26.1%\t\nDiabetes mellitus\t22.4%\t0%\t22.4%\t\nIschemic/ congestive heart disease\tIHD 20.5%\n\nCHF 12.1%\n\n\tIHD 37.5%\n\nCHF 12.5%\n\n\tIHD 19.1%\n\nCHF 12.1%\n\n\t\nRecent fracture or traumatic brain injury\t11.2%\t37.5%\t0.9%\t\nFalling tendency\t7.5%\t12.5%\t0.7%\t\nDeath in 2 years\t18.6%\t25%\t18.1%\t\n\n\nModified HAS-BLED score\nPrior anticoagulation is not considered in the HAS-BLED score as a parameter. Indeed, the HAS-BLED score is employed to assess the risk of bleeding following initiation of an anticoagulative therapy in patients who were not being anticoagulated before. As taking anticoagulants before admission might have predictive value for hemorrhagic complications, we defined and applied a modified score by considering the prior anticoagulation as a criterion as well. Another rationale for employing the modified value is the above-mentioned finding that more than 66% of TDA patients were on anticoagulation therapy before admission. The modified HAS-BLED score was calculated by adding one score for prior anticoagulation to the HAS-BLED score. Using the modified HAS-BLED score, the TDA population had a mean value of 3.04 (CI95% 2.8–3.28) and about 67.2% of TDA patients had a score of at least 3.\n\nRate of anemia prior to medication error of TDA\nFor 8 patients, no hemoglobin value has been found within 72 h prior to TDA. The rest population with available pre-error hemoglobin had a mean hemoglobin value of 120.7 (95%CI: 116–125). 47 out of 72 male patients (65.2%) had a hemoglobin value lower than 140 g/L prior to error. From 35 females with TDA, 21 patients (60%) had a hemoglobin value lower than 120 g/L prior to error. Altogether, 63.5% of TDA patients had anemia prior to medication error.\n\nTDA-related parameters\nDuration of TDA\nTDA lasted, before detection and stop, for a minimum and maximum of 1 and 7 days, respectively. The mean duration of TDA was 1.68 (95%CI: 1.42–1.94).\n\nTime interval of the error to admission or discharge\nTDA events began in a short interval to the admission or discharge with a mean interval of 2.15 (95%CI: 1.67–2.63). In 21.4% of patients the TDA began on the day of admission or discharge. In 86 patients (83.3%) the error began in within 72 h after admission or before discharge (Table 3).\nTable 3 Comparison of characteristics of TDA between the whole population and the patients with Hb-relevant bleeding\n\nParameters\tTDA-patients (whole population)\tPatients with Hb-relevant bleeding\t\nDuration of TDA\t1.68 (SD 1.35)\t1.75 (SD 1.38)\t\nTime interval to admission or discharge\t2.15 (SD 2.55)\t1.125 (SD 0.99)\t\nWard\tMedical 38.3%\n\nSurgical 61.6%\n\n\tMedical 62.5%\n\nSurgical 37.5%\n\n\t\nSetting\t27.1% post-op\n\n8.4% pre-op\n\n\t25% post-op\n\n12.5% pre-op\n\n\t\nInvolved anticoagulants\tLMWH+DOAC (88.7%)\n\nHeparin+DOAC (7.5%)\n\nLMWH+Heparin (0.9%)\n\nDOAC+DOAC (0.9%)\n\nVKA + Heparin+LMWH (0.9%)\n\n\tLMWH+DOAC (87.5%)\n\nLMWH+Heparin (12.5%)\n\n\t\n\n\nInvolved anticoagulants\nMost of TDA patients (88.7%) had a combination of LMWH and DOAC. Among them, 43 patients (40.1%) have been treated with the combination of rivaroxaban and dalteparin and 40 patients (37.3%) with the combination of apixaban and dalteparin as the most common combination of anticoagulants (Table 4).\nTable 4 The anticoagulants involved in the TDA events of 107 patients\n\nInvolved ACs\tNr. of patients\tProportion\t\nRivaroxaban+Dalteparin\t43\t40.1%\t\nApixaban+ Dalteparin\t40\t37.3%\t\nDabigataran+ Dalteparin\t7\t6.5%\t\nEdoxaban+ Dalteparin\t5\t4.6%\t\nLiquemin+ Rivaroxaban\t3\t2.8%\t\nLiquemin+Apixaban\t2\t1.8%\t\nLiquemin+ Dalteparin\t2\t1.8%\t\nEdoxaban+Heparin\t1\t0.9%\t\nLiquemin+Dabigatran\t1\t0.9%\t\nApixaban+rivaroxaban\t1\t0.9%\t\napixaban+Arixtra\t1\t0.9%\t\nMarcoumar+Liquemin+Dalteparin\t1\t0.9%\t\n\n\nIn total, 1737 patients received at least one DOAC during the study period. Among them, 104 patients who were included in the study (See Table 4) and all of the excluded TDA patients i.e. fourteen patients were under DOAC at the time of TDA. Thus, TDA occurred in 6.7% of patients who were on DOAC.\n\nSignificant Hb-drop following TDA\nTo evaluate the bleeding events following TDA, we considered the last hemoglobin value reported within 72 h prior to TDA and the fist hemoglobin value reported within 72 h after TDA. A significant Hb-drop, which could be attributed to the bleeding, has been defined as a drop of more than 10 g/L within 24 h. The patients with Hb-drops, which could be attributed to other etiologies rather than TDA such as infusion therapies, operations, or known bleeding sources prior to TDA have been excluded. A total of 8 patients showed significant Hb-drop, which could not be attributed to the above-mentioned etiologies; please see the diagram of patients recruitment. Among patients with significant Hb-drop, two patients were taking platelet-aggregation inhibitors before admission; one was on acetylsalicylic acid 100 mg daily and the other one was on clopidogrel 75 mg daily (See case 2 in the part case study). Both drugs were stopped upon admission i.e. none of the patients with significant Hb-drop was receiving any platelet-aggregation inhibitors at the time of TDA events.\n\nBleeding risk factors in TDA patients\nUnpaired T-test and Chi-square have been done for all continuous and binary variables, respectively, to study whether there is a significant difference of variables between two patients groups; with and without Hb-drop. A p-value under 0.05 was defined as statistically significant. The relative risks for binary variables are also reported in Table 4. The modified HAS-BLED score was the only variable that reached the statistical significance in the univariate analysis (p = 0.028). HAS-BLED score did not reach the significance (p = 0.064). Although the TDA patients with a history of prior anticoagulation may have been at increased risk of bleeding (RR 3.55, CI95% 0.45–27.75), this risk was not translated into statistically significant TDA events (p = 0.22) (Table 5).\nTable 5 Univariate Analysis results\n\nRisk factor\tOdds ratio\tRelative risk\t\nAnemia\t0.17 (CI 95% 0.03–0.87)\t0.19\t\nAbnormal renal function\t0.78 (CI 95% 0.18–3.45)\t0.8\t\nUncontrolled hypertention\t1.91(CI 95% 0.45–8.12)\t1.82\t\nStroke\t2.53 (CI 95% 0.55–11.51)\t2.32\t\nAge > 65\t2.0 (CI 95% 0.23–17.14)\t1.92\t\nPrior anticoagulation\t3.83 (CI 95% 0.45–32.39)\t3.55\t\nAbnormal liver function\t2.21 (CI 95% 0.23–21.05)\t2.04\t\nDrug/ alcohol concomitantly\t0.94 (CI 95% 0.18–4.93)\t0.94\t\nBleeding diathesis\t1.87 (CI 95% 0.34–10.14)\t1.76\t\n\n\nLegend. The odds ratio and relative risks of bleeding risk factors have been reported. As mentioned above, the prior anticoagulation carries the highest relative risk between 3 and 4.\n\nMultivariate logistic regression\nTo determine the effect of different risk factors on the bleeding following TDA, we performed a multivariate logistic regression. Only two of 15 independent variables did reach the significance. The female sex (odds ratio .075 and a coefficient − 2.58) and anemia (odds ratio .022 and a coefficient − 3.80) showed a p-value lower than 0.05. As the coefficient of these variables is negative, they negatively correlate the risk of bleeding secondary to TDA. The HAS-BLED score (p = 0.97) and the modified HAS-BLED score (p = 0.13) did not reach the statistical significance in the multivariate regression model.\n\nDiscussion\nAnticoagulants are among the most common medications prescribed in clinical practice. Although they are given in order to prevent or treat life-threatening thromboembolic events such as stroke or pulmonary embolism, they could be dangerous if prescribed inappropriately [21]. Owing to the wider therapeutic window and the lower dietary and drug interactions of the newer ACs, which are recently introduced to the pharmaceutical marketing, their use in clinical practice have been surpassed that of vitamin-K-antagonists or heparin. However, lack of specific blood tests with wide availability for monitoring the blood level and therapeutic effects of the newer ACs increases the risk of drug bioaccumulation and, subsequently, the risk of bleeding complications [19]. Owing to being critically harmful in the case of medication errors, the AC- related errors have been largely studied. The adverse drug events commonly occur in clinical practice, with a frequency of 6.5 pro 100 admissions [22]. It has been shown that ACs-related medication errors comprise a significant proportion of medication errors in in-patient setting (7.2–8.3%) and the subsequent adverse events could be prevented in about 70% of cases [3, 22]. Pizza et al. retrospectively analyzed the AC-associated adverse drug events reported to the drug safety system at their tertiary hospital and showed that AC-associated medication errors comprise about half of the adverse drug events owing to AC prescription [3]. In addition, these errors have been significantly correlated with the 30-days mortality rate and higher hospitalization costs [3, 23]. Despite similarities of different reports in showing the high frequency of AC-associated medication errors, there are discrepancies regarding involved AKs, the proportion of error types, and the time of medication process in which errors occur. It seems that the following parameters play a role in the above-mentioned discrepancies: time of study according to the first appearance of the newer AK agents, pharmaceutical market varieties among countries in which the studies have been done, and the difference in study population [2, 24].\n\nAlthough the therapeutic duplication of ACs (TDA) has been written in medication safety alerts of national and international healthcare authorities [25, 26], there is not any study investigating the frequency and the rate of bleeding complications secondary to TDA. From a total of 1663 patients who have received at least two ACs during a 1-year period, 121 TDA-events have occurred. Out of them, 14 patients have been excluded due to the refusal of participation. The TDA-events have been mainly occurred, in about 88.7% of cases, due to the concomitant prescription of DOACs and LMWHs in prophylactic doses. Consistently, Andreica I. et al. reported a few similar cases in which a new LMWH has been prescribed while the previous DOAC prophylaxis was not discontinued [7]. Among 105 patients treated with heparins, either LMWH or unfractionated heparin, 85 patients received the heparin in prophylactic dose (8 patients with low-dose and other with a prophylactic dose higher than 3400 U/d) and 20 patients in therapeutic dose. Leonardi MJ, et al. in a systematic review of 33 randomized control trial evaluating the bleeding complications of patients under pharmacologic deep vein thrombosis (DVT) prophylaxis showed that patients receiving a high prophylactic dose of LMWH carry a risk of 5.8, 1 and 0.3% for hematuria, gastrointestinal (GI) bleeding and retroperitoneal bleeding, respectively. In comparison, the patients receiving a low dose of LMWH develop in < 0.6% of cases the above-mentioned bleeding complications [27].\n\nWe found that the risk for TDA was higher for Rivaroxaban and apixaban compared to other DOACs. Although we do not know the specific reason for this difference, these drugs are routinely prescribed for patients with AF, which may also have a higher likelihood for receiving other anticoagulants. Thus, it is rather the patient population and underlying indication that puts them at risk than the drugs itself.\n\nAlthough different clinical trials have already investigated the bleeding complications due to each AC class and compared them together, there is not any study reporting the bleeding rate following the concomitant prescription of two different classes i.e. the TDA [9, 11–14]. It has been shown that DOACs, although are not superior to the VKA in the prevention of stroke and systemic embolism, are associated with a significantly lower rate of intracranial bleeding [28–30].\n\nAccording to the ROCKET-AF study, clinically relevant bleeding occurs in about 14.9% of atrial fibrillation (AF) patients (per year) under rivaroxaban therapy [31]. The ARISTOTLE study assessed the risk of major bleeding complications in AF patients receiving apixaban as prophylaxis for stroke. The study reported a bleeding rate of 0.33, 0.13, 0.68, and 0.01% for intracranial hemorrhage, hematuria, GI bleeding, and retroperitoneal bleeding, respectively [14]. Notably, about 85% of TDA patients received either apixaban or rivaroxaban, mostly as prophylaxis for AF.\n\nHerein, we showed that TDA leads in about 7.5% of cases to Hb-relevant bleeding, defined as a drop more than 10 g/L in hemoglobin value within 24 h, in the first 3 days following the medication error. Pre-existing anemia has been attributed to an increased risk of bleeding secondary to AC therapy [31, 32]. From a clinical standpoint, a bleeding event in anemic patients, especially those with ischemic heart disease, would be more devastating. In our study, 63.5% of patients had anemia and 20.5% suffered from ischemic heart disease (IHD) before a TDA occurred. Furthermore, anemia and IHD were documented in 3 patients with TDA-associated bleeding. It has been demonstrated that AC therapy in patients with deep vein thrombosis leads more frequently to bleeding complications compared to those with atrial fibrillation [19, 20]. It has been attributed to the concomitant polymorbidity and polypharmacy of patients with venous thromboembolic disorders [33, 34]. Among patients with TDA, more than 70% have been subjected to AC-therapy due to atrial fibrillation. Therefore, in a population with a higher proportion of patients having been anticoagulated due to venous thromboembolism (VTE) rather than AF, TDA may lead more frequently to bleeding events compared with the present study.\n\nTo assess the risk of bleeding prior to AC therapy, different risk stratification tools have been proposed. Among them, HAS-BLED score, HEMORR2HAGES, and ATRIA are most commonly used in daily clinical practice. Despite having a similar accuracy, the HAS-BLED score has the best predictive performance [35, 36]. These scores have been mainly validated for VKA therapy in patients with atrial fibrillation and, therefore, modified HAS-BLED scores have been proposed to assess the risk of bleeding in other circumstances such as anticoagulation with DOACs [18, 37]. Except for one patient who has been found to concomitantly receive VKA, LMWH, and heparin and one other who received the combination of LMWH and heparin, all other TDA patients have been anticoagulated by DOACs. In addition, 66.3% of TDA patients have been received anticoagulants prior to admission. Prior anticoagulation, though, increases the bleeding risk, has not been considered in the above-mentioned risk stratification tools. Therefore, we measured in addition to the currently used HAS-BLED score, a modified score considering the prior anticoagulant therapy similar to the other medications such as NSAIDs and thrombocyte-aggregation inhibitors, as well.\n\nInterestingly, TDA patients have a mean HAS-BLED score of more than 2 and a mean modified score of more than 3, indicating that the affected population carries a high bleeding risk before TDA-event takes place. In addition to the components of the HAS-BLED score, other clinical parameters predisposing the AK-receiving patients to bleed such as the history of congestive heart failure, cerebrovascular disease, and anemia have also been taken into account. Tamaya et al. in a case-control study of 3252 patients with atrial fibrillation under rivaroxaban-therapy showed that the mentioned parameters, which have been ignored by HAS-BLED score, are the strongest predictive factors for bleeding complications [18]. Consistently, more than 20% of patients with TDA had a positive history of stroke or TIA. In addition, about 18.6% of TDA patients were died at the time of this study i.e. within a maximum of 2 years after discharge from hospital. Altogether, the above-mentioned findings indicate that the involved population carries a high risk of bleeding.\n\nCase study\nHerein, we discuss two cases with TDA-related bleeding.\nAn 80 years-old hypertensive patient presented with frequent episodes of syncope to the emergency department. The clinical examination revealed a hematoma in the right flank and also multiple ecchymosis in different locations. The falling episodes have been attributed to the side effects of Ropinirole, a dopamine agonist prescribed due to Parkinson’s disease. Furthermore, atrial fibrillation has been detected at the time of admission and, therefore, anticoagulation with apixaban (5 mg daily) has begun. As admitted, the patient received also dalteparin in prophylactic dose (5000 IU daily). Just after 1 day of combinative anticoagulation with apixaban and dalteparin the hemoglobin value dropped from 140 g/L to the 117 g/L. The occurrence of gastrointestinal bleeding presenting with melena has been documented during admission. One day later the TDA has been detected and stopped.\n\nA 98 years-old hypertensive patient under long-term anticoagulation with rivaroxaban (20 mg daily) due to atrial fibrillation, presented with bilateral subarachnoidal hemorrhage following falling. The patient has been admitted in neurosurgical ward and her medical situation improved without surgical intervention. She received clopidogrel (75 mg daily) following percutaneous transluminal angioplasty, since 1 month ago. Both medications have been stopped at admission. Instead, she received dalteparin in prophylactic dose (2500 IE daily), which has been continued until 1 day before discharge. Clopidogrel and rivaroxaban have been re- started from 4 and 3 days before discharge, respectively. Thus, the patient received for 2 days the combination of Clopidogrel, rivaroxaban and dalteparin, which resulted in Hb-drop from 86 g/L to the 66 g/L (= the Hb-value at first day of TDA) within 48 h. The Hb-value after the second day of TDA is not available. The patient was still disoriented at discharge and has been referred to the nursing house. Finally, she died 3 days after discharge. However, the reason of death is not documented, whether it occurred due to the deterioration of the pre-existing intracranial hemorrhage or/ and new bleeding events or not.\n\n\n\nConclusion\nTDA is a known medication error of anticoagulants with unknown frequency and clinical importance. We retrospectively analyzed the frequency and complications of TDA in all patients admitted to our 450-bed referral hospital in 1 year. TDA occurred in 0.8% of patients who were under anticoagulation and in 6.7% of patients who received DOACs. TDA led in about 7.4% of cases to hemoglobin-relevant bleeding. The old patients with significant comorbidities and a high HAS-BLED score were mainly affected. The female gender and presence of anemia independently predicted the occurrence of bleeding following TDA. Moreover, we introduced a new risk stratification tool by modifying the HAS-BLED score to assess the risk of bleeding in patients who are already on anticoagulants. Although the significance of the proposed tool is the matter of further investigations with larger sample sizes, our analyses suggest the consideration of prior anticoagulation as a parameter in addition to the HAS-BLED score lead to the prediction of the bleeding risk in TDA patients at a higher level of significance.\n\nAbbreviations\nTDAtherapeutic duplication of anticoagulants\n\nACanticoagulants,\n\nLMWHlow-molecular weight heparins\n\nDOACdirect oral anticoagulants\n\nVKAvitamin-K antagonists\n\nDVTdeep vein thrombosis\n\nIHDischemic heart disease\n\nVTEvenous thromboembolism\n\nAFatrial fibrillation\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nRR and ARS and PS devised the project, the main conceptual idea and proof outlines. RR and FC and CZ gathered the data. RR analyzed the data. RR took the lead in writing the manuscript and wrote it in consultation with other authors. RR and PS and ARS revised and proofed the final version of the manuscript. The author(s) read and approved the final manuscript.\n\nFunding\nThis research work has been done without receiving any financial support.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nApproval was obtained from the local ethics committee named Ethikkommission Nordwest- und Zentralschweiz (EKNZ).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nHerein the authors declare that there’s not any conflict of interest with this research work.\n==== Refs\nReferences\n1. Institute for Safe Medication Practices Canada. ISMP List of High-Alert Medications in Acute Care Settings. Inst Safe Medicat Pract. 2014.\n2. 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Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487–98.\n35. Hellenbart EL, Faulkenberg KD, Finks SW. Evaluation of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag. 2017;13:325–42.\n36. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM, Andresen D, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263–72.\n37. Tsu LV, Berry A, Wald E, Ehrlich C. Modified HAS-BLED score and risk of major bleeding in patients receiving dabigatran and rivaroxaban: a retrospective, case-control study. Consult Pharm. 2015;30(7):395–402.\n\n", "fulltext_license": "CC BY", "issn_linking": "1477-9560", "issue": "18()", "journal": "Thrombosis journal", "keywords": "Anticoagulants; Direct Oral anticoagulants; HAS-BLED score; Medication error; Therapeutic duplication", "medline_ta": "Thromb J", "mesh_terms": null, "nlm_unique_id": "101170542", "other_id": null, "pages": "14", "pmc": null, "pmid": "32774174", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "16924087;18579811;23861122;8368229;27585515;25249791;21870978;21175312;28271315;28860793;30165484;21830957;9002493;11157645;18309033;9727814;21219407;21428778;30298305;27747717;30213217;28603628;23808982;19762550;22111719;16983130;31127504;22114827;27250070;23479259;26173191;24315724", "title": "Therapeutic duplication of anticoagulants: a retrospective study of frequency and consequences in a tertiary referral hospital.", "title_normalized": "therapeutic duplication of anticoagulants a retrospective study of frequency and consequences in a tertiary referral hospital" }

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{ "abstract": "OBJECTIVE\nTo review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).\n\n\nMETHODS\nData were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer's postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (> or = 65 and > or = 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and alpha-blockers) and incorrect use.\n\n\nRESULTS\nSildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged > or = 65 years, and in those aged > or = 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.\n\n\nCONCLUSIONS\nThis collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.", "affiliations": "AP-HP, Neuro-Uro-Andrology, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, Garches, France. [email protected]", "authors": "Giuliano|F|F|;Jackson|G|G|;Montorsi|F|F|;Martin-Morales|A|A|;Raillard|P|P|", "chemical_list": "D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate", "country": "England", "delete": false, "doi": "10.1111/j.1742-1241.2009.02254.x", "fulltext": "\n==== Front\nInt J Clin PractijcpInternational Journal of Clinical Practice1368-50311742-1241Blackwell Publishing Ltd 10.1111/j.1742-1241.2009.02254.xReview ArticlesSafety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database Giuliano F 1Jackson G 2Montorsi F 3Martin-Morales A 4Raillard P 51 AP-HP, Neuro-Uro-Andrology, Department of Physical Medicine and Rehabilitation, Raymond Poincaré HospitalGarches, France2 Cardiac Department, St. Thomas’ HospitalLondon, UK3 Department of Urology, Università-Vita Salute San RaffaeleMilan, Italy4 Servicio de Urologia, Complejo, Hospitalario Carlos HayaMálaga, Spain5 Safety and Risk Management, Pfizer IncNew York, NY, USAFrançois Giuliano, Pr, MD, PhD, Raymond Poincaré Hospital, Physical Medicine and Rehabilitation, Neuro-Uro-Andrology, 104 Boulevard Raymond Poincaré, Garches 92380, France Tel.:+ 33 147107832 Fax:+ 33 147104443 Email:[email protected] François Giuliano is a consultant for Johnson & Johnson, Pfizer Inc, Bayer Schering Pharma, Sanofi-Aventis and Lilly; a meeting participant for Johnson & Johnson, Pfizer Inc and Lilly; and a study investigator for Pfizer Inc and Bayer. Graham Jackson is a consultant for Lilly and Pfizer Inc; and a meeting participant for Lilly, Pfizer Inc and Bayer. Francesco Montorsi is a consultant for Pfizer Inc, Bayer, GSK and AMS; and a study investigator for Astra, Pfizer Inc, Eli Lilly, GSK, MSD, Bayer, Novartis and Lilly ICOS. Antonio Martin-Morales is a consultant for Pfizer Inc, Bayer Schering Pharma, Lilly ICOS, Ipsen Pharma, Prostrakan, Pierre-Fabre and Johnson & Johnson; a meeting participant/lecturer for Pfizer Inc, Bayer Schering Pharma, Lilly ICOS, Ipsen Pharma, Johnson & Johnson and a scientific study/trial investigator for Pfizer Inc, Bayer Schering Pharma, Lilly ICOS, Johnson & Johnson and Prostrakan Pierre Raillard is an employee of Pfizer Inc.\n\nRe-use of this article is permitted in accordance with the Terms and Conditions set out at http://www3.interscience.wiley.com/authorresources/onlineopen.html\n\n1 2010 64 2 240 255 1 2009 10 2009 © 2009 Blackwell Publishing LtdRe-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.Aim:\nTo review special safety topics associated with sildenafil and to document the tolerability of 50- and 100-mg doses, overall and by age, in men with erectile dysfunction (ED).\n\nMethods:\nData were collated from 67 double-blind placebo-controlled (DBPC) trials (> 14,000 men) conducted by the manufacturer and from the manufacturer’s postmarketing safety database (39,277 patients). The DBPC data were stratified by dose, starting dose and age (≥ 65 and ≥ 75 years). Special safety topics included cardiovascular risk, priapism, non-arteritic anterior ischaemic optic neuropathy (NAION), impaired renal and hepatic function, drug interactions (i.e. nitrates, cytochrome P3A4 inhibitors, other ED therapies and α-blockers) and incorrect use.\n\nResults:\nSildenafil was well tolerated at a dose of 50 or 100 mg in men with ED, overall, in those aged ≥ 65 years, and in those aged ≥ 75 years. Analyses of the databases did not reveal any causal link between sildenafil and cardiovascular events, or any new safety risks relating to cardiovascular events, priapism, NAION, hearing loss or drug interactions. In the small number of men with moderate impairment of renal function or hepatic function who were treated with sildenafil in DBPC trials, the safety profile was similar to that in men with no impairment of renal or hepatic function. Overdose with sildenafil was rare in the ED population. No new safety issues, emerging trends or adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse.\n\nConclusion:\nThis collated review confirms generally the good tolerability and established safety profile of sildenafil 50 and 100 mg in men with ED and reveals no new safety issues.\n==== Body\nReview Criteria\nUsing a database of 67 double-blind placebo-controlled trials conducted by the manufacturer and the manufacturer’s postmarketing safety database, we reviewed special safety topics and, for the most frequently prescribed doses (50 and 100 mg), conducted a comprehensive assessment of the tolerability of sildenafil overall and by age (i.e. stratifying cut-offs of ≥ 65 and ≥ 75 years).\n\nMessage for the Clinic\nSildenafil 50 and 100 mg were generally well tolerated, including by elderly men. There was no causal link with cardiovascular events. Furthermore, no new safety risks relating to priapism, non-arteritic anterior ischaemic optic neuropathy or incorrect use were detected. In addition, there were no unexpected adverse reactions from drug interactions, and a similar safety profile was present in men with or without moderate impairment of renal or hepatic function.\n\nIntroduction\nSildenafil citrate (VIAGRA®, Pfizer Limited, Sandwich, Kent, UK), approved by the United States Food and Drug Administration in March 1998 and by the European Medicines Agency in September 1998 for the on-demand treatment of erectile dysfunction (ED), was the first phosphodiesterase type 5 (PDE5) inhibitor licensed for this indication. Initial clinical trials of sildenafil were conducted in the United Kingdom (1), Europe (2) and the United States (3) and were followed by trials performed in Central and South America (4–6), Africa (7,8), Asia (9,10) and Australia (11). The effectiveness and safety of sildenafil for treating ED have been established in over 120 manufacturer-sponsored clinical trials with a cumulative exposure of more than 14,000 patient-years and in other independent studies (12,13). In most of the trials, sildenafil was administered on demand with a starting dose of 50 mg and subsequent adjustment to 25 mg or, more usually, 100 mg depending on toleration and efficacy, but it has also been studied in once-daily dosage (10, 25 and 50 mg) (14) and in single-doses up to 800 mg (15). Comprehensive reviews examining the efficacy and safety profile of sildenafil have been published (16,17). As of August 2008, sildenafil had been prescribed to more than 37 million men, and more than a billion tablets (averaging six per second) have been dispensed worldwide (18).\n\nTreatment-related adverse events with PDE5 inhibitors such as sildenafil, vardenafil (Levitra®, Bayer AG, Leverkusen, Germany) and tadalafil (Cialis®, Eli Lilly Nederland B.V., Houten, the Netherlands) are generally mild to moderate, showing minor differences across the PDE5 inhibitor class (19,20). Headache, facial flushing, nasal congestion and dyspepsia are the most common adverse events (19,21–23). Postmarketing surveillance of PDE5 inhibitors has provided additional data that, in general, indicate a safety profile consistent with that reported in premarketing clinical studies (24–30). However, there are some gaps in the knowledge base. For example, the safety of PDE5 inhibitor therapy has not previously been reported by age,1 despite an increased prevalence of ED in older men (31). Given the ageing populations of the developed and developing world, with an expected increase in the prevalence of ED to more than 300 million men worldwide by 2025 (32), this will become increasingly important.\n\nUsing a database of all 67 of the manufacturer’s double-blind placebo-controlled (DBPC) trials and the manufacturer’s postmarketing safety database, we conducted a comprehensive assessment of the tolerability of sildenafil overall, by dose and by age (cut-offs of ≥ 65 and ≥ 75 years). The objective of this collated review was to assess special safety topics and to document the tolerability by age of the most frequently prescribed doses (50 and 100 mg).2\n\nMethods\nDBPC database\nThe DBPC database contains all routine safety data and serious adverse event data for the 67 DBPC sildenafil trials for the indication of ED, which were completed by June 1, 2007. Appropriate Institutional Review Board approval and patient informed consent were obtained for all trials.\n\nAlthough sildenafil was studied in doses of up to 800 mg in phase I, single-dose, healthy volunteer studies (15), doses in the DBPC database ranged from 5 to 200 mg. However, most of the trials used the currently approved doses for the treatment of ED (25, 50 and 100 mg) and included a double-blind phase of 12 weeks (15). In 45 trials, the dose was flexible (most had dose adjustment at an interim visit according to efficacy and toleration while blinding was maintained), and in 22 trials, the dose was fixed. In most of the flexible-dose trials, the initial dose of sildenafil was 50 mg and most patients were titrated to 100 mg. In nearly all of the trials, sildenafil could be taken on demand approximately 1 h before sexual activity but not more than once daily. Many of the trials also included an open-label extension phase after the completion of the DBPC phase, in which most patients used sildenafil 100 mg.\n\nParticipants were generally required to have a documented history of ED of at least 3–6 months and to be in a stable sexual relationship. Trials that investigated conditions that contribute to the aetiology of ED generally required that the condition (e.g. diabetes mellitus) be stable or stable under treatment. Otherwise, the inclusion and exclusion criteria of the trials were broadly consistent with the Viagra prescribing information (15). In most of the trials, men receiving nitrate therapy and nitric oxide donors were excluded but, in some early trials, a few men randomised to sildenafil (n = 16) or placebo (n = 9) were taking glyceryl trinitrate ‘as required’. In some of the more recent trials, to avoid potential hypotension, any patient who was currently prescribed, taking, and/or likely to be treated with an α-blocker was either excluded from entering the trial or was not to take study medication within 4 h of dosing with the α-blocker.\n\nThere were no restrictions on other vasoactive and antihypertensive medications. Men with severe cardiac failure, unstable angina or a recent history (i.e. within 3–6 months) of stroke or myocardial infarction were excluded. Otherwise, efficacy and safety were assessed in men with a variety of comorbid conditions that share risk factors with ED, including diabetes mellitus, hypertension, cardiovascular disease (coronary artery disease, angina, myocardial infarction and stroke), radical prostatectomy, spinal cord injury and depression.\n\nPostmarketing safety database\nFrom first launch in 1998 through September 2007 (when the database was closed), > 35 million patients are estimated to have used sildenafil worldwide for the treatment of ED. In accordance with Pfizer Pharmacovigilance Standard Operating Procedures, the postmarketing safety database contains all cases of adverse events that were reported spontaneously to Pfizer by healthcare professionals, persons other than healthcare professionals, national or local registries (when applicable) and health authorities, or that are systematically identified from the medical literature. It excludes cases from the sildenafil clinical trials programme (except for cases of serious adverse events). It also excludes cases representative of sildenafil indications other than ED (i.e. pulmonary hypertension). For cases reporting a dose, the dose represents the first daily dose taken by the patient at the onset of an adverse event.\n\nAnalyses\nIn the clinical trials included in the DBPC database, the severity of each adverse event was categorised according to investigator judgment as mild (usually transient, required no special treatment and did not interfere with daily activities), moderate (low level of inconvenience and may have interfered with daily activities; usually ameliorated by simple therapeutic measures), or severe (interrupted daily activity and required systemic drug therapy or other medical treatment). A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Each event is presented using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (version 10.0) and with causality assessed by the trial investigator.\n\nUsing the DBPC database, incidence of adverse events, severe and serious adverse events and discontinuations were derived from the double-blind phase only. Data were analysed by dose (fixed-dose trials) and by modal flexible-dose (flexible-dose trials). Modal flexible-dose was defined as the dose the man was exposed to the longest during the trial period; if the exposure duration was equal for two different doses, the higher dose was selected as the modal dose. Data were also analysed by starting dosage (< 50, 50 and 100 mg) and by starting dose stratified by age groups. In this report, only the data for starting doses of 50 and 100 mg are considered. Death listings are reported for all phases of the study (e.g. including open-label extension).\n\nMost postmarketing adverse event reports are submitted voluntarily, causality is not assessed, clinical information may be missing or incomplete, follow-up information may not be available, the magnitude of underreporting is unknown and many factors influence reporting (i.e. length of time since marketing, market share of the drug, publicity or media reports about the drug or an adverse event, the seriousness of an adverse reaction, regulatory actions and awareness by healthcare professionals and consumers of adverse event reporting and litigation) (33,34). Furthermore, because the source of medication is usually not captured, reports related to non-genuine products can enter a database. For example, an estimated 44% of tablets labelled ‘Viagra’ and sold over the Internet is counterfeit (35). Counterfeit ED medications may contain none or an unknown quantity of the purported active ingredient, other possibly active ingredients of unknown efficacy and safety, or even toxic ingredients (36). Therefore, the spontaneous reporting system yields reporting rates, not incidence rates, and it is generally not appropriate to make comparisons between drugs in reporting rates. The most important role of the spontaneous reporting system is for signal detection (34).\n\nCommon adverse events were defined as those occurring in > 2% of men in ≥ 1 treatment or age group in the DBPC database, or at a reporting rate ≥ 1% in at least one of the two dosage groups in the postmarketing safety database.\n\nSpecial safety topics\nSeveral safety topics of special interest were selected for more detailed analysis, including certain adverse events [e.g. cardiovascular risk, priapism and non-arteritic anterior ischaemic optic neuropathy (NAION)] and events that might arise from intrinsic factors (e.g. impairment of renal and hepatic function), drug interactions [e.g. with nitrates, cytochrome P3A4 (CYP3A4) inhibitors, concomitant ED medications and α-blockers] or incorrect use (e.g. overdose and abuse). Some of these topics (cardiovascular risk and impaired renal and hepatic function) are medical history factors, which are not coded in the postmarketing safety database and therefore could not be searched in that database. Cardiovascular risk was assessed using the DBPC database, in men with cardiovascular disease, receiving antihypertensive medications, or with diabetes. Also using the DBPC database, baseline laboratory parameters were used to identify moderate renal impairment (defined as > 1.5 times the upper limit of normal blood urea nitrogen/urea and creatinine) and moderate hepatic impairment [defined as > 1.5 times the upper limit of normal for ≥ 2 tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and total bilirubin]. MedDRA-preferred terms were used to search for priapism, NAION, hearing loss and incorrect use [although cases having the intent to self-harm (e.g. suicide or suicide attempt) were excluded from the overdose analysis]. Comprehensive lists of α-blockers, nitrates, nitric oxide donors, CYP3A4 inhibitors and concomitant ED medications (37) were used to search for drug interactions.\n\nResults and discussion\nDatabases\nThe DBPC database contained more than 14,000 men, who were enrolled and received at least one dose of study drug. The mean age of sildenafil and placebo patients in the 54 parallel design trials was 55 years, with the majority aged ≥ 45 years; similar trends were observed for the 13 cross-over trials. Most of the men were white. At the time of enrolment ED had persisted, on average, for 4.5 years; it was most frequently organic in origin. The most common concomitant illnesses were of cardiovascular aetiology or associated with cardiovascular risk factors [i.e. hypertension, diabetes mellitus (non-insulin dependent), hyperlipidaemia, hypercholesterolaemia, coronary artery disease and a history of myocardial infarction] reflecting the age-related prevalence of these conditions. Benign prostatic hyperplasia and localised prostate cancer, treated with transurethral prostatectomy and radical prostatectomy, respectively, were also relatively common, as were conditions associated with an elderly or ageing population (e.g. osteoarthritis and visual disturbance).\n\nConsistent with a population of advancing age and with the underlying comorbidity frequently seen in patients with ED, the most common medications taken were those used to treat hypertension, hyperlipidaemia, diabetes mellitus, arthritic conditions and skeletal muscular injuries, and to prevent myocardial infarction. Thus, the DBPC database includes a heterogeneous ED population that is representative of the ED population as a whole.\n\nThe postmarketing safety database identified 39,277 sildenafil patients with adverse events through July 15, 2007. The vast majority of these were reported spontaneously by health or non-health professionals (Table 1). The first daily dose was identified in slightly less than half of the cases (i.e. > 25 and ≤ 50 mg, n = 12,843; > 50 and ≤ 100 mg, n = 5066). Demographical and case characteristics, where known, were comparable to those observed for the DBPC database, in that the majority of the population was ≥ 50 years of age and the majority of cases reported a first total daily dose of 25–100 mg. Most of the cases were non-serious (80.4%) and approximately half (54%; 21,334/39,277) of the men reported a case outcome. Of the cases with known case outcomes, nearly half (49%; 10,498/21,334) reported an outcome of recovered/recovering/recovering with sequelae, and very few reported a fatal outcome (6.1%; 1303/21,334). Medical history is not a coded search function in the postmarketing safety database, but concomitant medications were consistent with common concomitant medications used by men in the DBPC database.\n\nTable 1 Sources of cases populating the postmarketing safety database\n\nSource\tNumber (%)\t\nSpontaneous\t\nHealth professional\t15,894 (40.5)\t\nNon-health professional\t22,397 (57.0)\t\nTotal\t38,391 (97.5)\t\nHealth authority\t\nHealth professional\t658 (1.7)\t\nNon-health professional\t21 (0.1)\t\nTotal\t679 (1.7)\t\nPublished report\t307 (0.8)*\t\nTotal\t39,277 (100)\t\n*The international literature is carefully screened daily to identify all relevant cases. Although an attempt is consistently made to avoid counting events twice, there may be a few duplicate cases, i.e. reported in observational studies published in the literature (e.g. the International Men’s Health Study (29) and Prescription Event Monitoring study (24)) and as spontaneous postmarketing cases.\n\nTolerability of 50 mg vs. 100 mg\nThe safety profile of sildenafil, based on data from the DBPC database that included more than 7500 men treated with sildenafil 50 or 100 mg (Tables 2–4), remained consistent with that presented in the original regulatory submissions from approximately 10 years ago. Very rare were the serious adverse events of priapism (n = 11 patients), NAION (n = 0 patients) and hearing loss (n = 1 patient of unilateral loss considered to be embolic in aetiology), which are discussed in detail in subsequent sections of this review. Common adverse events in men treated with sildenafil were those related to the pharmacology of PDE5 inhibition, such as headache, vasodilation and facial flushing. These were reported in a higher incidence of men treated with sildenafil than with placebo (Table 4) and in a comparable incidence to that documented in the Viagra product information leaflet (15). Previously reported data collated from 17 of the randomised, DBPC, flexible-dose trials showed that the rate of these common adverse events decreased markedly over a 16-week treatment period such that, during the first 4–6 weeks of treatment, the rate among sildenafil-treated patients was higher than that for placebo-treated patients but, by 8 weeks and thereafter, the rate was similar between sildenafil- and placebo-treated patients (Figure 1) (38).\n\nTable 4 Common treatment-related adverse events, stratified by dose and age, in 67 double-blind placebo-controlled trials\n\n\tEvent by disorder system, number (%) of patients with event [with severe event]*\t\n\tEye\tGI\tNervous system\tRespiratory\tVascular\t\nTrial design dosage (n)† Age group (n)\tChromatopsia\tCyanopsia\tVisual disturbance\tDyspepsia\tDizziness\tHeadache\tNasal congestion\tFlushing\tHot flush\t\nFixed-dose\t\nSildenafil 50 mg (804)\t4 (0.5)\t1 (0.1)\t1 (0.1)\t35 (4.4) [3]\t14 (1.7) [1]\t116 (14.4) [9]\t15 (1.9) [1]\t107 (13.3) [1]\t27 (3.4) [1]\t\nSildenafil 100 mg (1373)\t17 (1.2) [1]\t19 (1.4)\t35 (2.5)\t64 (4.7) [6]\t18 (1.3)\t167 (12.2) [13]\t29 (2.1) [1]\t130 (9.5) [5]\t30 (2.2)\t\nPlacebo (1623)\t0\t1 (0.1)\t1 (0.1)\t7 (0.4)\t9 (0.6)\t39 (2.4) [1]\t2 (0.1)\t16 (1.0)\t3 (0.2)\t\nFlexible-dose\t\nSildenafil 50 mg (2060)\t8 (0.4)\t14 (0.7)\t12 (0.6)\t50 (2.4) [6]\t58 (2.8)\t264 (12.8) [21]\t42 (2.0) [3]\t205 (10.0) [2]\t28 (1.4) [1]\t\nSildenafil 100 mg (3479)\t13 (0.4)\t36 (1.0)\t23 (0.7)\t101 (2.9) [5]\t53 (1.5)\t305 (8.8) [19]\t65 (1.9) [3]\t271 (7.8) [4]\t12 (0.3)\t\nPlacebo (4979)\t2 (0)\t1 (0)\t5 (0.1)\t15 (0.3) [1]\t40 (0.8) [2]\t155 (3.1) [11]\t12 (0.2)\t65 (1.3) [1]\t7 (0.1)\t\nAll trials‡\t\nSildenafil 50 mg, initial dose\t\nAll ages (6207)\t24 (0.4)\t51 (0.8)\t35 (0.6)\t181 (2.9)\t127 (2.0)\t705 (11.4)\t125 (2.0)\t577 (9.3)\t56 (0.9)\t\n< 65 years (5003)\t21 (0.4)\t42 (0.8)\t27 (0.5)\t146 (2.9)\t103 (2.1)\t587 (11.7)\t107 (2.1)\t472 (9.4)\t47 (0.9)\t\n≥ 65 years (1203)\t3 (0.2)\t9 (0.7)\t8 (0.7)\t35 (2.9)\t24 (2.0)\t118 (9.8)\t18 (1.5)\t105 (8.7)\t9 (0.7)\t\n≥ 75 years (134)\t1 (0.7)\t0\t2 (1.5)\t9 (6.7)\t0\t13 (9.7)\t1 (0.7)\t13 (9.7)\t1 (0.7)\t\nSildenafil 100 mg, initial dose\t\nAll ages (1337)\t16 (1.2) [1]\t19 (1.4)\t35 (2.6)\t64 (4.8) [6]\t18 (1.3)\t163 (12.2) [13]\t28 (2.1) [1]\t124 (9.3) [5]\t23 (1.7)\t\n< 65 years (1026)\t10 (1.0) [1]\t15 (1.5)\t32 (3.1)\t49 (4.8) [4]\t12 (1.2)\t134 (13.1) [10]\t26 (2.5) [1]\t98 (9.6) [5]\t18 (1.8)\t\n≥ 65 years (308)\t6 (1.9)\t4 (1.3)\t3 (1.0)\t15 (4.9) [2]\t6 (1.9)\t29 (9.4) [3]\t2 (0.6)\t26 (8.4)\t5 (1.6)\t\n≥ 75 years (37)§\t1 (2.7)\t0\t1 (2.7)\t3 (8.1)\t1 (2.7)\t2 (5.4)\t0\t3 (8.1)\t1 (2.7)\t\nPlacebo\t\nAll ages (6602)\t2 (0)\t2 (0)\t6 (0.1)\t22 (0.3) [1]\t49 (0.7) [2]\t194 (2.9) [12]\t14 (0.2)\t81 (1.2) [1]\t10 (0.2)\t\n< 65 years (5294)\t2 (0)\t2 (0)\t3 (0.1)\t21 (0.4) [1]\t40 (0.8) [1]\t161 (3.0) [12]\t12 (0.2)\t63 (1.2) [1]\t9 (0.2)\t\n≥ 65 years (1303)\t0\t0\t3 (0.2)\t1 (0.1)\t9 (0.7) [1]\t33 (2.5)\t2 (0.2)\t18 (1.4)\t1 (0.1)\t\n≥ 75 years (128)\t0\t0\t0\t0\t0\t2 (1.6)\t0\t1 (0.8)\t0\t\nAE, adverse event; DC, discontinuation; GI, gastrointestinal.\n\n* Events occurring in > 2% of men in ≥ 1 group. An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. Listed are DCs, dose reductions and temporary DCs that were caused by an AE. Severe events are shown only when ≥ 1 occurred. Because of the small number of severe events, percentages are not given.\n\n† In flexible-dose trials, dose is the modal dose, the dose that the patient was exposed to the longest during the study period. If the duration was the same for two different doses, the higher dose was selected as the modal dose of the patient.\n\n‡ Sum of patient numbers in the ‘< 65 years’ group plus the ‘≥ 65 years group’. do not total the numbers in the ‘All ages’ group because age was missing for one patient (50 mg) and three patients (100 mg).\n\n§ In addition to the tabulated events, there were also 1 (2.4%) case each of iris disorder (mild), abdominal discomfort (mild), diarrhoea haemorrhagic (moderate), gastroesophageal reflux (mild), nausea (mild), fatigue (moderate), heart rate increase (mild), musculoskeletal pain (moderate), pain in extremity (moderate) and hypoesthenia (mild).\n\nTable 2 Overview of adverse events and discontinuations stratified by dose, in 67 double-blind placebo-controlled trials\n\n\tFixed-dose trials\tFlexible-dose trials\t\n\tSildenafil dose\tModal sildenafil dose*\t\nAdverse events†\t50 mg (N = 804)\t100 mg (N = 1373)\tPlacebo (N = 1623)\t50 mg (N = 2060)\t100 mg (N = 3479)\tPlacebo (N = 4979)\t\nAE, number of events\t\nAll causality\t1101\t1419\t769\t1807\t2768\t2491\t\nTreatment-related\t501\t781\t181\t1077\t1421\t668\t\nAE, number (%) of patients\t\nAll causality\t498 (61.9)\t655 (47.7)\t489 (30.1)\t951 (46.2)\t1549 (44.5)\t1572 (31.6)\t\nSevere\t51 (6.3)\t56 (4.1)\t41 (2.5)\t87 (4.2)\t102 (2.9)\t127 (2.6)\t\nSerious\t17 (2.1)\t19 (1.4)\t23 (1.4)\t37 (1.8)\t55 (2.6)\t67 (1.3)\t\nDC\t14 (1.7)\t20 (1.5)\t19 (1.2)\t50 (2.4)\t27 (0.8)\t49 (1.0)\t\nDose reduction or temporary DC\t20 (2.5)\t18 (1.3)\t17 (1.0)\t118 (5.7)\t59 (1.7)\t68 (1.4)\t\nTreatment-related\t295 (36.7)\t436 (31.8)\t136 (8.4)\t655 (32.3)\t885 (25.4)\t480 (9.6)\t\nSevere\t21 (2.6)\t19 (1.4)\t6 (0.4)\t35 (1.7)\t29 (0.8)\t19 (0.4)\t\nSerious\t1 (0.1)\t1 (0.1)\t1 (0.1)\t3 (0.1)\t5 (0.1)\t3 (0.1)\t\nDC\t8 (1.0)\t10 (0.7)\t7 (0.4)\t28 (1.4)\t10 (0.3)\t18 (0.4)\t\nDose reductions or temporary DC\t1 (0.1)\t8 (0.6)\t1 (0.1)\t102 (5.0)\t29 (0.8)\t32 (0.6)\t\nAE, adverse event; DC, discontinuation.\n\n* Modal dose: dose the patient was exposed to the longest during the study period. If the duration was the same for two different doses, the higher dose was selected as the modal dose of the patient.\n\n† An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Listed are DCs, dose reductions and temporary DCs that were caused by an AE.\n\nFigure 1 Rate of treatment-related adverse events over time collated from 17 randomised, double-blind, placebo-controlled, flexible-dose trials (sildenafil 25–100 mg, n = 2362; placebo, n = 1986). Treatment periods of up to 4 months were divided into 2-week intervals; the number of patients who experienced any adverse event was recorded for each interval and divided by the total number of patients who received treatment during that interval (38)\n\nThe safety profiles of sildenafil 50 and 100 mg in the DBPC trials were comparable, in that there was no apparent increase in the incidence of men with all-causality or treatment-related adverse events among those receiving 100 mg as a fixed or flexible-dose compared with those receiving 50 mg as a fixed or flexible-dose (Tables 2 and 4). The exception to this was a known increased incidence of men with transient altered colour vision (chromatopsia and cyanopsia) at doses of ≥ 100 mg (15). Indeed, for some adverse events, the incidence was higher among those receiving 50 mg than among those receiving 100 mg. For example, headache [fixed-dose: 14.4% (50 mg) vs. 12.2% (100 mg); modal flexible-dose: 12.8% (50 mg) vs. 8.8% (100 mg)] and flushing [fixed-dose: 13.3% (50 mg) vs. 9.5% (100 mg); flexible-dose: 10.0% (50 mg) vs. 7.8% (100 mg)] (Table 4). It is likely that the differences between fixed-doses are clinically meaningless and that those between flexible-doses reflect enrichment of the 50-mg group with patients having tolerability issues that prevented dosage increase, such that their most frequent dose throughout the study was 50 mg.\n\nIn the population as a whole and in all subgroups stratified by age, the overall incidence of men with adverse events was similar in those initiating treatment with 100 mg vs. 50 mg, except for a slight dose-related increase in the incidence of treatment-related adverse events among older men (Table 3). Among the most common treatment-related adverse events, the incidence was generally similar with a starting dose of 100 mg vs. 50 mg (Table 4). The exception to this was headache in men aged ≥ 75 years, which occurred in 5.4% (2/37) of those starting with 100 mg and in 9.7% (13/134) of those starting with 50 mg. For most events, the incidence was also similar across age subgroups for each starting dose. Noteworthy exceptions to this were a higher incidence of men with dyspepsia in the subgroup of men aged ≥ 75 years, which was relatively small (50 mg, n = 134; 100 mg, n = 37), and a lower incidence of men with headache and nasal congestion in the subgroups of men aged ≥ 75 or ≥ 65 years.\n\nTable 3 Overview of adverse events and discontinuations stratified by starting dose and age, in 67 double-blind placebo-controlled trials\n\n\tOverall*\t< 65 years\t≥ 65 years\t≥75 years\t\n\t50 mg\t100 mg\tPL\t50 mg\t100 mg\tPL\t50 mg\t100 mg\tPL\t50 mg\t100 mg\tPL\t\nAdverse events†\t(n = 6207)\t(n = 1337)\t(n = 6602)\t(n = 5003)\t(n = 1026)\t(n = 5294)\t(n = 1203)\t(n = 308)\t(n = 1303)\t(n = 134)\t(n = 37)\t(n = 128)\t\nAE, number of events\t\nAll causality\t5539\t1391\t3260\t4395\t1038\t2513\t1144\t353\t747\t123\t44\t75\t\nTreatment-related\t3011\t758\t849\t2476\t607\t692\t535\t151\t157\t61\t21\t10\t\nAE, number (%) of patients\t\nAll causality\t2935 (47.3)\t638 (47.7)\t2061 (31.2)\t2344 (46.9)\t487 (47.5)\t1610 (30.4)\t591 (49.1)\t151 (49.0)\t451 (34.6)\t67 (50.0)\t19 (51.4)\t42 (32.8)\t\nSevere\t229 (3.7)\t56 (4.2)\t168 (2.5)\t187 (3.7)\t41 (4.0)\t122 (2.3)\t42 (3.5)\t15 (4.9)\t46 (3.5)\t2 (1.5)\t0\t6 (4.7)\t\nSerious\t106 (1.7)\t19 (1.4)\t90 (1.4)\t78 (1.6)\t14 (1.4)\t60 (1.1)\t28 (2.3)\t5 (1.6)\t30 (2.3)\t4 (3.0)\t1 (2.7)\t5 (3.9)\t\nDC\t113 (1.8)\t25 (1.9)\t89 (1.3)\t88 (1.8)\t16 (1.6)\t64 (1.2)\t25 (2.1)\t9 (2.9)\t25 (1.9)\t5 (3.7)\t2 (5.4)\t3 (2.3)\t\nDose reduction or temporary DC\t237 (3.8)\t18 (1.3)\t85 (1.3)\t194 (3.9)\t12 (1.2)\t66 (1.2)\t43 (3.6)\t6 (1.9)\t19 (1.5)\t4 (3.0)\t2 (5.4)\t2 (1.6)\t\nTreatment-related\t1840 (29.6)\t422 (31.6)\t616 (9.3)\t1510 (30.2)\t329 (32.1)\t496 (9.4)\t330 (27.4)\t93 (30.2)\t120 (9.2)\t40 (29.9)\t13 (35.1)\t7 (5.5)\t\nSevere\t81 (1.3)\t19 (1.4)\t25 (0.4)\t68 (1.4)\t14 (1.4)\t23 (0.4)\t13 (1.1)\t5 (1.6)\t2 (0.2)\t0\t0\t0\t\nSerious\t9 (0.1)\t1 (0.1)\t4 (0.1)\t6 (0.1)\t1 (0.1)\t3 (0.1)\t3 (0.2)\t0\t1 (0.1)\t0\t0\t0\t\nDC\t54 (0.9)\t12 (0.9)\t29 (0.4)\t40 (0.8)\t9 (0.9)\t22 (0.4)\t14 (1.2)\t3 (1.0)\t7 (0.5)\t1 (0.7)\t1 (2.7)\t1 (0.8)\t\nDose reduction or temporary DC\t176 (2.8)\t8 (0.6)\t34 (0.5)\t150 (3.0)\t6 (0.6)\t28 (0.5)\t26 (2.2)\t2 (0.6)\t6 (0.5)\t3 (2.2)\t1 (2.7)\t0\t\nAE, adverse event; DC, discontinuation; NA, data not available; PL, placebo.\n\n* Sum of patient numbers in the ‘< 65 years’ group plus the ‘≥ 65 years group’. do not total the numbers in the ‘All ages’ group because age was missing for one patient (50 mg) and three patients (100 mg).\n\n† An event was categorised according to investigator judgment as severe if it interrupted daily activity and required systemic drug therapy or other medical treatment. A serious adverse event was defined as any untoward medical occurrence that resulted in death, was life threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in a persistent or significant disability/incapacity or a congenital anomaly/birth defect. Listed are DCs, dose reductions and temporary DCs that were caused by an AE.\n\nThe majority of adverse events included in the postmarketing safety database were known sildenafil adverse drug reactions, similar to those reported in DBPC trials. Overall, the onset of more of the adverse events occurred in association with a total daily dose of 50 mg [i.e. > 25–50 mg; 32.7% (12,843/39,277)] than with a total daily dose of 100 mg [i.e. > 50–100 mg; 12.9% (5066/39,277)]. The higher number of reports in association with a total daily dose of 50 mg likely reflects that most adverse event reports are generated in men newly on treatment and that 50 mg is the recommended sildenafil staring dose. For most types of events, the reporting rates were similar between the 50- and 100-mg dose (Table 5). Not listed in Table 5 are reports of drug ineffective [50 mg, n = 3803 (29.6%); 100 mg, n = 2038 (40.2%)], drug effect decreased [50 mg, n = 1090 (8.5%); 100 mg, n = 397 (7.8%)], or ED [50 mg, n = 1132 (8.8%); 100 mg, n = 449 (8.9%)] because the efficacy of sildenafil is well established (12,13), an increase in dose or second-line treatment should be considered in cases in which sildenafil is ineffective (39), and it is the role of the healthcare professional to establish realistic treatment goals and expectations. Most men in whom sildenafil treatment failed responded successfully after re-education and counselling, which included information on patient and partner expectations, how to properly take the drug, titration to maximum dose and a minimum trial of eight attempts (40).\n\nTable 5 In the postmarketing safety database, reporting rate of common adverse drug reactions for which the first total daily dose was 50 or 100 mg\n\n\tFirst total daily dose\t\nDisorder system Event, n (%)*\t50 mg N = 12,843 reports†\t100 mg N = 5,066 reports†\t\nCardiac\t\nMyocardial infarction\t273 (2.1)\t95 (1.9)\t\nPalpitation\t236 (1.8)\t48 (0.9)\t\nTachycardia\t165 (1.3)\t36 (0.7)\t\nEye disorders\t\nCyanopsia\t233 (1.8)\t189 (3.7)\t\nVision blurred\t244 (1.9)\t89 (1.8)\t\nVisual disturbance\t149 (1.2)\t74 (1.5)\t\nGastrointestinal\t\nDyspepsia\t415 (3.2)\t174 (3.4)\t\nNausea\t276 (2.2)\t82 (1.6)\t\nGeneral and administration site\t\nChest pain\t220 (1.7)\t59 (1.2)\t\nDrug interaction\t248 (1.9)\t121 (2.4)\t\nFeeling hot\t202 (1.6)\t47 (0.9)\t\nMalaise\t130 (1.0)\t40 (0.8)\t\nInjury, poisoning and procedural complications\t\nIntentional drug misuse\t85 (0.7)\t66 (1.3)\t\nIntentional overdose\t153 (1.2)\t121 (2.4)\t\nOverdose\t154 (1.2)\t65 (1.3)\t\nNervous system\t\nDizziness\t502 (3.9)\t167 (3.3)\t\nHeadache\t1929 (15.0)\t574 (11.3)\t\nReproductive system\t\nPriapism and related events‡\t305 (2.4)\t132 (2.6)\t\nRespiratory\t\nDyspnoea\t163 (1.3)\t54 (1.1)\t\nNasal congestion\t530 (4.1)\t156 (3.1)\t\nSkin and subcutaneous tissue\t\nErythema\t304 (2.4)\t59 (1.2)\t\nVascular\t\nFlushing\t1367 (10.6)\t409 (8.1)\t\nHot flush\t183 (1.4)\t26 (0.5)\t\n* Events constituting ≥ 1% of reported events in ≥ 1 of the two dosage groups are listed.\n\n† 50 mg = > 25–50 mg; 100 mg = > 50–100 mg.\n\n‡ Priapism and erection increased.\n\nIn the DBPC database, the safety profiles of sildenafil 50 and 100 mg were comparable in that there were no apparent dose-related increases in the incidence of men with severe adverse events, serious adverse events, discontinuations caused by adverse events or dose reductions caused by adverse events in the population as a whole (Table 3) and in either the fixed-dose trials or the flexible-dose trials (Table 2). Across subgroups stratified by starting dose and age, there was a low incidence of men with treatment-related serious events (< 1%), severe events (< 2%), discontinuations caused by adverse events (< 3%) and dose reductions or temporary discontinuations caused by adverse events (≤ 3%) (Table 3).\n\nThe overall frequency of death was low in the DBPC database and was comparable between men using sildenafil (13/8691, 0.15%) and placebo (7/6602, 0.11%). Most deaths were in men aged ≥ 50 years. Among the deaths were six men using 50 mg (mean age, 56.8 years), of whom two were ≥ 65 years and one was ≥ 75 years; five men using 100 mg (mean age, 62.4 years), of whom three were ≥ 65 years and one was ≥ 75 years; and seven men using placebo (mean age, 67.2 years), of whom six were ≥ 65 years and one was ≥ 75 years. None of the deaths was considered to be treatment related.\n\nIn the postmarketing safety database, approximately 20% (7683/39,277) of patients were considered serious and 3.3% of patients (1310/39,277) had an outcome of death. Of the 882 deaths for which age was reported, the majority of cases [79.4% (700/882)] involved patients aged > 50 years. For serious adverse events and deaths, the order of magnitude differences between the incidence rates of the DBPC database and the reporting rates of the postmarketing safety database reflects the vastly different natures of these metrics, as described in Methods section.\n\nCardiovascular risk\nThe prevalence of ED is increased in men at risk for cardiovascular disease (41–47). Further evidence for the relationship between ED and cardiovascular disease is that the most common organic cause of ED is vascular disease (31,48) and some of the most common comorbid diagnoses in men with ED are cardiovascular disease risk factors (i.e. hypertension, hyperlipidaemia and diabetes mellitus) (49). However, previous extensive study revealed no evidence that sildenafil use was associated with increased risk of adverse cardiovascular disease events (27,29,50–52).\n\nNot surprisingly, given the known association between ED and cardiovascular disease, and between age and cardiovascular disease, the most commonly reported adverse events that resulted in death in the DBPC database were cardiac related (i.e. myocardial infarction, cardiac arrest, cardiac failure and coronary artery disease), and most of these were in men aged ≥ 50 years. However, it should be noted that the deaths were not attributed to sildenafil and that the overall cardiovascular death rate was slightly higher in the placebo groups (3 of 7 deaths) than in the sildenafil groups (4 of 11 deaths). Similarly, the incidence of men with serious cardiovascular events was comparable and not significantly different in the sildenafil and placebo groups [i.e. acute myocardial infarction (4.1% vs. 4.5%), chest pain (3.0% vs. 2.3%), coronary artery disease (2.7% vs. 5.3%), myocardial infarction (2.5% vs. 3.8%) and cerebrovascular accident (2.5% vs. 2.3%)], and none of these serious cardiovascular events was related to sildenafil treatment.\n\nBased on available safety data, there is no evidence of a causal link between sildenafil and cardiovascular events. Safety data from the original regulatory submissions, postmarketing observational studies (24,29) and published literature demonstrate that sildenafil does not increase the rate of myocardial infarction or other serious cardiovascular events in men with ED. Furthermore, the safety profile of sildenafil in men with ED and diabetes mellitus (11,53,54), arterial hypertension (55) or cardiovascular conditions (56,57) is similar to that in men with ED without these conditions. The safety of sildenafil has not been studied in men with hypotension (blood pressure < 90/50 mmHg) or recent history of stroke or myocardial infarction, and its use is therefore currently contraindicated in men with these conditions (15).\n\nPriapism\nPriapism is a rare adverse drug reaction with sildenafil. In the DBPC database, the incidence of men with priapism or related events was 0.1% (11/8691) in sildenafil recipients and < 0.1% (2/6602) in placebo recipients. Most cases reported events that were considered mild in severity; none that was considered as severe or defined as serious; and most of which resolved with no action, intervention or reduction of dose. Eight of the cases were associated with sildenafil 50 mg, including two that were characterised by multiple events and two (one of which resolved with a dose reduction) that were characterised by a duration of > 1 day. Three of the cases were associated with sildenafil 100 mg, including two that were characterised by multiple events that resolved, and two that were characterised by a duration of > 1 day and resolved with no action.\n\nThe postmarketing safety database was searched for priapism-related events (coded in the MedDRA as ‘priapism’ and ‘erection increased’). Comparison of priapism-related events as reported by healthcare professionals and consumers, respectively, shows that, although the same pathological entity gets reported (in most cases as a serious event), reports of healthcare professionals tend to use the term ‘priapism,’ whereas those of consumers tend to use the term ‘erection increased.’ The reporting rate was 2.5% for sildenafil 50 mg (320/12,843 total patients) and 2.7% for sildenafil 100 mg (138/5066 total patients). In contrast to the DBPC database, for which none of the cases of priapism was considered by the investigator to be severe or fulfilled the definition for ‘serious’, 56% (180/320) of the reports in the postmarketing safety database that were associated with sildenafil 50 mg and 64% (89/138) of the reports in the postmarketing safety database that were associated with sildenafil 100 mg were reported as serious events. However, for most of the priapism cases, the reporter indicated that the case was not clinically severe. Also, for most of the priapism cases, the reporter indicated that the patient had recovered or was recovering without sequelae at the time of the report.\n\nThe risk of priapism appears to be increased in certain situations. For example, in cases of sildenafil overdose, priapism was reported at a rate more than twice that of the overall postmarketing safety database. Also, across all sildenafil doses, concomitant medication use was reported in 377 reports of priapism, in 27% (102/377) of which the concomitant medication(s) could have contributed to the priapism [i.e. other ED medications, alpha-adrenergic antagonists (phentolamine), psychotropics (amitriptyline, nortriptyline, trazodone, fluphenazine), amphetamines and cocaine]. In the subgroup of cases that reported concomitant use of another ED medication, alprostadil was used concomitantly with sildenafil in 74% (14/19) of the patients of priapism.\n\nAs priapism, although rare, is a potentially serious adverse event, the Viagra summary of product characteristics (SmPC) recommends use with caution in patients with anatomic deformation of the penis or in patients who have conditions that may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia) (15). Interestingly, sildenafil has been reported to be successful in relieving priapism in patients with sickle cell disease (58).\n\nNAION\nEvents suggestive of NAION were not discovered in the DBPC database. In the postmarketing safety database, the reporting rate for events suggestive of NAION was 0.8% (333/39,277). Nearly half (48%) of the cases for which medical history or concomitant medication information was available reported possible predisposing risk factors, including previous ocular disorders (n = 52), hypertension (n = 58), hyperlipidaemia (n = 47), diabetes mellitus and related conditions (n = 29), smoking (n = 36) and coronary artery disease (n = 21). More than half of the events suggestive of NAION were reported by attorneys rather than healthcare professionals and lack appropriate medical information.\n\nNo cases of NAION were discovered in a retrospective review of > 13,000 patients in the manufacturer’s clinical trials database or during 2935 patient-years of follow up in a prospective observational study of 3813 men (mean age, 57 years) (59). In another prospective observational study, one case of NAION was identified in a total of 35,569 patient-years of observation, representing an unadjusted NAION incidence estimated to be 2.8 patients per 100,000 patient-years of exposure to sildenafil, which is similar to or lower than estimates in general population samples (59).\n\nThe data cited herein do not suggest an increased incidence of NAION in men who took sildenafil for their ED. However, because a causal association between visual field defects and NAION has not been excluded, sildenafil is contraindicated in patients who have loss of vision in one eye because of NAION, regardless of whether this episode was related to previous exposure to a PDE5 inhibitor (15). Should a sudden visual defect occur, the patient should stop taking sildenafil and consult a physician immediately (15).\n\nHearing loss\nIn the DBPC database, events of hearing loss were limited to one case of severe unilateral deafness which is considered to be embolic in aetiology and unrelated to sildenafil treatment and a case of mild deafness that was related to sildenafil treatment. In the latter case, the event is reported as ‘exacerbation of hearing loss,’ implying a relevant medical history, and the patient had concurrent multiple sclerosis.\n\nIn the postmarketing safety database, reports were extremely rare, with a reporting rate of 0.01% (3/39,277) for sudden hearing loss and 0.07% (26/39,277) for impaired hearing. The one literature case report in a patient with ED indicated emergence of the event shortly after dosing. This report appears to be isolated, and critical information around dosing and patient characteristics is omitted (60).\n\nHearing loss is a prevalent condition in the general population and is associated with a number of underlying risk factors, including several drugs. The pharmacological action of sildenafil is not consistent with known ototoxic mechanisms, and there have been no cases that demonstrate the absence of known risk factors and clear evidence of sildenafil challenge/dechallenge or dosing in relation to onset.\n\nImpaired renal function and hepatic function\nMedical history is not a search function that is coded in the postmarketing safety database, but the DBPC database was searched for safety data in men with ED and moderate impairment of renal or hepatic function.\n\nSildenafil has a low renal clearance (< 2%) and excretion because of high tubular reabsorption in the kidney. Sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose) (61). In the DBPC database, the sildenafil safety profile in the 21 men with moderate impairment of renal function was similar to that in men with ED and no impairment of renal function. None had a worsening of blood urea nitrogen/urea or creatinine values, and only 2 of 7 (29%) randomised to sildenafil and 9 of 14 (64%) randomised to placebo had adverse events. The adverse events in the two sildenafil recipients (moderate abdominal pain and sciatica; mild peripheral oedema) were not related to sildenafil treatment. Furthermore, published literature suggests that sildenafil is well tolerated in men with ED and receiving dialysis (62), chronic dialysis (63), haemodialysis (64) and peritoneal dialysis (65); across these published trials, in which a total of 86 men received sildenafil, the most common adverse events were similar in frequency, nature and severity to those observed in patients without renal impairment (i.e. headache, flushing, visual disturbances, hypertension, nasal congestion and dyspepsia). Thus, results from approximately 100 men treated with sildenafil in the DBPC database and the published literature suggest that sildenafil is well tolerated in patients with moderate renal impairment. As sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance < 30 ml/min), a 25-mg initial dose should be considered; based on efficacy and toleration, the dose may be increased to 50 or 100 mg (15).\n\nSildenafil is extensively and rapidly metabolised by the liver, primarily by CYP3A4 enzymes (15). In men with moderate impairment of hepatic function, the DBPC database suggested a sildenafil safety profile that was similar to that in men with ED and no impairment of hepatic function. Of the 26 men in the DBPC database who had moderate hepatic impairment and were treated with sildenafil, 23% (6/25) experienced a worsening of their alkaline phosphatase, AST, ALT or total bilirubin values, none of which was attributed to sildenafil. Adverse events were experienced by 77% (20/26) of the sildenafil recipients with hepatic impairment compared with 37% (7/19) of the placebo patients with hepatic impairment. In these men, all of the adverse events that were attributed to sildenafil treatment were mild in severity. As sildenafil clearance is reduced in men with hepatic impairment (e.g. cirrhosis), a 25-mg initial dose should be considered; based on efficacy and toleration, the dose may be increased to 50 or 100 mg (15). The safety of sildenafil has not been studied in men with severe hepatic impairment, and its use is therefore contraindicated (15).\n\nDrug interactions\nAs sildenafil potentiates the hypotensive effects of nitrates, its concomitant administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is contraindicated (15). Drug interaction studies have shown that concomitant administration of sildenafil and nitrates is associated with known sildenafil adverse drug reactions (mainly class effects associated with PDE5 inhibition) and consistent reductions in blood pressure (18). Very few men in the DBPC database took nitrates concomitantly with sildenafil (16/8691) or placebo (9/6602), and none of these reported hypotension as an adverse event. Treatment-related adverse events were limited to one man treated with 50 mg who had dyspepsia and one man treated with 100 mg who had periorbital swelling, severe headache and facial flushing. In the postmarketing safety database, concomitant nitrate use represented approximately 1% (478/39,277) of patients, and the most frequent associated adverse events were consistent with the underlying cardiovascular conditions treated by nitrates [e.g. myocardial infarction (18%) and chest pain (15%)] or were hypotensive events from the known pharmacodynamic interaction of sildenafil and nitrates (11%).\n\nSildenafil metabolism is principally mediated by the CYP450 isoforms 3A4 (major route) and 2C9 (minor route); sildenafil clearance is reduced when administered concomitantly with CYP3A4 inhibitors such as ketoconazole, erythromycin and cimetidine. Concomitant administration of a single 100 mg dose of sildenafil with ritonavir (an HIV protease inhibitor that is a highly potent P450 inhibitor) at steady state (500 mg twice daily) resulted in increases of 300% (4-fold) in the sildenafil maximum serum concentration and 1000% (11-fold) in the sildenafil area under the plasma concentration vs. time curve (15). In the DBPC database, a small number of men took a CYP3A4 inhibitor, most commonly erythromycin or cimetidine, concomitantly with sildenafil (67/8691) or placebo (43/6602). In this subgroup, treatment-related adverse events occurred in nine men taking sildenafil 50 mg and in 11 men taking sildenafil 100 mg, including one man who had treatment-related adverse events at each dose. Treatment-related adverse events were generally known sildenafil adverse drug reactions that occurred at a slightly higher incidence than in the placebo group or in the entire DBPC database. There were too few postmarketing cases (n = 19) of concomitant CYP3A4 inhibitor and sildenafil use to make an assessment. Although the Viagra SmPC advises against the concomitant administration of sildenafil with ritonavir and recommends considering a sildenafil starting dose of 25 mg when administered concomitantly with other CYP3A4 inhibitors (15), this collated data review suggests little difference in the safety profile of sildenafil across doses (25–100 mg) when administered concomitantly with CYP3A4 inhibitors.\n\nThe current Viagra SmPC advises that patients should be haemodynamically stable on α-blocker therapy before initiating sildenafil treatment, and that initiation of sildenafil at lower doses (25 mg) should be considered (to minimise the potential for developing postural hypotension) (15). The safety of sildenafil administered concomitantly with α-blockers was investigated in three randomised, double-blind, placebo-controlled, cross-over drug interaction trials summarised in the SmPC, in which administration of sildenafil to men with benign prostatic hyperplasia and stabilised on the non-selective α-blocker doxazosin (4 and 8 mg) was associated with mean additional supine blood pressure reductions of 7/7 mmHg (25 mg dose), 9/5 mmHg (50 mg dose) and 8/4 mmHg (100 mg dose) respectively, and with mean additional standing blood pressure reductions of 6/6 mmHg (25 mg dose), 11/4 mmHg (50 mg dose) and 4/5 mmHg (100 mg dose) respectively, but with infrequent reports of symptomatic postural hypotension, which included dizziness and light-headedness, but not syncope) (15). These trials assessed men aged 35–75 years who had documented benign prostatic hyperplasia, had been receiving doxazosin for at least 2 months and took sildenafil after they had taken doxazosin 4 mg once daily for 2 weeks (66). In the first trial, one of four men who took sildenafil 100 mg had a serious adverse event of postural hypotension that began 35 min postdose and lasted for 8 h, but none of the 17 men who took sildenafil 25 mg experienced symptomatic postural hypotension. In the second trial, one of 20 men discontinued prematurely because of hypotension after taking sildenafil 50 mg, but he was also taking minoxidil concomitantly; two other men experienced hypotension as a moderately severe adverse event, with onset 1 h after taking sildenafil 50 mg and resolution of hypotension after 7.5 h. In the third trial, one of 25 men screened with open-label sildenafil 50 mg was discontinued because of symptomatic hypotension (a moderately severe adverse event) 30 min postdose, but none of the 20 men who took sildenafil 100 mg during the trial had a severe adverse event related to blood pressure. In addition to these single-dose, drug interaction trials, several published reports of data from randomised, clinical trials have assessed the safety of sildenafil administered concomitantly with α-blocker therapy and found no evidence of symptomatic postural hypotension associated with concomitant tamsulosin (n = 93) or terazosin (n = 78) therapy (67), doxazosin therapy (n = 14) (68) or alfuzosin therapy (n = 21) (69).\n\nIn the DBPC database, concomitant α-blocker and study drug administration was uncommon, occurring in only 4.2% (368/8691) of sildenafil recipients and 5.0% (329/6602) of placebo patients. It was also infrequent in the postmarketing safety database, occurring in 4.1% (1600/39,277) of patients. In both databases, non-selective α-blocker use (e.g. doxazosin or terazosin) was reported in most cases. In the DBPC database, the most commonly reported adverse events in sildenafil recipients administered α-blockers concomitantly were dyspepsia, headache and flushing, which are known adverse drug reactions with sildenafil treatment. The incidence of events expected from a pharmacological interaction between sildenafil and an α-blocker (decreased blood pressure, orthostatic hypotension) was very low, and there were no cases of hypotension. Adverse events were similar between men using sildenafil 50 and 100 mg, except for a greater incidence of flushing, dyspepsia and nasopharyngitis in the latter. Of sildenafil recipients with adverse events, 46% (168/349) had treatment-related adverse events, mostly mild events [80% (134/168) mild; 1.8% (3/168) severe]. In comparison, 16.9% (32/189) of placebo patients who were taking an α-blocker had an adverse event that was treatment related, of which 9.4% (3/32) were severe. Overall, sildenafil appears to be well tolerated by men receiving concomitant α-blockers. This collated data review suggests little difference in the safety profile of sildenafil across doses (25–100 mg) with concomitant use of α-blockers.\n\nGuidelines on the treatment of ED recommend PDE5 inhibitors as a first-line treatment (39,70). Other treatments include apomorphine sulphate, vacuum devices, intracavernosal injection with prostaglandin E1 and intraurethral delivery of prostaglandin E1. The safety profile of sildenafil administered concomitantly with other ED treatments has not been investigated in clinical trials and, in the DBPC database, few men used other ED medications concomitantly with sildenafil (13/8691) or placebo (12/6602). Treatment-related events, all of which resolved, occurred in three of these men: mild dyspepsia (alprostadil concomitantly with sildenafil 25 mg), mild chromatopsia and headache (alprostadil concomitantly with sildenafil 50 mg and then 100 mg) and moderate atypical chest pain (sildenafil concomitantly with sildenafil 100 mg). In the postmarketing safety database, 1.7% (670/39,277) of all patients reported concomitant ED medications; approved PDE5 inhibitors in more than half and alprostadil in one-third. In the subgroup that reported concomitant ED medications, the adverse events that occurred at more than twice the rate found in the overall postmarketing safety database usually represented the known dose-related increase in visual effects associated with PDE5 inhibition (cyanopsia and visual disturbance) or a synergistic pharmacological effect on the penis (erection increased, penis disorder and priapism). In most (22/40; 55%) of the patients with visual effects, another PDE5 inhibitor was used concomitantly, and in most (14/19; 74%) of the patients with priapism, alprostadil was used concomitantly. Other events that occurred at more than twice the rate found in the overall postmarketing safety database were related to underlying medical conditions (e.g. pain, dyspnoea and increased blood cholesterol and blood pressure) or to alprostadil injection (e.g. pain). Although the concomitant use of sildenafil with other treatments for ED is advised against in the Viagra SmPC (15), this collated data review identified no unexpected adverse drug reactions, suggesting that the safety risk is likely to be low in the general ED population.\n\nOverdose\nOverdose results from intentionally or inadvertently exceeding the maximum recommended daily dose or dosing frequency of a drug, which for sildenafil is a daily dose of 100 mg and (even if the total daily dose does not exceed 100 mg) a dosing frequency of not more than once per day. Sildenafil has low general toxicity; no relevant reproductive toxicity, genotoxicity or carcinogenic properties; and a substantial safety margin (18,71). Clinical studies of doses higher than the approved maximum showed an increased frequency and severity of known adverse drug reactions, including a dose-related increase in the frequency of visual adverse events, but no clear relationship between dose and maximum decreases in blood pressure and no clinically significant changes in electrocardiograms (18). With administration more frequently than once a day, there was an increased frequency of muscular ache, which was transient and without evidence of muscular damage, and dyspepsia (15,18). In the DBPC database, there were no reports of sildenafil overdose. In the postmarketing safety database, excluding cases in conjunction with suicides or suicide attempts, the reporting rate for sildenafil overdose was 2.3% (884/39,203).\n\nAdverse events in the postmarketing cases of overdose were generally known sildenafil adverse drug reactions (i.e. headache and flushing), which were generally reported at a slightly higher frequency than in the overall postmarketing safety database. Priapism was reported at a rate more than twice that of the overall postmarketing safety database. Of the 884 patients with overdose identified in the postmarketing safety database, 165 reported a first total daily dose > 100 mg. In this subset, the reporting rate was more than twice that for the overall postmarketing safety database for acute myocardial infarction (3.0% vs. 0.7%), myocardial infarction (6.1% vs. 2.5%), tachycardia (2.4% vs. 1.0%), drug interaction (4.8% vs. 2.4%), malaise (2.4% vs. 1.0%), dyspnoea (2.4% vs. 1.0%) and hypotension (5.5% vs. 1.1%). Although a relationship with sildenafil overdose cannot be excluded in 4 of the 12 patients with myocardial infarction and in 14 of the 57 deaths, neither can a relationship between overdose and increased cardiac risk be assumed based on the small number of postmarketing cases. However, we recommend admission to hospital and cardiac monitoring, preferably in a coronary care unit, for 48 h. In this way, any cardiovascular complication can be addressed by experienced healthcare professionals. Standard supportive measures should be adopted as required, but renal dialysis is not expected to accelerate clearance because sildenafil is highly bound to plasma proteins and is not eliminated in the urine.\n\nThe highest first total daily dose reported was 2400 mg in a 33-year-old man who took 24 tablets of sildenafil 100 mg. He was diagnosed with annular scotoma, defective colour vision, vascular retinal dilatation, visual field defect and papilloedema. He recovered from all events except for visual field defect and annular scotoma.\n\nThus, the collated data review determined that overdose with sildenafil is rare in the ED population and identified no new safety issues or adverse reactions in conjunction with overdose. It is noteworthy that, in a parallel-group, double-blind, randomised trial and its long-term open-label extension study, the safety profile of sildenafil, in doses up to 240 mg/day for the treatment of pulmonary arterial hypertension, was unchanged compared with lower dosages (72). In single-dose volunteer studies of doses up to 800 mg, adverse reactions were similar to those seen at lower doses, but the incidence rates and severities were increased (15).\n\nExtensive data (clinical trial data from > 13,000 patients (50,51), 7 years of international postmarketing data, observational studies of > 28,000 men in the United Kingdom (24) and 3813 men in the European Union (73)) was used to support the previously published conclusion that there are no special cardiovascular concerns when sildenafil is used in accordance with product labelling (27).\n\nAbuse\nAbuse can be classified as addiction/dependence (an involuntary compulsion, which is usually marked by tolerance to the effects and withdrawal symptoms when use is terminated), abuse (recreational use without medical rationale but without addiction or dependence) and misuse (intentional or unintentional incorrect use by a healthcare provider or patient). Unintentional misuse includes accidental exposure, drug administration error, incorrect dose administered and medication error. Events relating to addiction/dependence, abuse or misuse of sildenafil were not identified in the DBPC database, but were identified in the postmarketing safety database.\n\nThe mode of action of sildenafil is peripheral rather than central (71,74). Consequently, sildenafil lacks the libido-stimulating activity that classically defines an aphrodisiac agent. In addition, there is no evidence that men with ED develop physical dependence or tolerance to sildenafil. The absence of evidence of tolerance developing to the erectogenic effects of sildenafil is further supported by the results of a long-term study over 4 years (75). However, in the postmarketing safety database, sildenafil dependence was reported in a few [0.15% (58/39,277)] patients, mostly psychological dependence on sildenafil to achieve erection or insecurity in initiating intercourse without sildenafil.\n\nSildenafil abuse represented 0.11% (42/39,277) of all reported events, in 76% of which the patient did not have a diagnosis of ED. Intentional misuse was identified in 1.4% (535/39,277) of all patients, most commonly taking sildenafil for recreational purposes, without a prescription, and/or without a diagnosis of ED (n = 207) and adjusting the dose or route/form of administration without direction of a physician (n = 141). Unintentional misuse was identified in 0.91% (357/39,277) of patients, including patients who accidentally took the drug, accidentally took more of the drug than intended or altered their dose or dosing frequency without first consulting a physician.\n\nThus, in the postmarketing safety database, the predominant form of improper use was obtaining sildenafil without a prescription and/or taking sildenafil without a diagnosis of ED. Sildenafil is often obtained through uncontrolled channels outside of the healthcare system, a risky behaviour that is a medical concern that needs to be addressed (76–78). Also, some men take sildenafil for what they perceive as a better sexual performance, even though they do not have ED. No new safety signals or emerging trends were identified from this review of cases reporting sildenafil dependence, abuse and misuse.\n\nConclusions\nThis collated data review found that sildenafil was well tolerated at a dose of 50 or 100 mg, overall, in men who were aged ≥ 65 years and in those who were aged ≥ 75 years. No causal link was identified between sildenafil administered in accordance with product labelling and cardiovascular events, and further support was lent to the safety of sildenafil in men at risk for cardiovascular disease, in that no new safety risks relating to cardiovascular events were identified in patients with cardiovascular conditions, hypertension or diabetes mellitus. No new safety risks were identified with sildenafil relating to priapism or NAION. In the small number of men with ED and moderate impairment of renal function or hepatic function who have been treated with sildenafil in DBPC trials, the sildenafil safety profile was similar to that in men with ED and no impairment of renal or hepatic function. As sildenafil was well tolerated, has a relatively short half-life (4–5 h) and is administered as needed in a maximum of one dose per day, the safety risk from drug interactions is likely to be low in the general ED population. Indeed, no unexpected adverse drug reactions were identified from the concomitant use of sildenafil with nitrates, nitric oxide donors, CYP3A4 inhibitors, other ED medications or α-blockers. Overdose with sildenafil was rare in the ED population, and no new adverse reactions were identified in conjunction with overdose, dependence, abuse or misuse. It can be concluded that sildenafil in all registered doses has a good safety profile.\n\n1 PubMed search: ‘erectile dysfunction’ (Mesh) and ‘drug toxicity’ (Mesh) and (sildenafil or vardenafil or tadalafil) and [‘age factors’ (Mesh) or ‘age groups’ (Mesh)].\n\n2 The recommended starting dose is 50 mg taken as needed approximately 1 h before sexual activity [VIAGRA® (sildenafil citrate) summary of product characteristics, http://www.emea.europa.eu/humandocs/PDFs/EPAR/viagra/H-202-PI-en.pdf]. Based on efficacy and toleration, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day.\n\nThe authors thank Gabriel Schnetzler, MD, Pfizer International Operations, Paris, France, for his assistance in reviewing the manuscript. All financial and material support for the preparation of this manuscript was provided by Pfizer Inc, which was involved in the data collection and analysis. Editorial support was provided by Deborah M. Campoli-Richards, BSPHA, RPh, of Complete Healthcare Communications, Inc. and was funded by Pfizer Inc.\n\nAuthor contributions\nFrançois Giuliano, Graham Jackson, Francesco Montorsi, Antonio Martin-Morales and Pierre Raillard were involved in data interpretation and in the drafting, critical revision and approval of the manuscript.\n==== Refs\nReferences\n1 Dinsmore WW Hodges M Hargreaves C Sildenafil citrate (VIAGRA) in erectile dysfunction: near normalization in men with broad-spectrum erectile dysfunction compared with age-matched healthy control subjects Urology 1999 53 800 5 10197860 \n2 Montorsi F McDermott TED Morgan R Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies Urology 1999 53 1011 8 10223498 \n3 Goldstein I Lue TF Padma-Nathan H Oral sildenafil in the treatment of erectile dysfunction N Engl J Med 1998 338 1397 404 9580646 \n4 Becher E Tejada Noriega A Gomez R Decia R Sildenafil citrate (Viagra) in the treatment of men with erectile dysfunction in southern Latin America: a double-blind, randomized, placebo-controlled, parallel-group, multicenter, flexible-dose escalation study Int J Impot Res 2002 14 Suppl. 2 S33 41 12161766 \n5 Glina S Bertero E Claro J Efficacy and safety of flexible-dose oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction in Brazilian and Mexican men Int J Impot Res 2002 14 Suppl. 2 S27 32 12161765 \n6 Gomez F Davila H Costa A Efficacy and safety of oral sildenafil citrate (Viagra) in the treatment of male erectile dysfunction in Colombia, Ecuador, and Venezuela: a double-blind, multicenter, placebo-controlled study Int J Impot Res 2002 14 Suppl. 2 S42 7 12161767 \n7 Levinson IP Khalaf IM Shaeer KZ Smart DO Efficacy and safety of sildenafil citrate (Viagra) for the treatment of erectile dysfunction in men in Egypt and South Africa Int J Impot Res 2003 15 Suppl. 1 S25 9 12825106 \n8 Osegbe DN Shittu OB Aghaji AE Sildenafil citrate (Viagra) for the treatment of erectile dysfunction in Nigerian men Int J Impot Res 2003 15 Suppl. 1 S15 8 12825104 \n9 Tan HM Moh CL Mendoza JB Asian sildenafil efficacy and safety study (ASSESS-1): a double-blind, placebo-controlled, flexible-dose study of oral sildenafil in Malaysian, Singaporean, and Filipino men with erectile dysfunction. 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RIVM report 2005. http://www.rivm.nl/bibliotheek/rapporten/267041001.pdf [Accessed 28 November 2007] \n37 WHO Drug Dictionary 2002 Uppsala, Sweden Uppsala Monitoring Centre 2nd Quarter \n38 Carson C Siegel R Orazem J Sildenafil citrate treatment for erectile dysfunction: rate of adverse events decreases over time J Urol 2002 167 Suppl. 179 \n39 Wespes E Amar E Hatzichristou D EAU guidelines on erectile dysfunction: an update Eur Urol 2006 49 806 15 16530932 \n40 McCullough AR Barada JH Fawzy A Achieving treatment optimization with sildenafil citrate (Viagra®) in patients with erectile dysfunction Urology 2002 60 28 38 12414331 \n41 Bacon CG Mittleman MA Kawachi I A prospective study of risk factors for erectile dysfunction J Urol 2006 176 217 21 16753404 \n42 Kupelian V Link CL McKinlay JB Association between smoking, passive smoking, and erectile dysfunction: results from the Boston Area Community Health (BACH) Survey Eur Urol 2007 52 416 22 17383811 \n43 Kupelian V Shabsigh R Araujo AB Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study J Urol 2006 176 222 6 16753405 \n44 Millett C Wen LM Rissel C Smoking and erectile dysfunction: findings from a representative sample of Australian men Tob Control 2006 15 136 9 16565463 \n45 Ponholzer A Temml C Mock K Prevalence and risk factors for erectile dysfunction in 2869 men using a validated questionnaire Eur Urol 2005 47 80 5 15582253 \n46 Riedner CE Rhoden EL Ribeiro EP Fuchs SC Central obesity is an independent predictor of erectile dysfunction in older men J Urol 2006 176 1519 23 16952671 \n47 Selvin E Burnett AL Platz EA Prevalence and risk factors for erectile dysfunction in the US Am J Med 2007 120 151 7 17275456 \n48 Feldman HA Johannes CB Derby CA Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study Prev Med 2000 30 328 38 10731462 \n49 Seftel AD Sun P Swindle R The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction J Urol 2004 171 2341 5 15126817 \n50 Mittleman MA Maclure M Glasser DB Evaluation of acute risk for myocardial infarction in men treated with sildenafil citrate Am J Cardiol 2005 96 443 6 16054479 \n51 Mittleman MA Glasser DB Orazem J Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo Int J Clin Pract 2003 57 597 600 14529061 \n52 Blonde L Sildenafil citrate for erectile dysfunction in men with diabetes and cardiovascular risk factors: a retrospective analysis of pooled data from placebo-controlled trials Curr Med Res Opin 2006 22 2111 20 17076971 \n53 Boulton AJ Selam JL Sweeney M Ziegler D Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus Diabetologia 2001 44 1296 301 11692178 \n54 Buranakitjaroen P Mangklabruks A Leungwattanakij S Efficacy and safety of sildenafil in Asian males with erectile dysfunction and cardiovascular risk J Med Assoc Thai 2007 90 1100 8 17624203 \n55 Pickering TG Shepherd AM Puddey IB Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial Am J Hypertens 2004 17 1135 42 15607620 \n56 Katz SD Parker JD Glasser DB Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure Am J Cardiol 2005 95 36 42 15619391 \n57 Olsson AM Persson CA Efficacy and safety of sildenafil citrate for the treatment of erectile dysfunction in men with cardiovascular disease Int J Clin Pract 2001 55 171 6 11351770 \n58 Bialecki ES Bridges KR Sildenafil relieves priapism in patients with sickle cell disease Am J Med 2002 113 252 12208390 \n59 Gorkin L Hvidsten K Sobel RE Siegel R Sildenafil citrate use and the incidence of nonarteritic anterior ischemic optic neuropathy Int J Clin Pract 2006 60 500 3 16620369 \n60 Mukherjee B Shivakumar T A case of sensorineural deafness following ingestion of sildenafil J Laryngol Otol 2007 121 395 7 17166328 \n61 Muirhead GJ Rance DJ Walker DK Wastall P Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil Br J Clin Pharmacol 2002 53 Suppl. 1 13S 20S 11879255 \n62 Rosas SE Wasserstein A Kobrin S Feldman HI Preliminary observations of sildenafil treatment for erectile dysfunction in dialysis patients Am J Kidney Dis 2001 37 134 7 11136178 \n63 Chen J Mabjeesh NJ Greenstein A Clinical efficacy of sildenafil in patients on chronic dialysis J Urol 2001 165 819 21 11176477 \n64 Seibel I Poli De Figueiredo CE Teloken C Moraes JF Efficacy of oral sildenafil in hemodialysis patients with erectile dysfunction J Am Soc Nephrol 2002 13 2770 5 12397048 \n65 Mahon A Sidhu PS Muir G Macdougall IC The efficacy of sildenafil for the treatment of erectile dysfunction in male peritoneal dialysis patients Am J Kidney Dis 2005 45 381 7 15685517 \n66 Kloner RA Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions Am J Cardiol 2005 96 42M 6M 15979430 \n67 Narayan P Gagnier P Doyle C Concomitant use of sildenafil with tamsulosin or terazosin: a retrospective safety evaluation (abstract) J Urol 2004 171 Suppl. 4 357 14665927 \n68 De Rose AF Giglio M Traverso P Combined oral therapy with sildenafil and doxazosin for the treatment of non-organic erectile dysfunction refractory to sildenafil monotherapy Int J Impot Res 2002 14 50 3 11896478 \n69 Kaplan SA Gonzalez RR Te AE Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction Eur Urol 2007 51 1717 23 17258855 \n70 Lue TF Giuliano F Montorsi F Summary of the recommendations on sexual dysfunctions in men J Sex Med 2004 1 6 23 16422979 \n71 European Medicines Agency VIAGRA European Public Assessment Report (EPAR), revision 11 European Public Assessment Reports (EPAR) for authorised medicinal products for human use 03/09/2008. http://www.emea.europa.eu/humandocs/Humans/EPAR/viagra/viagra.htm [Accessed 19 September 2008] \n72 Galie N Ghofrani HA Torbicki A Sildenafil citrate therapy for pulmonary arterial hypertension N Engl J Med 2005 353 2148 57 16291984 \n73 Giuliano F Porst H Hedelin H Cardiovascular safety of Viagra® (sildenafil citrate): results of the international men’s health study Eur Urol 2005 4 Suppl. 3 137 \n74 Boolell M Allen MJ Ballard SA Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction Int J Impot Res 1996 8 47 52 8858389 \n75 McMurray JG Feldman RA Auerbach SM Long-term safety and effectiveness of sildenafil citrate in men with erectile dysfunction Ther Clin Risk Manag 2007 3 975 81 18516312 \n76 Smith KM Romanelli F Recreational use and misuse of phosphodiesterase 5 inhibitors J Am Pharm Assoc 2005 45 63 72 \n77 Romanelli F Smith KM Recreational use of sildenafil by HIV-positive and -negative homosexual/bisexual males Ann Pharmacother 2004 38 1024 30 15113986 \n78 Sugar SJ Reply to ‘Viagra: the risks of recreational use’ Am J Med 2006 119 92 3 16431206\n\n", "fulltext_license": "CC BY", "issn_linking": "1368-5031", "issue": "64(2)", "journal": "International journal of clinical practice", "keywords": null, "medline_ta": "Int J Clin Pract", "mesh_terms": "D000368:Aged; D002318:Cardiovascular Diseases; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D062787:Drug Overdose; D007172:Erectile Dysfunction; D006311:Hearing Disorders; D006801:Humans; D007674:Kidney Diseases; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011317:Priapism; D011358:Product Surveillance, Postmarketing; D011687:Purines; D016032:Randomized Controlled Trials as Topic; D000068677:Sildenafil Citrate; D013450:Sulfones; D016896:Treatment Outcome", "nlm_unique_id": "9712381", "other_id": null, "pages": "240-55", "pmc": null, "pmid": "19900167", "pubdate": "2010-01", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": "16431206;11018621;12208390;16952671;12352386;10197860;15582253;12161765;12825104;11176477;17087804;8858389;17011375;16753405;16620369;15730119;11692178;11220982;12161767;11494079;18261073;18507892;12414335;12435622;17313426;12399521;12657355;18516312;15766322;12397048;12161766;15126817;9580646;17258855;16565463;11136178;16422979;15938595;8254833;15685517;16530932;12414330;10223498;15049992;16753404;11896478;15113986;11879255;12547849;15619391;16409214;15983284;16387566;17383811;10731462;12825106;12414331;10444124;17076971;17287834;16291984;15607620;11351770;16054479;17275456;17166328;12841917;14529061;17624203", "title": "Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database.", "title_normalized": "safety of sildenafil citrate review of 67 double blind placebo controlled trials and the postmarketing safety database" }

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Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. 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{ "abstract": "Pulmonary sarcomatoid carcinoma is a rare, poorly differentiated, and highly aggressive type of non-small cell lung cancer. High tumor mutational burden and PD-L1 overexpression make it an excellent candidate for immunotherapy.\nWe presented the case of a patient who underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for an infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV pulmonary sarcomatoid carcinoma. He received first- and second-line chemotherapy without any benefit. Since March 2016, he has been treated with the anti-PD1 agent nivolumab with a dramatic improvement of symptoms, disappearance of a brain lesion, and partial response on other metastatic sites. He tolerated the treatment well and is still responding after 22 months from the beginning.\nIn very lethal non-small cell lung cancer subtypes such as the sarcomatoid variants, high tumor burden and deteriorated general conditions should not preclude, at least in some cases, the use of immunotherapy. Anti-PD1 may also have a reliable role in disease control in the brain. Lastly, the strong rationale behind sarcomatoid histology should further prompt trials exploring immunotherapeutic approaches in this subset of non-small cell lung cancer.", "affiliations": "Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, Italy.;Pathology Unit, Azienda AUSL Romagna, Regional Hospital Ravenna, Ravenna, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.;Department of Oncology, University of Modena and Reggio Emilia - Policlinico of Modena, Modena, Italy.", "authors": "Salati|Massimiliano|M|;Baldessari|Cinzia|C|;Calabrese|Fiorella|F|;Rossi|Giulio|G|;Pettorelli|Elisa|E|;Grizzi|Giulia|G|;Dominici|Massimo|M|;Barbieri|Fausto|F|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000492666", "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] 10.1159/000492666cro-0011-0615Case ReportNivolumab-Induced Impressive Response of Refractory Pulmonary Sarcomatoid Carcinoma with Brain Metastasis Salati Massimiliano aBaldessari Cinzia a*Calabrese Fiorella bRossi Giulio cPettorelli Elisa aGrizzi Giulia aDominici Massimo aBarbieri Fausto aaDepartment of Oncology, University of Modena and Reggio Emilia – Policlinico of Modena, Modena, ItalybDepartment of Cardio-Thoracic and Vascular Sciences, University of Padova, Padova, ItalycPathology Unit, Azienda AUSL Romagna, Regional Hospital Ravenna, Ravenna, Italy*Cinzia Baldessari, Department of Oncology, University of Modena and Reggio Emilia – Policlinico of Modena, Via del Pozzo 71, IT-41124 Modena (Italy), E-Mail [email protected] Salati and Cinzia Baldessari contributed equally to this work.\n\nSep-Dec 2018 7 9 2018 7 9 2018 11 3 615 621 31 7 2018 3 8 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Background\nPulmonary sarcomatoid carcinoma is a rare, poorly differentiated, and highly aggressive type of non-small cell lung cancer. High tumor mutational burden and PD-L1 overexpression make it an excellent candidate for immunotherapy.\n\nObjectives and Method\nWe presented the case of a patient who underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for an infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV pulmonary sarcomatoid carcinoma. He received first- and second-line chemotherapy without any benefit. Since March 2016, he has been treated with the anti-PD1 agent nivolumab with a dramatic improvement of symptoms, disappearance of a brain lesion, and partial response on other metastatic sites. He tolerated the treatment well and is still responding after 22 months from the beginning.\n\nResults and Conclusions\nIn very lethal non-small cell lung cancer subtypes such as the sarcomatoid variants, high tumor burden and deteriorated general conditions should not preclude, at least in some cases, the use of immunotherapy. Anti-PD1 may also have a reliable role in disease control in the brain. Lastly, the strong rationale behind sarcomatoid histology should further prompt trials exploring immunotherapeutic approaches in this subset of non-small cell lung cancer.\n\nKeywords\nImmunotherapyLung cancerPulmonary sarcomatoid carcinomaBrain metastasis\n==== Body\nIntroduction\nPulmonary sarcomatoid carcinoma (PSC) is a rare, poorly differentiated, and highly aggressive tumor entity accounting for less than 3% of non-small cell lung cancer (NSCLC) [1]. Early metastatic dissemination and resistance to conventional therapies result in a prognosis usually poorer than other lung cancers [2]. Recently, the targeting of immunologic checkpoints turned out to be a major breakthrough in oncology. Nivolumab is a fully human IgG4 PD-1 blocking antibody approved for previously treated advanced NSCLC [3, 4]. High tumor mutational burden and PD-L1 overexpression make PSC an excellent candidate for immunotherapy [5]. However, only anecdotal case reports on anti-PD1 efficacy in PSC have been described so far [6].\n\nCase Report\nOn November 2015, a 74-year-old male with ECOG PS 0 and no smoking history underwent left inferior lobectomy with concurrent right paravertebral muscular metastasectomy for a large infiltrative neoplastic mass, whose final diagnosis was consistent with stage IV PSC (Table 1). Medical history also reports HCV-related hepatitis successfully treated with PEG interferon in 2005 and a melanoma of the scalp surgically removed in 2013.\n\nAt histology, the tumor was characterized by mixed non-small cell carcinoma and sarcoma. The epithelial component showed highly pleomorphic tumor cells with striking nuclear atypia, including atypical mitoses and large area of necrosis and moderate reactive inflammation. Sarcoma-like elements (spindle and giant cells) were present in about half of neoplasia. A large panel of antibodies was used in order to well characterize the tumor and rule out other tumors, firstly melanoma, given his past medical history (Table 1). Tumor samples were analyzed by 30-gene next-generation sequencing, but no mutations were detected. ALK (D5F3 clone) and ROS1 rearrangements (D4D6 clone) and MET investigated either by immunohistochemistry or fluorescence in situ hybridization were also negative. Interestingly, immunohistochemistry for PDL-1 (clones SP263 by Ventana Medical System and E1L3N by Cell Signaling) showed a strong expression both in tumoral cells (tumor proportion score ≥50%) and in inflammatory cells (Fig. 1).\n\nOn January 2016, following surgery, the patient initiated a first-line chemotherapy regimen consisting of carboplatin/pemetrexed at conventional doses. After cycle 1, he experienced grade 2 nausea and vomiting and complained of abdominal right-sided pain. A computed tomography (CT) scan was then performed showing progressive disease with the appearance of lung, adrenal, liver, and lymph node metastases. A second-line chemotherapy with weekly docetaxel was then started, although the patient's general health conditions rapidly deteriorated and diffuse pain worsened requiring opioids.\n\nAfter 2 cycles with docetaxel, a CT scan demonstrated the appearance of a brain lesion and an increase in size of lung, hepatic, and right paravertebral muscle lesions.\n\nIn March, the patient started receiving the anti-PD1 agent nivolumab at the recommended dose of 3 mg/kg every 2 weeks within an expanded access program. After only one administration, he experienced a dramatic improvement of symptoms associated with a rapid decrease of LDH and a progressive tapering of opioids therapy until discontinuation. A subsequent reassessment by CT scan showed disappearance of the brain lesion and partial response on other sites (Fig. 2). Since December 2016, according to the patient's request, nivolumab administration has been modified to a 3-weekly schedule. Treatment was well tolerated, except for grade 1 transient cutaneous rash, vitiligo on the hands, and a slow recovery from pneumonia successfully treated by the combination of oral steroids (prednisone maximum dose 50 mg for no more than 10 days) and antibiotics on July 2017 (Fig. 3). Currently, at the end of July 2018, 28 months after the initiation of the anti-PD1, the patient is still on therapy and further responding.\n\nDiscussion and Conclusion\nTo our knowledge, the case presented herein is adding valuable insights into the use of a checkpoint inhibitor in very lethal NSCLC subtypes, such as the sarcomatoid variants. Firstly, high tumor burden and deteriorated general conditions should not preclude the use of immunotherapy as, at least in some cases, it may result in rapid tumor shrinkage together with profound and lasting response. Secondly, anti-PD1 may have a reliable role in disease control also in the brain, despite earlier concerns about its capability of crossing the blood-brain barrier. Lastly, the strong rationale behind sarcomatoid histology should further prompt trials exploring immunotherapeutic approaches in this subset of NSCLC.\n\nOther open questions remain to be answered. For instance, whether the prior therapy with PEG interferon could have acted as trigger for T cells thus boosting nivolumab activity and, again, whether changing the treatment schedule to 3-weekly could be a safe, effective, and cost-saving way to deliver immune checkpoint inhibitors while improving patients' distress.\n\nStatement of Ethics\nThe authors have no ethical conflicts to disclose\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nAuthor Contributions\nMassimiliano Salati, Cinzia Baldessari, Giulia Grizzi, Stefano Cascinu, Massimo Dominici, and Fausto Barbieri: medical oncologists in charge of the patient; Fiorella Calabrese and Giulio Rossi: pathologists in charge of the tumor specimen analyses; Elisa Pettorelli: data manager.\n\nAcknowledgement\nBristol-Myers-Squibb Italy for providing nivolumab.\n\nFig. 1. Immunohistochemistry for PDL-1 (clones SP263 by Ventana Medical System and E1L3N by Cell Signaling) showing a strong expression in both tumoral cells (a, tumor proportion score ≥50%; original magnification ×200) and inflammatory cells inside an area of tumor necrosis (b, macrophages and lymphocytes with arrows; original magnification ×100).\n\nFig. 2. Abdomen and brain CT scans. T0 images are related to the clinical status before nivolumab (March 21, 2016), T2 images refer to the situation after 2 months (May 20, 2016), and T20 images describe the tumor after 20 months (November 16, 2017). In the left column, images refer to the CT follow-up on the hepatic lesion (arrow), then the adrenal gland lesions (arrow), and the lesion of right paravertebral muscle (arrow). In the right column, images refer to the CNS lesion (arrow) before nivolumab therapy (T0), after 4 cycles (T2), and after 34 cycles (T20).\n\nFig. 3. Pulmonary CT scans. Images refer to the slow recovery from pneumonia from May 11 to July 17 to November 16, 2017 (from left to right).\n\nTable 1 Histopathological and molecular features of the lung cancer biopsy\n\nFeature/biomarker\tResults\t\nMNF-116\t–/+\t\nAE1/AE3\t–/+\t\nEMA\t–/+\t\nCK7\t–\t\nTTF1\t–\t\nVimentin\t+ (mainly in sarcomatoid component)\t\nP63\t–\t\nNapsin\t–\t\nCalretinin\t–/+\t\nD240\t–\t\nWT1\t–/+\t\nHMB45\t–\t\nS100\t–\t\nKi67\t40%\t\nALK (D5F3 clone)\tnegative\t\nROS1 rearrangements (clone D4D6)\tnegative\t\nMET IHC and FISH\tnegative\t\n30-gene next-generation sequencing\tno mutations detected\n==== Refs\nReferences\n1 Yendamuri S Caty L Pine M Adem S Bogner P Miller A Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis Surgery 2012 9 152 (3) 397 402 22739072 \n2 Shum E Stuart M Borczuk A Wang F Cheng H Halmos B Recent advances in the management of pulmonary sarcomatoid carcinoma Expert Rev Respir Med 2016 3 10 (4) 1 10 26567613 \n3 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer N Engl J Med 2015 10 373 (17) 1627 39 26412456 \n4 Brahmer J Reckamp KL Baas P Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer N Engl J Med 2015 373 (2) 123 35 26028407 \n5 Schrock AB Li SD Frampton GM Suh J Braun E Mehra R Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling J Thorac Oncol 2017 6 12 (6) 932 42 28315738 \n6 Gounant V Brosseau S Naltet C Opsomer MA Antoine M Danel C Nivolumab-induced organizing pneumonitis in a patient with lung sarcomatoid carcinoma Lung Cancer 2016 9 99 162 5 27565934\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "11(3)", "journal": "Case reports in oncology", "keywords": "Brain metastasis; Immunotherapy; Lung cancer; Pulmonary sarcomatoid carcinoma", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "615-621", "pmc": null, "pmid": "30323751", "pubdate": "2018", "publication_types": "D002363:Case Reports", "references": "26412456;27565934;28315738;26028407;22739072", "title": "Nivolumab-Induced Impressive Response of Refractory Pulmonary Sarcomatoid Carcinoma with Brain Metastasis.", "title_normalized": "nivolumab induced impressive response of refractory pulmonary sarcomatoid carcinoma with brain metastasis" }

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{ "abstract": "Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.\n\n\n\nWe conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.\n\n\n\nOf the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both [i.e., IKZF1 plus]). ABL1 mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).\n\n\n\nA chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).", "affiliations": "From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.;From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.", "authors": "Foà|Robin|R|;Bassan|Renato|R|;Vitale|Antonella|A|;Elia|Loredana|L|;Piciocchi|Alfonso|A|;Puzzolo|Maria-Cristina|MC|;Canichella|Martina|M|;Viero|Piera|P|;Ferrara|Felicetto|F|;Lunghi|Monia|M|;Fabbiano|Francesco|F|;Bonifacio|Massimiliano|M|0000-0003-0716-1686;Fracchiolla|Nicola|N|;Di Bartolomeo|Paolo|P|;Mancino|Alessandra|A|;De Propris|Maria-Stefania|MS|;Vignetti|Marco|M|;Guarini|Anna|A|;Rambaldi|Alessandro|A|;Chiaretti|Sabina|S|;|||", "chemical_list": "D018033:Antibodies, Bispecific; C510808:blinatumomab; D000069439:Dasatinib", "country": "United States", "delete": false, "doi": "10.1056/NEJMoa2016272", "fulltext": null, "fulltext_license": null, "issn_linking": "0028-4793", "issue": "383(17)", "journal": "The New England journal of medicine", "keywords": null, "medline_ta": "N Engl J Med", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064591:Allografts; D018033:Antibodies, Bispecific; D000971:Antineoplastic Combined Chemotherapy Protocols; D060830:Consolidation Chemotherapy; D000069439:Dasatinib; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome", "nlm_unique_id": "0255562", "other_id": null, "pages": "1613-1623", "pmc": null, "pmid": "33085860", "pubdate": "2020-10-22", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults.", "title_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults" }

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"reactionmeddrapt": "Venoocclusive disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Rash maculovesicular", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Haemorrhage intracranial", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Central nervous system leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Neurotoxicity", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Testicular pain", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Gamma-glutamyltransferase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary arterial hypertension", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Testicular oedema", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nervous system disorder", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Oedema peripheral", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplantation complication", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Pleural effusion", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Chronic graft versus host disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Leukaemic infiltration extramedullary", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Confusional state", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Aphasia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypoxia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Atrial fibrillation", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Diarrhoea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Tremor", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Acute lymphocytic leukaemia recurrent", "reactionmeddraversionpt": "23.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Acute graft versus host disease", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Cytomegalovirus viraemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hepatic function abnormal", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bradyphrenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Alanine aminotransferase increased", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Hypogammaglobulinaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Asthenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infusion related reaction", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, 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CHIARETTI S.? FERRARA F. ET AL.. DASATINIB-BLINATUMOMAB FOR PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS. THE NEW ENGLAND JOURNAL OF MEDICINE. 2020?383 (17):1613-1623", "literaturereference_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201104", "receivedate": "20201104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18463649, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20210114" }, { "companynumb": "IT-AMGEN-ITASP2020004632", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "28 MICROGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "B PRECURSOR TYPE ACUTE LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "28", "drugstructuredosageunit": "004", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLINATUMOMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DASATINIB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "140 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "140", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "DASATINIB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "125557", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK UNK, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BLINATUMOMAB" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LEVETIRACETAM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "500 MILLIGRAM, BID", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LEVETIRACETAM." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Central nervous system leukaemia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FOA R.? CHIARETTI S.? FERRARA F. ET AL.. DASATINIB-BLINATUMOMAB FOR PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS. NEW ENGLAND JOURNAL OF MEDICINE. 2020?383 (17):1613-1623", "literaturereference_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201104", "receivedate": "20200116", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17278060, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" }, { "companynumb": "IT-AMGEN-ITASP2019157222", "fulfillexpeditecriteria": "2", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "BLINATUMOMAB" }, "drugadditional": null, 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CHIARETTI S.? FERRARA F. ET AL.. DASATINIB-BLINATUMOMAB FOR PH-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS. THE NEW ENGLAND JOURNAL OF MEDICINE. 2020?383 (17):1613-1623", "literaturereference_normalized": "dasatinib blinatumomab for ph positive acute lymphoblastic leukemia in adults", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20201104", "receivedate": "20190926", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16857775, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210113" } ]

{ "abstract": "A 24-year-old pregnant woman (29.4 weeks of gestation) with A (H1N1) influenza-associated adult respiratory distress syndrome was admitted to the intensive care unit. The patient was connected to femoral-jugular veno-venous extracorporeal membrane oxygenation (ECMO) 8 hours after admission. On the 7(th) day of ECMO support, due to the increasing threat to the life of the mother and the fetus, a decision was made to carry out a cesarean section (CS) without discontinuing the ECMO support. The CS was performed uneventfully under general anesthesia, 5 hours after the discontinuation of heparin infusion. A live, premature 1200 g female neonate was delivered. No complications occurred in the perioperative period. On the 17(th) day, the patient was successfully weaned off the ECMO and discharged 10 days later. The newborn was discharged from the hospital in good health 41 days after the delivery.", "affiliations": "Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland.;Department of General and Pediatric Radiology, Medical University of Wroclaw, Poland.;1 Department and Clinic of Gynecology and Obstetrics, Medical University of Wroclaw, Poland.;Department and Clinic of Cardiac Surgery, Medical University of Wroclaw, Poland.;Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland.;Department and Clinic of Cardiac Surgery, Medical University of Wroclaw, Poland.;Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland.", "authors": "Łysenko|Lidia|L|;Zaleska-Dorobisz|Urszula|U|;Blok|Radosław|R|;Dumański|Andrzej|A|;Zielińska|Marzena|M|;Kustrzycki|Wojciech|W|;Durek|Grażyna|G|", "chemical_list": null, "country": "Poland", "delete": false, "doi": "10.5114/kitp.2014.43855", "fulltext": "\n==== Front\nKardiochir Torakochirurgia PolKardiochir Torakochirurgia PolKITPKardiochirurgia i Torakochirurgia Polska = Polish Journal of Cardio-Thoracic Surgery1731-55301897-4252Termedia Publishing House 2308710.5114/kitp.2014.43855Case ReportsA successful cesarean section in a pregnant woman with A (H1N1) influenza requiring ECMO support Łysenko Lidia 1Zaleska-Dorobisz Urszula 2Blok Radosław 3Dumański Andrzej 4Zielińska Marzena 1Kustrzycki Wojciech 4Durek Grażyna 11 Department and Second Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Poland2 Department of General and Pediatric Radiology, Medical University of Wroclaw, Poland3 1st Department and Clinic of Gynecology and Obstetrics, Medical University of Wroclaw, Poland4 Department and Clinic of Cardiac Surgery, Medical University of Wroclaw, PolandAddress for correspondence: Lidia Łysenko, MD, PhD, Department and First Clinic of Anaesthesiology and Intensive Therapy, Medical University of Wroclaw, Chałubińskiego 1a, 50-368 Wrocław, Poland29 6 2014 6 2014 11 2 216 219 08 10 2013 14 10 2013 04 4 2014 Copyright © 20142014This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A 24-year-old pregnant woman (29.4 weeks of gestation) with A (H1N1) influenza-associated adult respiratory distress syndrome was admitted to the intensive care unit. The patient was connected to femoral-jugular veno-venous extracorporeal membrane oxygenation (ECMO) 8 hours after admission. On the 7th day of ECMO support, due to the increasing threat to the life of the mother and the fetus, a decision was made to carry out a cesarean section (CS) without discontinuing the ECMO support. The CS was performed uneventfully under general anesthesia, 5 hours after the discontinuation of heparin infusion. A live, premature 1200 g female neonate was delivered. No complications occurred in the perioperative period. On the 17th day, the patient was successfully weaned off the ECMO and discharged 10 days later. The newborn was discharged from the hospital in good health 41 days after the delivery.\n\nCiężarna, lat 24, w 29,4 tygodniu ciąży z objawami ostrej niewydolności oddechowej dorosłych w przebiegu zakażenia wirusem grypy A (H1N1) została przyjęta na oddział intensywnej terapii. Osiem godzin po przyjęciu chorej rozpoczęto udowo-szyjne, żylno-żylne przezmembranowe natlenianie pozaustrojowe (ECMO). W 7. dobie leczenia, w związku z narastającym zagro-żeniem życia matki i płodu, podjęto decyzję o wykonaniu cięcia cesarskiego (CS) bez wyłączania ECMO. Odstawiono wlew heparyny i po 5 godzinach, w znieczuleniu ogólnym, wykonano CS. Urodziła się dziewczynka, żywa, niedonoszona, o wadze 1200 g. W okresie okołooperacyjnym nie obserwowano powikłań. W 17. dobie leczenia pacjentka została z sukcesem odłączona od ECMO, a 10 dni później wypisana do domu. Dziecko w dobrym stanie ogólnym zostało wypisane do domu 41 dni po urodzeniu.\n\ninfluenzapregnancyECMOcesarean section\n==== Body\nIntroduction\nThe influenza A (H1N1) virus was identified as the cause of the pandemic of 2009. As is the case with seasonal influenza, the pandemic virus A (H1N1) carried the risks of serious complications requiring treatment in an intensive care unit (ICU); pregnant and postpartum women were included in the risk group [1]. Pregnancy is associated with immunological changes, such as increased ventilatory demand as well as decreased functional residual capacity and oncotic pressure, which constitute predisposing factors for serious complications in pregnant and postpartum women when exposed to respiratory infection caused by an influenza virus [1, 2]. Primary viral pneumonia, which leads to the development of adult respiratory distress syndrome (ARDS), is the most serious complication of influenza. The treatment of ARDS should be comprehensive and include a pharmacological strategy (anti-viral and antibiotic treatment), a non-pharmacological strategy (lung protective strategy, recruitment maneuvers, prone position ventilation), and verification of the diagnosis with a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay, as well as a therapy adjunctive to mechanical ventilation – nitric oxide, extracorporeal membrane oxygenation (ECMO), arterial venous carbon dioxide removal, and high-frequency oscillatory ventilation. The following report describes the case of a pregnant woman who developed ARDS as a complication resulting from influenza A (H1N1) and was successfully treated with ECMO, during which an emergency cesarean section (CS) was performed.\n\nCase report\nIn March 2011, a 24-year-old pregnant woman (29.4 weeks of gestation), primigravida, was admitted to the ICU of a teaching hospital with symptoms of acute respiratory failure, having been transferred from the department of internal medicine of a district hospital. In anamnesis, the patient had been ill for the previous 5 days, exhibiting signs of acute upper respiratory tract infection, for which she had been treated on an outpatient basis with antibiotics and antipyretic medication. On admission to the ICU, the patient was in a critical condition, under analgosedation, intubated, and on mechanical ventilation. The mechanical ventilation settings were: controlled mandatory ventilation, volume control, fraction of inspired oxygen (FiO2) – 1.0, positive end-expiratory pressure (PEEP) – 5.0 cmH2O, tidal volume (TV) – 550 mL, respiratory rate (RR) – 22 per minute, with plateau pressure in the respiratory tract (Pplat) – 34 cmH2O, and compliance – 19 mL/cmH2O. Blood pressure was 120/75 mmHg (without catecholamines), sinus tachycardia was 140 beats per minute (bpm), diuresis – 80-100 mL per hour, and body temperature – 36.6°C. Extensive crackling could be heard over both lung fields. Arterial blood gas (ABG) showed profound hypoxia with an oxygenation index PaO2/FiO2 of 48.1, pH of 7.317, and normocapnia. The patient's plain chest PA X-ray image taken on admission to the ICU showed diffuse, almost homogeneous opacity of both lungs (Fig. 1).\n\nFig. 1 Plain chest PA X-ray on admission to the ICU shows diffuse, almost homogeneous opacity of both lungs\n\nLung injury score was established at 3.25 points, which indicated a diagnosis of ARDS. Laboratory tests showed elevated levels of inflammatory response (C-reactive protein, CRP – 195.3 mg/L, N: < 10 mg/L) and infection parameters (procalcitonin, PCT – 0.49 ng/mL, N: < 0.05 ng/mL). The consulting gynecologist found no signs of threatened premature delivery. A decision was made to delay the delivery. Pneumonia was suspected as a complication resulting from the influenza A (H1N1) virus; treatment with oseltamivir, empiric piperacillin/tazobactam, and azithromycin was started. A virological examination was performed using the RT-PCR assay, giving a positive result for the presence of the influenza A (H1N1) virus. Although the parameters of mechanical ventilation were modified (TV of approximately 6 ml/kg), high Pplat (37 cmH2O) and low compliance (17.7 mL/cmH2O) were observed. The ABG (FiO2 1.0) showed PaO2 of 48 mmHg, paCO2 of 48.7 mmHg, and pH of 7.304. A decision was made to place the patient on femoral-jugular veno-venous ECMO, which was commenced 8 hours after admitting the patient to the ICU. Once the ECMO was started, the patient required systemic heparinization. The ECMO flow was kept at 5.4 L/min (cardiac index – 4.56 l/min/m2) with 4500 revolutions per minute; protective lung ventilation was applied (pressure-controlled ventilation) with FiO2 – 0.3, Pplat – 20 cmH2O, RR – 10 per minute, PEEP – 10 cmH2O, and PaO2 kept at 70 mmHg. On the first day of ECMO support, the patient developed symptoms of acute kidney insufficiency, and renal replacement therapy with the use of continuous veno-venous hemodiafiltration was started and maintained for three days until normal diuresis was observed. The values of inflammation and infection parameters gradually dropped. The patient received two 12 mg doses of dexamethasone separated by a one-day interval to accelerate fetal lung maturity. Fetal heart rate (FHR) monitoring was carried out every 2 hours, while cardiotocography (CTG) recordings were performed 2 times a day. On day 6 of ECMO support, an elevation in body temperature (38.8°C) and an increase in inflammation and infection parameters occurred (CRP – 131 mg/L, PCT – 0.46 ng/mL). The results of microbiological tests were negative. The antibiotic therapy was modified – piperacillin/tazobactam and azithromycin were discontinued, and empiric linezolid, cilastatin/imipenem, and fluconazole were commenced. The CTG recordings detected silent oscillation and FHR of 180 bpm. On day 7, the FHR was 190 bpm. A decision was made to perform a cesarean section (CS) without disconnecting the ECMO. The CS (30.3 weeks of gestation) was uneventfully performed under general anesthesia after a five-hour discontinuation of heparin infusion. A female neonate was delivered with Apgar scores of 2 and 5 (respectively at 1, and 5 minutes of life) and a weight of 1200 g. Endotracheal intubation and mechanical ventilation of the newborn were started immediately after delivery. The neonate was transferred to the pediatric ICU for further treatment. Heparin infusion was restarted 14 hours after completing the CS. No bleeding or thromboembolic events within the ECMO circuit were reported. On day 8, the test for the influenza A (H1N1) virus using an RT-PCR assay was repeated; the result was positive. For this reason, oseltamivir was discontinued and zanamivir inhalation was started. On day 10 of ECMO support, the patient's fever subsided. On day 14, a plain chest PA X-ray demonstrated increased aeration in the middle and upper parts of both lung fields with a regression of intra-alveolar changes. Inflammation and infection parameters returned to normal. A 15-day follow-up test was performed with the RT-PCR assay for the presence of the influenza A (H1N1) virus. The result was negative and zanamivir was discontinued. On day 17, the patient was successfully weaned off the ECMO. After two more days, the patient was extubated, and empirical antibiotic therapy was discontinued. On day 23, computed tomography (CT) of the chest was performed, confirming the presence of bilateral multi-lobar infiltrates and radiological symptoms of ARDS (Fig. 2).\n\nFig. 2 CT of the lungs on the 23rd day of treatment shows bilateral multilobar infiltrates and radiological symptoms of ARDS\n\nOn day 27, the patient was discharged in good health. The newborn, having reached a weight of 2000 g, was discharged from the hospital in good health after 41 days. Three months after discharge from the hospital, the mother underwent a follow-up CT chest scan and spirometry. The CT scan revealed regression of the changes in the lungs after treatment (Fig. 3). The spirometry tests did not indicate any abnormalities.\n\nFig. 3 CT of the lungs 3 months after hospital discharge shows the regression of the changes in the lungs after treatment\n\nDiscussion\nInfluenza A (H1N1) infection during pregnancy carries risks for the mother and the fetus. The rate of hospital admission for pregnant women with influenza A (H1N1) is higher than for non-pregnant women. During the 2009 flu pandemic caused by the A (H1N1) virus, studies showed that pregnant women were 7.2 times more likely to be hospitalized and 4.3 times more likely to be admitted to an ICU than non-pregnant women [3]. Mortality among pregnant women with influenza A (H1N1) who had required treatment in the ICU varied according to different sources from 8 to 17.6% [1, 2, 4]. In one group of patients, which included pregnant women, the conventional treatment for ARDS that developed as a result of influenza A (H1N1) was ineffective, and it was then necessary to use ECMO as a rescue therapy [4–6]. This paper presents the use of ECMO on a pregnant woman suffering from ARDS that developed as a result of influenza A (H1N1) infection. In a case such as this, starting ECMO saves the life of the mother, but exposes the fetus to complications associated with systemic heparinization and extracorporeal circulation. Using the quickest possible intervention to deliver the fetus may shorten the ECMO use. It is, however, best to take the risk of starting ECMO, so that the child can reach a later gestational age, which increases the chance of survival. In the case described in this study, a CS was successfully performed using ECMO, and the decision to do this was taken due to the increasing threat to the life of the mother and the fetus. Previously, only one other similar case of performing a CS while using ECMO was mentioned in the scientific literature [7]. In other cases of pregnant women with influenza A (H1N1) requiring the use of ECMO that have been described to date, CS was performed either before starting ECMO or after its discontinuation [4]. The decision to perform a CS while the patient was on ECMO was not easy due to the increased risk of thrombosis from the required duration of heparin discontinuation. Major operations have been successfully performed under urgent conditions with temporary discontinuation of heparin infusion during the use of ECMO [8–10]. The case presented in this article ended with complete success for both the mother and the child. It seems that, while keeping the pros and cons fully in mind, it is worthwhile in certain situations to take the risk of performing a CS while ECMO is being administered. Certainly, the new generation of equipment for ECMO reduces the risk of complications from bleeding or thromboembolic events and makes the procedure safer.\n==== Refs\nReferences\n1 Louie JK Acosta M Jamieson DJ Honein MA Severe 2009 H1N1 influenza in pregnant and postpartum Women in California NEJM 2012 362 27 35 20032319 \n2 Jamieson DJ Honein MA Rasmussen SA Williams JL Swerdlow DL Biggerstaff MS Lindstrom S Louie JK Christ CM Bohm SR Fonseca VP Ritger KA Kuhles DJ Eggers P Bruce H Davidson HA Lutterloh E Harris ML Burke C Cocoros N Finelli L MacFarlane KF Shu B Olsen SJ H1N1 2009 influenza virus infection during pregnancy in the USA Lancet 2009 374 451 458 19643469 \n3 Creanga AA Johnson TF Graitcer SB Hartman LK Al-Samarrai T Schwarz AG Chu SY Sackoff JE Jamieson DJ Fine AD Shapiro-Mendoza CK Jones LE Uyeki TM Balter S Bish C Finelli L Honein MA Severity of 2009 pandemic influenza A (N1N1) virus infection in pregnant women: New York City, May-June 2009 Obstet Gynecol 2010 115 717 726 20308830 \n4 Fine A Dentinger C Johnson TF Kossowski A Steiner-Sichel L Schwarz AG Hartman LK Honein MA Jamieson D Uyeki T Al-Samarrai T Creanga AA Graitcer SB 2009 pandemic influenza A (HH1N1) in pregnant women requiring intensive care – New York City, 2009 MMWR 2010 59 321 326 20339343 \n5 Critical Care Services and 2009 H1N1 influenza in Australia and New Zealand The ANZIC Influenza Investigators N Engl J Med 2009 361 1925 1934 19815860 \n6 Grasselli G Foti G Patroniti N Giuffrida A Cortinovis B Zanella A Pagni F Mergoni M Pesci A Pesenti A A case of ARDS associated with influenza A-H1N1 infection treated with extracorporeal respiratory support Minerva Anestesiol 2009 5 741 745 19940827 \n7 Panarello G Ancona GD Capitanio G Occhipinti G Attardo G Bertani A Arcadipane A Cesarean section during ECMO support Minerva Anestesiol 2011 77 654 657 21525834 \n8 Noorani A Vuylsteke A Lewis C Parameshwar J Catarino P A moribund athlete Lancet 2012 380 74 22770460 \n9 Huang PM Ko WJ Tsai PR Kuo SW Hsu HH Chen JS Lee JM Lee YC Aggressive management of massive hemothorax in patients on extracorporeal membrane oxygenation Asian J Surg 2012 35 16 22 22726559 \n10 Lamb K Cowan S Evans N Pitcher H Moritz T Lazar M Hirose H Cavarocchi N Successful management of bleeding complications in patients supported with extracorporeal membrane oxygenation with primary respiratory failure Perfusion 2012 28 125 131 23104582\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1731-5530", "issue": "11(2)", "journal": "Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery", "keywords": "ECMO; cesarean section; influenza; pregnancy", "medline_ta": "Kardiochir Torakochirurgia Pol", "mesh_terms": null, "nlm_unique_id": "101279148", "other_id": null, "pages": "216-9", "pmc": null, "pmid": "26336425", "pubdate": "2014-06", "publication_types": "D002363:Case Reports", "references": "19643469;22726559;23104582;20032319;19940827;20308830;19815860;21525834;22770460", "title": "A successful cesarean section in a pregnant woman with A (H1N1) influenza requiring ECMO support.", "title_normalized": "a successful cesarean section in a pregnant woman with a h1n1 influenza requiring ecmo support" }

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{ "abstract": "BACKGROUND\nPost-transplant lymphoproliferative disorders (PTLDs) represent a spectrum of heterogenetic lymphoid proliferations. PTLD is a serious complication that affects the long-term survival of kidney transplant patients. Imaging examination is an important method for detecting and diagnosing PTLD. Contrast-enhanced ultrasonography (CEUS) and CEUS-guided biopsy are important modalities for tumor detection and diagnosis. In this case, we describe a 69 years old man in whom a native kidney PTLD was confirmed by CEUS.\n\n\nMETHODS\nA 69-year-old male patient who had a kidney transplant 1 year earlier presented with 3 months of progressive myasthenia of both lower limbs associated with amyotrophy and weight loss. Although positron emission tomography/computed tomography (PET-CT) showed a high metabolic lesion in the untransplanted kidney, abdominal contrast enhanced computed tomography cannot detect the lesion in the atrophic left kidney. The above examinations showed that the transplanted kidney was normal. CEUS can detect a homogeneously enhanced lesion in the same location as PET-CT. Subsequently, a biopsy was performed under CEUS guidance, and the final pathological diagnosis was diffuse large B-cell lymphoma. The patient then received the R-CHOP treatment. Unfortunately, pulmonary thromboembolism occurred 2 weeks later, and the patient's condition was not alleviated through active treatment. Finally, the patient's family gave up treatment, and the patient was discharged.\n\n\nCONCLUSIONS\nThe case suggested that CEUS was a valuable imaging method for patient with renal transplantation to detect and diagnose of PTLD.", "affiliations": "Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Guangdong Second People's Hospital, Haizhu District, Guangzhou, 510317, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China.;Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China. [email protected].", "authors": "Zhang|Jian-Chao|JC|http://orcid.org/0000-0003-0685-2311;Lan|Hui-Xia|HX|;Zhao|Hui-Juan|HJ|;Lei|Yang-Yang|YY|;Ma|Li|L|;Xie|Xiao-Yan|XY|;Lu|Ming-de|MD|;Wang|Wei|W|http://orcid.org/0000-0002-9485-583X", "chemical_list": "D003287:Contrast Media; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.1186/s12885-019-6355-0", "fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 635510.1186/s12885-019-6355-0Case ReportApplication of contrast-enhanced ultrasonography in the diagnosis of post-kidney transplant lymphoproliferative disorder in native kidney- a case report http://orcid.org/0000-0003-0685-2311Zhang Jian-Chao [email protected] 1Lan Hui-Xia [email protected] 1Zhao Hui-Juan [email protected] 1Lei Yang-Yang [email protected] 1Ma Li [email protected] 2Xie Xiao-Yan [email protected] 1Lu Ming-de [email protected] 1http://orcid.org/0000-0002-9485-583XWang Wei [email protected] 11 grid.412615.5Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital of Sun Yat-Sen University, No.58 Zhongshan Road 2, Guangzhou, 510080 People’s Republic of China 2 Department of Medical Ultrasonics, Guangdong Second People’s Hospital, Haizhu District, Guangzhou, 510317 People’s Republic of China 21 11 2019 21 11 2019 2019 19 11352 5 2019 11 11 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\nPost-transplant lymphoproliferative disorders (PTLDs) represent a spectrum of heterogenetic lymphoid proliferations. PTLD is a serious complication that affects the long-term survival of kidney transplant patients. Imaging examination is an important method for detecting and diagnosing PTLD. Contrast-enhanced ultrasonography (CEUS) and CEUS-guided biopsy are important modalities for tumor detection and diagnosis. In this case, we describe a 69 years old man in whom a native kidney PTLD was confirmed by CEUS.\n\nCase presentation\nA 69-year-old male patient who had a kidney transplant 1 year earlier presented with 3 months of progressive myasthenia of both lower limbs associated with amyotrophy and weight loss. Although positron emission tomography/computed tomography (PET-CT) showed a high metabolic lesion in the untransplanted kidney, abdominal contrast enhanced computed tomography cannot detect the lesion in the atrophic left kidney. The above examinations showed that the transplanted kidney was normal. CEUS can detect a homogeneously enhanced lesion in the same location as PET-CT. Subsequently, a biopsy was performed under CEUS guidance, and the final pathological diagnosis was diffuse large B-cell lymphoma. The patient then received the R-CHOP treatment. Unfortunately, pulmonary thromboembolism occurred 2 weeks later, and the patient’s condition was not alleviated through active treatment. Finally, the patient’s family gave up treatment, and the patient was discharged.\n\nConclusion\nThe case suggested that CEUS was a valuable imaging method for patient with renal transplantation to detect and diagnose of PTLD.\n\nKeywords\nContrast-enhanced ultrasonographyBiopsyPost transplantation lymphoproliferativeKidney transplantationNational Natural Science Foundation of ChinaNO.81701701Wang Wei Natural Science Foundation of Guangdong ProvinceNO.2016A030310143Wang Wei Department of Finance of Guangdong ProvinceNo.20160904Wang Wei issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nPost-transplant lymphoproliferative disorders (PTLDs) represent a group of heterogenetic lymphoid proliferations ranging from polyclonal lymphoid proliferation to lymphomas. PTLD occurs after solid organ transplantation and is associated with administration of immunosuppressive agents [1]. Prompt diagnosis of PTLD is critical to prognosis, to prevent the further development of malignant lymphoma [2]. Imaging examination is an important method to detect and diagnose PTLD, including conventional ultrasonography (US), Doppler ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) are important image modalities for characterizing PTLD [3, 4]. However both the iodinated contrast agent for CE-CT and the gadolinium for MRI have potentially nephrotoxic, restricting their use in patients with impaired renal function [5]. Compared with CE-MRI and CE-CT, the contrast agents used for contrast-enhanced ultrasonography (CEUS) are no nephrotoxic and can be safety applied to patients with renal dysfunction. CEUS can also provide real-time visualization of contrast-enhanced patterns, which can be used for differential diagnosis of renal lesions [6]. In addition, the exact real-time aspect of CEUS makes it uniquely suited for interventions [7]. CEUS therefore has gradually become the preferred method to detect and diagnose renal tumors in chronic kidney disease and post-transplant patients in recent years [8, 9]. We report a case of a 69 year old man with a native renal lymphoma associated with PTLD. We describe the contrast-enhanced features of the tumor and the application of a CEUS guided biopsy on the tumor, which is not well visualized using US. To the best of our knowledge this is the first report on CEUS manifestations of native renal lymphoma following renal transplantation.\n\nCase presentation\nA 69-year-old male patient with kidney transplantation was submitted to our hospital for further evaluation and treatment of a left native kidney mass. The patient had chronic kidney disease for 2 years and had undergone dialysis for 10 months before kidney transplantation. The patient had a 20 years history of hypertension (the highest blood pressure: 170/106 mmHg) without diabetes. The patient underwent kidney transplantation 11 months prior to our study, and maintained a triple immunosuppressive regimen that consisted of tacrolimus, mycophenolatemofetil and prednisolone after transplantation. Two months prior, the patient was submitted to the local hospital for progressive myasthenia both lower limbs and weight loss. Routine laboratory tests showed the following: creatinine and urea were normal, but Epstein-Barr virus (EBV) and cytomegalovirus (CMV) IgG antibodies were positive. An MRI of the lumbar showed multiple vertebral bone destruction. A positron emission tomography/computed tomography (PET-CT) scan was then performed for further information, showing an intense FDG accumulation lesion (approximately 1.4 cm, standardized uptake values max: 4.7) in the medial portion of the left untransplanted kidney (Fig. 1a). PET-CT then proposed possible diagnosis of a renal malignant tumor and bone metastasis, but it could not confirm diagnosis. CE-CT was performed with following scanning parameters: tube voltage, 120 kV; tube current, 250 mA; and slice thicknesses, 1 mm and 10 mm. CE-CT (Fig. 1b) and US detect multiple cysts only and cannot find a solid lesion proposed by PET-CT. PET-CT and CE-CT did not reveal any abnormalities in transplanted kidney. To further evaluate the tumor and definite diagnosis, the patient was sent to our department.\nFig. 1 Positron emission tomography/computed tomography (PET-CT) and computed tomography (CT) images of the outer hospital. a PET-CT revealed a 1.4 cm intense FDG uptake (Standardize Uptake Values max: 4.7) lesion (wide arrow) at the medial portion of the left native kidney; b AS the same level of PET-CT, contrast-enhanced CT did not detect any solid lesion in the left native kidney (narrow arrow)\n\n\n\nUltrasonography was performed using the Aplio500 (Toshiba Medical Systems, Tokyo, Japan) equipped with a 375BT convex transducer (frequency range 3.0–6.0 MHz). The transplanted kidney was located in the right iliac fossa, and showed no abnormalities in conventional B-mode and Doppler ultrasonography. Only atrophic untransplanted kidneys with multiple cystic lesions were observed in US (Fig. 2a). Then a bolus of 2.4 ml of SonoVue (Bracco, Milan, Italy) was administered intravenously and flushed by 5.0 ml of 0.9% saline was performed. The examination was performed at a low mechanical index of 0.09. CEUS revealed a completely homogeneously enhancement lesion (approximately 1.3 × 1.1 cm) in the medial portion of the left untransplanted kidney in 33 s post-injected of contrast agent. Enhancement had progressed from the periphery towards the center of the lesion at 20 s post-injection (Fig. 2b). The lesion exhibited completely enhancement at 33 s (Fig. 2c) and was slightly higher enhanced than the surrounding parenchymal. The lesion gradually turned to hypo-enhancement at 90 s (Fig. 2d). These features of CEUS suggested a diagnosis of renal malignancy. Subsequently a biopsy was performed under CEUS –guidance because of poor differentiation between the target and adjacent cysts in US. Then a further bolus of agent was injected, and a BARD automatic biopsy gun with an 18G percutaneous core needle biopsy was repeated under CEUS guidance to enhanced lesion (Fig. 3). Two tissue core samples with 2 cm in length were obtained from the targeted area (Fig. 4a). Histological examination of the specimen provided a diagnosis of diffuse large B-cell lymphoma (DLBCL) (Fig. 4b, c) with immunohistochemistry staining showing positive results for CD20, CD79, Bcl-2 and Bcl-6. Finally, clinical diagnosis was non-Hodgkin’s lymphoma (diffuse large cell, stage III B). Clinicians consider the prognosis very poor and communicate effectively with patients and their families. The patient consented to accepted chemotherapy consisting of rituximab and cyclophosphamide, hydroxydaunomycin, oncovin and prednisolone at the standard dose. Unfortunately, the patient developed deep vein thrombosis in the right side of his lower limb and pulmonary thromboembolism 2 weeks after one cycle chemotherapy. Despite active treatment, the patient’s condition has not been alleviated. Finally, the patient’s family gave up treatment and the patient was discharged.\nFig. 2 The contrast-enhanced ultrasonography features of the tumor in native left kidney .a the tumor (arrow) and cysts (asterisk) are presenting hypoechoic lesions in conventional ultrasonography which is difficult to differentiate from surrounding cysts. b. After injection of contrast agent, the edge of tumor (wide arrow) start enhancing at 20 s, showing hypo-enhancement as surrounding parenchyma. c The lesion achieved peak-enhancement at 33 s, more intense than surrounding kidney parenchyma (narrow arrow). d The lesion gradually turned to hypo-enhancement at 90 s, showing hypo-enhancement in comparison to surrounding parenchyma .The cyst (asterisk) around the lesion still non-enhancing during whole examination\n\n\nFig. 3 Contrast-enhanced ultrasonography guided biopsy of the mass. The needle tip (wide arrow) has correctly been inserted into the completely enhanced mass (narrow arrow)\n\n\nFig. 4 Histological findings of the core needle biopsy specimen from the mass. a The core needle biopsy specimen from the mass; b, c Hematoxylin and eosin staining of specimen from the mass revealed diffuse infiltration of atypical lymphoid cells. (B 10×,C 40×)\n\n\n\nDiscussion and conclusions\nThe incidence of PTLD in kidney transplant patients is approximately 1–10%, and it occurs most frequently during the first year after transplantation. Immunosuppression and EBV infection, are two major factors associated with the progression of PTLD [2] .The Gastrointestinal tract, allograft kidney and abdominal cavity are common sites of PTLD, but it is rare in the native kidney, which has been described in only three studies [10–12]. In previous reports, both US and CE-CT can clearly show the tumor and be used to characterize the tumor. The tumors showed persistent hypo-enhancement throughout the examination with CE-CT. The enhancement pattern of the tumor is the main difference from clear cell renal cell carcinoma, which present avid early hyper-enhancement and early wash-out throughout the examination [13, 14].\n\nIn our case, the tumor showed avid early hyper enhancement on CEUS; however, this was not visible on US and CE-CT. There are three possible explanations for this difference in our case: First, since the microvasculature of the atrophic renal parenchyma was reduced compared to a normal kidney, less iodine contrast agent entered the renal parenchyma [13]. In addition, the tumor was small in size, and there was much less iodine contrast agent entering the tumor. As a result, the tumor presented no enhancement on CE-CT, which caused a failure to distinguish tumors from surrounding cysts. Second, because CEUS contrast material is purely intravascular, it better correlates with the microvessel density of a tumor. Therefore, CEUS is even more sensitive for detection of hypovascular lesions than contrast-enhanced CT [15]. Although the native kidney perfusion reduced in our case, the microvascular density of the tumor is relatively more abundant than the peripheral renal parenchyma. As a result, the tumor appeared hyper enhanced compare to the surrounding renal parenchyma on CEUS. Third, the CE-CT scan often started at 35 s after the beginning of the injection, but the lesion showed peak enhancement at 33 s during CEUS examination. This may result in missing the peak enhancement phase of the tumor on CE-CT. In contrast, real-time CEUS can continually provide information about blood perfusion for the renal lesion after injection, which can offer more diagnostic clues to differential the tumor from adjacent cysts.\n\nUS-guided biopsy is a common clinical method to obtain tissue specimens for histopathological analysis [16]. However, this technique may be unsuccessful when the tumor is poorly differentiated from adjacent structures. CEUS is well placed to address this problem because of its capacity to differentiate between the altered vascularization of a tumor and surrounding structures. CEUS could help further confirm the tumor border and guide the needle to the target area. CEUS also can be used to differentiate enhanced active area from non-enhanced necrotic area. By directing the biopsy needle toward enhanced areas of the lesion, the sample from necrotic parts of the lesion can be reduced [17]. In a previous report, using the contrast agent, the lesion detection rate was increased from 77.3% with US to 92.0% with CEUS during the biopsy, with a 95.2% success rate for CEUS-guided biopsies of these lesions [18, 19]. According to these finding, we performed the biopsy in our patient under the guidance of CEUS. Finally, the pathology of the biopsy specimen confirmed the diagnosis of diffuse large B cell lymphoma.\n\nIn summary, CEUS can provide more useful information than CE-CT to detect and diagnose PTLDs derived from atrophic native kidneys; CEUS-guided biopsy can improve the diagnostic accuracy and success rate of percutaneous biopsy. We believe that CEUS and CEUS-guided biopsy may be an effective method for early screening and diagnosis of native kidney PTLD in kidney transplant patients.\n\nAbbreviations\nCE-CTContrast-enhanced computed tomography\n\nCE-MRIMagnetic resonance imaging\n\nCEUSContrast-enhanced ultrasonography\n\nCMVCytomegalovirus\n\nDLBCLDiffuse large B-cell lymphoma\n\nEBVEpstein-Barr virus\n\nFDGFluorodeoxyglucose F18\n\nPET-CTPositron emission tomography/computed tomography\n\nPTLDPost-transplant lymphoproliferative disorders\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\nDescription\nOur report described the imaging feature of native kidney lymphoma on contrast-enhanced ultrasonography (CEUS) in a post-kidney transplant patient. We found that the lymphoma showed different enhanced pattern in atrophic kidney from the normal kidney. Then, we performed the tumor biopsy under the guidance of CEUS\n\nPublication of clinical datasets\nNot applicable.\n\nAuthors’ contributions\nJCZ design the study and drafting of the manuscript; HXL, HJZ, YYL acquisition the data and images; LM designed and generated all of the submitted Figs; XYX and MDL analysis the data and images; WW interacted with the patient; made substantial contributions to the content and design of the study; critical revision of the manuscript and take accountable for all aspects of the work to ensure the reliability and accuracy of the data. All authors and all authors have made significant contribution to the content of this paper. All authors read and approved the final manuscript.\n\nFunding\nOur work is supported by National Natural Science Foundation of China (No.81701701) (to W.W), Natural Science Foundation of Guangdong Province (No.2016A030310143) (to W.W) and Department of Finance of Guangdong Province (No.20160904) (to W.W). All of the above funding was used to conduct laboratory analyses and cover publication fees.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nThe patient provided written informed consent to publish this report and associated images. We have de-identified demographic information and other specific information of the patient.\n\nCompeting interests\nOur manuscript has been read and approved by all authors and there are no any financial or other interests in the subject matter of the manuscript.\n==== Refs\nReferences\n1. Caillard S Dharnidharka V Agodoa L Bohen E Abbott K Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression Transplantation 2005 80 9 1233 1243 10.1097/01.tp.0000179639.98338.39 16314791 \n2. 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Sparchez Z Radu P Sparchez M Crisan N Kacso G Petrut B Contrast enhanced ultrasound of renal masses. A reappraisal of EFSUMB recommendations and possible emerging applications Med Ultrason 2015 17 2 219 226 10.11152/mu.2013.2066.172.fsum 26052574 \n7. Liu BX Huang GL Xie XH Zhuang BW Xie XY Lu MD Contrast-enhanced US-assisted percutaneous nephrostomy: a technique to increase success rate for patients with nondilated renal collecting system Radiology 2017 285 1 293 301 10.1148/radiol.2017161604 28467143 \n8. Chang EH Chong WK Kasoji SK Fielding JR Altun E Mullin LB Kim JI Fine JP Dayton PA Rathmell WK Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease BMC Nephrol 2017 18 1 266 10.1186/s12882-017-0681-8 28793871 \n9. Stock K, Kubler H, Maurer T, Slotta-Huspenina J, Holzapfel K. CEUS-diagnosis of solid renal tumors. Der Radiologe. 2018;58(6):553–62.\n10. Schultz TD Zepeda N Moore RB Post-transplant lymphoproliferative disorder and management of residual mass post chemotherapy: case report Int J Surg Case Rep 2017 38 115 118 10.1016/j.ijscr.2017.07.003 28756359 \n11. Lee M Kim SK Chung YE Choi JY Park MS Lim JS Kim MJ Kim H Necrotic lymphoma in a patient with post-transplantation lymphoproliferative disorder: ultrasonography and CT findings with pathologic correlation Ultrasonography 2015 34 2 148 152 10.14366/usg.14050 25541069 \n12. Chandra A Kaul A Aggarwal V Srivastava D Native kidney posttransplant lymphoproliferative disorder in a renal transplant recipient Saudi J Kidney Dis Transpl 2017 28 4 942 944 28748904 \n13. Ferda J Hora M Hes O Reischig T Kreuzberg B Mirka H Ferdova E Ohlidalova K Baxa J Urge T Computed tomography of renal cell carcinoma in patients with terminal renal impairment Eur J Radiol 2007 63 2 295 301 10.1016/j.ejrad.2007.01.027 17324547 \n14. Trenker C Neesse A Gorg C Sonographic patterns of renal lymphoma in B-mode imaging and in contrast-enhanced ultrasound (CEUS)--a retrospective evaluation Eur J Radiol 2015 84 5 807 810 10.1016/j.ejrad.2014.12.027 25650333 \n15. Quaia E Bertolotto M Cioffi V Rossi A Baratella E Pizzolato R Cov MA Comparison of contrast-enhanced sonography with unenhanced sonography and contrast-enhanced CT in the diagnosis of malignancy in complex cystic renal masses AJR Am J Roentgenol 2008 191 4 1239 1249 10.2214/AJR.07.3546 18806171 \n16. Sheafor DH Paulson EK Simmons CM DeLong DM Nelson RC Abdominal percutaneous interventional procedures: comparison of CT and US guidance Radiology 1998 207 3 705 710 10.1148/radiology.207.3.9609893 9609893 \n17. Partovi S Lu Z Kessner R Yu A Ahmed Y Patel IJ Nakamoto DA Azar N Contrast enhanced ultrasound guided biopsies of liver lesions not visualized on standard B-mode ultrasound-preliminary experience J Gastrointest Oncol 2017 8 6 1056 1064 10.21037/jgo.2017.08.17 29299367 \n18. Nolsoe CP Nolsoe AB Klubien J Pommergaard HC Rosenberg J Meloni MF Lorentzen T Use of ultrasound contrast agents in relation to percutaneous interventional procedures: a systematic review and pictorial essay J Ultrasound Med 2018 37 6 1305 1324 10.1002/jum.14498 29230842 \n19. Sparchez Z Radu P Kacso G Sparchez M Zaharia T Al HN Prospective comparison between real time contrast enhanced and conventional ultrasound guidance in percutaneous biopsies of liver tumors Med Ultrason 2015 17 4 456 463 26649339\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2407", "issue": "19(1)", "journal": "BMC cancer", "keywords": "Biopsy; Contrast-enhanced ultrasonography; Kidney transplantation; Post transplantation lymphoproliferative", "medline_ta": "BMC Cancer", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003287:Contrast Media; D003520:Cyclophosphamide; D004317:Doxorubicin; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D006801:Humans; D016030:Kidney Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D008232:Lymphoproliferative Disorders; D008297:Male; D011241:Prednisone; D011655:Pulmonary Embolism; D000069283:Rituximab; D014750:Vincristine", "nlm_unique_id": "100967800", "other_id": null, "pages": "1135", "pmc": null, "pmid": "31752767", "pubdate": "2019-11-21", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "9609893;25650333;17324547;28793871;26341369;29299367;28756359;29230842;26649339;10540643;25541069;18806171;28467143;29767316;16314791;28748904;14974943;26052574;28603715", "title": "Application of contrast-enhanced ultrasonography in the diagnosis of post-kidney transplant lymphoproliferative disorder in native kidney- a case report.", "title_normalized": "application of contrast enhanced ultrasonography in the diagnosis of post kidney transplant lymphoproliferative disorder in native kidney a case report" }

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APPLICATION OF CONTRAST-ENHANCED ULTRASONOGRAPHY IN THE DIAGNOSIS OF POST- KIDNEY TRANSPLANT LYMPHOPROLIFERATIVE DISORDER IN NATIVE KIDNEY- A CASE REPORT. J ADDICT MED. 2019?19 (1135):1-6.", "literaturereference_normalized": "application of contrast enhanced ultrasonography in the diagnosis of post kidney transplant lymphoproliferative disorder in native kidney a case report", "qualification": null, "reportercountry": "COUNTRY NOT SPECIFIED" }, "primarysourcecountry": "CN", "receiptdate": "20191218", "receivedate": "20191218", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17168393, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200122" } ]

{ "abstract": "BACKGROUND\nThere are several regimens used in hematopoietic stem cell (HSC) mobilization in multiple myeloma (MM). Cyclophosphamide (Cy) is one of the most commonly used agents, although it does not always result in collecting adequate number of CD34+ cells. Recently, cytarabine (Ara-C) has been proposed as potentially efficient and safe option.\n\n\nOBJECTIVE\nSince the data regarding Ara-C in HSC mobilization is limited, the aim of our study was to compare retrospectively the efficiency and toxicity of G-CSF combined with either Ara-C or Cy in MM patients.\n\n\nMETHODS\nOf a total of 89 patients, 43 received low or intermediate doses of Cy, and 46 were treated with 800 mg/m2 /day of Ara-C administered for two days.\n\n\nRESULTS\nThe mean peak of CD34+ cells/ul in peripheral blood was 132 (range, 84-202) in Ara-C and 51 (range, 29-69) in Cy cohort (p < 0.001). The median number of collected CD34+ cells (×106/kg) was 10.3 (range, 4.2-17.9) vs 4.5 (range, 2.7-8.9), respectively (p < 0.001). Mobilization failure was observed in one patient in Ara-C cohort (2%) and in 8 patients treated with Cy (19%) (p = 0.013). In the Ara-C group 98% of patients obtained more than 4×106 CD34+ cells/kg required for tandem transplantation. Moreover, we observed a trend toward increased paraprotein levels measured at transplant compared to before HSC mobilization in Ara-C cohort and significantly higher transfusion rates in that group.\n\n\nCONCLUSIONS\nOur findings confirm higher HSC mobilization efficacy of Ara-C compared to Cy in MM patients. However, lower transfusions rate and better disease control of Cy may justify its use in some cases.", "affiliations": "Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.;Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wrocław, Poland.", "authors": "Bogucka-Fedorczuk|Aleksandra|A|https://orcid.org/0000-0002-9322-354X;Czyz|Anna|A|;Kalicińska|Elżbieta|E|;Sawicki|Mateusz|M|;Laszkowska-Lewko|Magdalena|M|;Wicherska-Pawłowska|Katarzyna|K|https://orcid.org/0000-0001-6021-1123;Rybka|Justyna|J|;Szeremet|Agnieszka|A|;Prajs|Iwona|I|;Szymczak|Donata|D|;Wróbel|Tomasz|T|", "chemical_list": "D018952:Antigens, CD34; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide", "country": "United States", "delete": false, "doi": "10.1002/jca.21784", "fulltext": null, "fulltext_license": null, "issn_linking": "0733-2459", "issue": "35(4)", "journal": "Journal of clinical apheresis", "keywords": "chemomobilization; cyclophosphamide; cytarabine; hematopoietic stem cells mobilization; hematopoietic stem cells transplantation; multiple myeloma", "medline_ta": "J Clin Apher", "mesh_terms": "D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D001781:Blood Component Removal; D003520:Cyclophosphamide; D003561:Cytarabine; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D012074:Remission Induction; D012189:Retrospective Studies; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "8216305", "other_id": null, "pages": "246-254", "pmc": null, "pmid": "32298020", "pubdate": "2020-08", "publication_types": "D016428:Journal Article", "references": null, "title": "Higher efficacy of intermediate dose cytarabine + G-CSF compared to cyclophosphamide + G-CSF in hematopoietic stem cell mobilization in patients with multiple myeloma.", "title_normalized": "higher efficacy of intermediate dose cytarabine g csf compared to cyclophosphamide g csf in hematopoietic stem cell mobilization in patients with multiple myeloma" }

[ { "companynumb": "PL-AMGEN-POLSP2020142366", "fulfillexpeditecriteria": "2", "occurcountry": "PL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "5 MICROGRAM/KILOGRAM, BID, ON THE FIFTH DAY AFTER CHEMOTHERAPY TILL THE LAST APHERESIS DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "5", "drugstructuredosageunit": "008", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "FILGRASTIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 TO 2 OR 2 TO 4.5 MILLIGRAM/SQ. METER", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "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": "CYTARABINE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "400 MILLIGRAM/SQ. METER, BID (FOR TWO SUBSEQUENT DAYS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "400", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "CYTARABINE." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Plasma cell myeloma", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Treatment failure", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "KALICINSKA, E. HIGHER EFFICACY OF INTERMEDIATE DOSE CYTARABINE + G?CSF COMPARED TO CYCLOPHOSPHAMIDE + G?CSF IN HEMATOPOIETIC STEM CELL MOBILIZATION IN PATIENTS WITH MULTIPLE MYELOMA. JOURNAL OF CLINICAL APHERESIS. 2020?35(4):246?254", "literaturereference_normalized": "higher efficacy of intermediate dose cytarabine g csf compared to cyclophosphamide g csf in hematopoietic stem cell mobilization in patients with multiple myeloma", "qualification": "3", "reportercountry": "PL" }, "primarysourcecountry": "PL", "receiptdate": "20200911", "receivedate": "20200907", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 18237083, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201103" } ]

{ "abstract": "Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC), which was previously treated with non-steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2-MBC patients who received Exe-Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the 'everyday clinical practice' population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow-up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe-Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow-up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe-Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long-term survival. Overall, Exe-Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe-Eve is an active and safe therapeutic option for endocrine-sensitive MBC patients in a real-world clinical setting, regardless of treatment lines.", "affiliations": "Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy.;Medical Oncology, San Giuseppe Moscati Hospital, I-83100 Avellino, Italy.;Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', I-80131 Naples, Italy.;Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy.;Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy.;Medical Oncology, Department of Clinical Medicine and Surgery, University of Naples Federico II, I-80131 Naples, Italy.;Medical Oncology, Sacro Cuore di Gesù Fatebenefratelli Hospital, I-82100 Benevento, Italy.;Breast Cancer Unit, Cancer Institute G. Pascale Foundation, I-80131 Naples, Italy.;Medical Oncology, Frattamaggiore Hospital, I-80027 Frattamaggiore, Italy.;Medical Oncology, Santa Maria della Pietà Hospital, I-80035 Nola, Italy.;Medical Oncology, ASL Napoli 2 Nord Hospital, I-80014 Giugliano, Italy.;Medical Oncology, Department of Clinical Medicine and Surgery, University of Naples Federico II, I-80131 Naples, Italy.;Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', I-80131 Naples, Italy.;Division of Medical Oncology, Department of Precision Medicine, University of Campania 'Luigi Vanvitelli', I-80131 Naples, Italy.", "authors": "Riccardi|Ferdinando|F|;Colantuoni|Giuseppe|G|;Diana|Anna|A|;Mocerino|Carmela|C|;Cartenì|Giacomo|G|;Lauria|Rossella|R|;Febbraro|Antonio|A|;Nuzzo|Francesco|F|;Addeo|Raffaele|R|;Marano|Ombretta|O|;Incoronato|Pasquale|P|;De Placido|Sabino|S|;Ciardiello|Fortunato|F|;Orditura|Michele|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.3892/mco.2018.1672", "fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2018.1672MCO-0-0-1672ArticlesExemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety Riccardi Ferdinando 1Colantuoni Giuseppe 2Diana Anna 3Mocerino Carmela 1Cartenì Giacomo 1Lauria Rossella 4Febbraro Antonio 5Nuzzo Francesco 6Addeo Raffaele 7Marano Ombretta 8Incoronato Pasquale 9De Placido Sabino 4Ciardiello Fortunato 3Orditura Michele 31 Breast Unit, A. Cardarelli Hospital, I-80131 Naples, Italy2 Medical Oncology, San Giuseppe Moscati Hospital, I-83100 Avellino, Italy3 Division of Medical Oncology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, I-80131 Naples, Italy4 Medical Oncology, Department of Clinical Medicine and Surgery, University of Naples Federico II, I-80131 Naples, Italy5 Medical Oncology, Sacro Cuore di Gesù Fatebenefratelli Hospital, I-82100 Benevento, Italy6 Breast Cancer Unit, Cancer Institute G. Pascale Foundation, I-80131 Naples, Italy7 Medical Oncology, Frattamaggiore Hospital, I-80027 Frattamaggiore, Italy8 Medical Oncology, Santa Maria della Pietà Hospital, I-80035 Nola, Italy9 Medical Oncology, ASL Napoli 2 Nord Hospital, I-80014 Giugliano, ItalyCorrespondence to: Dr Anna Diana, Division of Medical Oncology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, 5 Sergio Pansini Street, I-80131 Naples, Italy, E-mail: [email protected] 2018 16 7 2018 16 7 2018 9 3 255 263 29 1 2018 05 6 2018 Copyright: © Riccardi et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC), which was previously treated with non-steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2-MBC patients who received Exe-Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow-up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe-Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow-up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe-Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long-term survival. Overall, Exe-Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe-Eve is an active and safe therapeutic option for endocrine-sensitive MBC patients in a real-world clinical setting, regardless of treatment lines.\n\nendocrine therapyeverolimusmetastatic breast cancerreal-life experience\n==== Body\nIntroduction\nBreast cancer (BC) is the most common malignancy and the leading cause of cancer death in women worldwide. Approximately 75% of BCs are hormone receptor positive (HR+), HER2-negative (HER2-); systemic therapy with endocrine agents represents the mainstay of treatment both in the early and advanced stages of disease (1,2).\n\nConsidering the efficacy and the favorable safety profile of endocrine-directed agents, sequential lines of endocrine therapy (ET) should be the preferred treatment strategy in the advanced setting, except in the case of immediate life-threatening disease or rapid visceral recurrence during adjuvant ET (3,4).\n\nDespite the effectiveness of ET in HR+ advanced BC, disease progression occurs in the majority of patients due to primary or acquired ET resistance.\n\nIn the last two decades, loss of estrogen receptor (ER) expression, ER mutations, alterations in co-regulatory proteins, and the upregulation of different signal transduction pathways have been identified as mechanisms leading to ET failure (5).\n\nAmong these mechanisms of resistance, cross-talk between the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mTOR axis and ER signaling plays a key role in BC proliferation and progression and confers endocrine insensitivity to ET.\n\nPreclinical and clinical studies have shown that co-targeting downstream elements of this pathway using mammalian target of rapamycin (mTOR) inhibitors may synergistically increase the antitumoral activity of ET and overcome anti-hormone therapy resistance in BCs (6–8).\n\nEverolimus (Eve) is a mTOR inhibitor which induces apoptosis by blocking S6K1 and 4E-BP1 activation and inhibits cell growth, proliferation, and G1-S transition. Eve in combination with Exemestane (Exe), a steroidal aromatase inhibitor (SAI), was approved in 2012 based on the results of the pivotal BOLERO-2 trial. In this study, dual-blockade significantly improved progression-free survival (PFS), as compared with Exe alone, in non-steroidal AI (NSAI)-pretreated post-menopausal patients affected by HR+/HER2-MBC, while maintaining health-related quality of life (HRQoL) (9–11).\n\nOver the past two years, a new class of drugs, namely, CDK4/6 inhibitors, in combination with letrozole or fulvestrant as first or second-line therapy, respectively, has increasingly been used in the treatment of luminal MBC disease. Despite the impressive results from recently published studies reporting a significant PFS benefit with CDK4-6 inhibitors (palbociclib, ribociclib, abemaciclib) in combination with ET compared with ET alone, overall survival (OS) data are still awaited and the optimal sequence of ET, as monotherapy or in combination with targeted agents, is still not well established (12–15). However, combination of CDK4-6 inhibitors and letrozole is reasonably expected to become the new gold standard as first-line therapy in post-menopausal patients with HR+/HER2-endocrine sensitive MBC.\n\nNevertheless, it is crucial to acquire data about long-term outcomes and toxicity profile of therapeutic options currently used in everyday clinical practice in order to define the best therapeutic strategy in HR+/HER2-advanced breast cancer (ABC). Of note, the ongoing phase III randomized trial GIM-16 FEVEX (EudraCT n. 2014-004035-38), where MBCs have been randomized to receive Exe-Eve, followed, in case of progression disease, by fulvestrant or vice versa, should define the best therapeutic sequence in second and third line.\n\nIn our multicenter observational study, we retrospectively analyzed data from 264 HR+/HER2-MBC patients who received Exe-Eve combination, following NSAI failure, in different lines of hormonal treatment to evaluate the efficacy and tolerability of this combination in the ‘real world’ setting.\n\nPatients and methods\nThe main aim of our retrospective study was the analysis of activity, efficacy, and safety of Exe-Eve treatment according to the line of therapy. From January 2012 to January 2017, 264 patients with HR+/HER-MBC who received Exe-Eve as first or further line of ET, were eligible for the final analysis. For all patients, inclusion criteria were histologically confirmed diagnosis of HR+ and HER-locally advanced or MBC, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, basal screening for hepatitis B and C, administration of at least one cycle of Exe-Eve until disease progression, unacceptable toxicity or patient refusal, availability of clinical-pathological, radiologic, and laboratory parameters before Exe-Eve treatment, response evaluation, and survival data.\n\nFurthermore, prior therapy with AI was permitted if recurrence had occurred during or within 12 months of completion of adjuvant therapy, or in case of progression during treatment for advanced stage disease; likewise, previous chemotherapy for metastatic disease and palliative radiotherapy on bone and/or brain were permitted. Eve starting dose was 10 mg once a day orally; a dose reduction (5 mg) was chosen by the caring physician in some instances. Supportive measures were allowed and implemented according to individual daily practice. Toxicity data were collected monthly at each patient visit and were classified according to the National Cancer Institute Common Criteria for Adverse Events (NCI-CTCAE), version 4 (16).\n\nAccordingly, in case of toxicity, dose adjustments or temporary interruptions of therapy as well as timing and modality of evaluation were independently implemented by each investigator (as a general rule, Eve dose was reduced for toxicity of grade 2 or higher, while temporary interruption of treatment was proposed for mild toxicities; tumor assessment was carried out every 3 months). Data were retrieved after an anonymization procedure from a centralized database at the Breast Unit of Cardarelli Hospital. Four patients were lost to follow-up, and the study was completed by January 31, 2017. All patients provided written informed consent about the use of their data for future medical research. The Institutional Review Board at ‘F. Magrassi’ Department of Clinical and Experimental Medicine of ‘Luigi Vanvitelli’ University of Campania, Naples (Italy) approved the study.\n\n\nStatistical analysis\nAll continuous data were expressed as mean ± SD, range and median value; frequencies and percentages were reported for categorical variables. Fisher's exact test was used to analyze associations with categorical variables. Survival distribution was estimated by the Kaplan-Meier method with 95% confidence interval (CI) (17). Progression Free Survival (PFS) was defined as the time elapsed between the first Exe-Eve dose to the detection of disease progression or death for any cause. Patients who died of causes other than breast cancer-without experiencing tumor progression-were regarded as censored events at the date of death when computing the PFS rate. Differences in PFS according to clinical parameters or line of treatment were evaluated by the log-rank test and described by the Kaplan-Meier method. For final analysis, the PFS status of all patients was updated within 1 month of January 2017 deadline. Overall survival (OS) was defined as the time from the first cycle of therapy with Exe-Eve to the date of death or last contact. Cox proportional-hazards model was applied to multivariate survival analysis, and P-values and hazard ratios (HRs) with 95% CI were obtained. All significant variables in the univariate model were used to build the multivariate model of survival. Statistical Package for the Social Sciences (SPSS) 20.0 software, (Chicago, IL, USA) was used for statistical analysis and integrated with Medcalc software V.9.4.2.0 (Mariakerke, Belgium). In all analyses, the significance level was specified as P<0.05.\n\nResults\n\nEfficacy\nExe-Eve combination was used as first, second, or third line of ET in 45 (17%), 115 (43.6%), and 104 (39.4%) patients with MBC (total: 264; median age 56 years, range 49-64), respectively. Of these, 192 (72.7%) and 229 (86.7%) received adjuvant chemotherapy and ET, respectively. Furthermore, 128 patients (48.5%) treated with chemotherapy as first line treatment for metastatic disease subsequently received Exe-Eve combination as first (3 patients), second (56 patients), or third (69 patients) hormonal line. The main characteristics of the series are reported in Table I. At the end of the study, 104 patients (39.4%) had died and 156 patients (59.1%) were still alive, while 4 (1.5%) patients were lost to follow-up; thus, 260 patients (43, 114, and 103 in first, second, or third line of treatment, respectively) were eventually considered for survival analysis.\n\nExe-Eve combination was shown to be active in all lines of therapy. Particularly, although no complete response was observed, 105 (39.8%) partial responses, 88 (33.3%) disease stabilizations, and 71 (26.9%) disease progressions were recorded. The overall Disease Control Rate (DCR) was 73.1%, with no statistically significant difference between the different settings (73.3, 79.2 and 66.3% in first, second and third-line therapy, respectively; P=0.105).\n\nAt the time of data censoring, 4.1% of patients were receiving Exe-Eve without evidence of disease progression; median PFS was 9.1 months (95% CI 7.4-10.2) (Fig. 1). At a median follow-up of 42 months, median PFS was 11.6 (95% CI 5.8-17.3), 9.7 (95% CI7.7-10.8), and 7.5 (95% CI 6.0-9.8) months for patients treated with Exe-Eve as first, second, or third line of treatment, respectively, with a statistically significant correlation on univariate analysis with younger age (P=0.024), no previous adjuvant chemotherapy (P=0.028), no previous adjuvant ET (P=0.030), adjuvant ET duration ≥36 months (P=0.013), involvement of liver and/or lung (P=0.054), no previous chemotherapy for metastatic disease (P=0.0050), PS=0 at the start of treatment (P<0.0001). The risk of disease progression between the different subgroups was not statistically significant (log-rank P-value=0.218) (Fig. 2).\n\nOn multivariate analysis, previous adjuvant ET (P=0.001; HR=2.78; 95% CI: 1.68-4.60), previous chemotherapy for advanced disease (P=0.0027; HR=1.39; 95% CI: 1.03-1.89), and poor PS (P=0.002; HR=2.70; 95% CI: 1.67-4.37) were shown to be independent prognostic factors related to poor recurrence rate. Conversely, the risk of progression was significantly lower in patients treated with hormonal drugs for 36 months or longer (HR=0.48; 95% CI: 0.34-0.68) in the adjuvant setting.\n\nMedian OS was 33.0 months (95% CI 25.2-41.2) (Fig. 3); at a median follow-up of 67 months, median OS was 43.1 months (95% CI 23.1-53.2), 31.7 months (95% CI 23.5-44.1) and 27.9 months (95% CI 22.7-38.9) for patients treated with Exe-Eve as first, second, or third line of treatment, respectively (the difference between the different OS medians was not statistically significant, P=0.538) (Fig. 4). On univariate analysis, the variables related to better survival were younger age (≤48 years) (P=0.041), Ki67 ≤20% (P=0.032), duration of adjuvant ET ≥36 months (P=0.028), disease-free interval ≥45 months (P=0.010), no previous chemotherapy for metastatic disease (P=0.001), ECOG PS=0 (P=0.032), duration of treatment with Exe-Eve longer than 6.3 months (P=0.012), partial response (P=0.009), presence of stomatitis (P=0.049), and absence of diabetes during the treatment (P=0.001). Finally, on multivariate analysis, the variables related to a worse outcome were diabetes [P=0.001; HR=2.35; 95% CI 1.52-3.58)] and previous chemotherapy for metastatic disease (P=0.032; HR=1.58; 95% CI 0.92-2.26); conversely, the presence of mucositis correlated with long-term survival (P=0.042; HR=0.64; 95% CI 0.30-0.82).\n\nToxicity\nOverall, Exe-Eve was fairly well tolerated, most toxicities being G1 or 2, while treatment discontinuation was required in 15 patients (5.7%) due to unacceptable toxicity. Particularly, one patient who received Exe-Eve as first line treatment suffered from G4 diarrhea and refused the treatment, 3 patients developed interstitial lung disease requiring hospitalization, and 1 case of persistent G4 neutropenia was registered among second line patients. Finally, in patients subjected to a third line of therapy, 3 cases of G3 pneumonitis, 3 cases of G4 diarrhea, 1 case of persistently increased hepatic transaminases, 1 case of hyperglycemia requiring insulin therapy and a brief hospitalization, and 2 cases of G4 stomatitis were recorded.\n\nTwo hundred and fifty patients were started on full dose Eve, while 16 patients (6%) began treatment with half dose per physician choice; due to toxicities, Eve dosage was reduced to 5 mg in 25 patients (9.45%).\n\nOverall, hematologic toxicity was mild and no G4 events were recorded, with the exception of the neutropenic patient described above. Of note, a significant difference among the three groups of patients was recorded in terms of incidence of G1-3 thrombocytopenia and neutropenia, which occurred more frequently in second and third line, respectively (Table II).\n\nThe most commonly reported extra-hematologic toxicities (all grades) were stomatitis (54.8%), fatigue (39.3%), rash (33.3%), and diarrhea (33.2%), which occurred in more than one third of patients (Table II). Nausea and decreased appetite were recorded in 28.7 and 27.6% of patients, respectively, even if G3-4 adverse events (AEs) were rare (about 1-2%). Elevated serum transaminases, cough, hyperglycemia, pneumonitis/interstitial lung disease were also observed and the majority of G3-4 toxicities occurred in patients treated with Exe-Eve as third line therapy.\n\nDiscussion\nThe outcome of MBC patients is continuously improving because of the availability of new active therapeutic options. The challenge for clinicians is to balance treatment-related toxicity with the likelihood of benefit and cancer-related symptom relief deriving from therapy. For this reason, current clinical guidelines advocate the use of ET as the preferred treatment for HR+, HER2-MBC, unless visceral crisis or concern/proof of endocrine resistance is observed.\n\nRecently, the introduction of CDK4/6 inhibitors in combination with endocrine agents resulted in a significant PFS benefit, however, overall survival data are still missing and there is no consensus on the optimal sequence of ET, that is, as monotherapy or in combination with targeted agents (12–15).\n\nCurrently, the combination of Eve and Exe is a widely used regimen for treatment of endocrine sensitive postmenopausal MBC patients progressing after NSAIs therapy. However, current international guidelines suggest taking into account the relevant class-effect AEs of this regimen with regard to the decision to treat, which nonetheless should be made on a case by case basis.\n\nFor this purpose, more experience has to be collected on toxicity profile and efficacy in different subsets of patients (i.e., differing in metastatic sites, performance status, number of prior therapies etc.) in order to help physicians to optimize the therapeutic strategy for each patient.\n\nThe main aim of our observational study was to explore the efficacy and tolerability of Eve-Exe combination, according to the line of therapy, in an unselected population from nine Cancer Centers in Campania region (South Italy). The hypothesis of the association between the onset of side effects and efficacy was also addressed in our analysis.\n\nThe pivotal phase III BOLERO-2 trial showed that dual-blockade based on the association of Eve plus Exe doubled the median PFS compared to Exe alone (7.8 vs. 3.2 by investigator review and 11 vs. 4.1 months by central review, respectively) in patients with HR+, HER2-MBC progressing after prior NSAIs. The clinical benefit rate (CBR), defined as CR+PR+SD ≥24 months, was also better in the Eve-Exe arm with respect to Exe alone arm (51.3% vs. 26.4%, respectively).\n\nOS was a secondary endpoint but did not meet statistical significance despite it was shown to increase (4.4 months) following addition of Eve to Exe (31.0 months in the experimental arm vs. 26.6 months in patients receiving Exe alone) (9–10,18).\n\nThe lack of a statistically significant survival gain could be due to the fact that BOLERO-2 trial was powered to detect only an eight-month OS improvement. Furthermore, the small imbalance in post-study salvage chemotherapy use (63 vs. 53%, control vs. experimental arm, respectively) has probably influenced OS results leading to a reduction in the survival gap between the two groups.\n\nIn our retrospective analysis, Exe-Eve combination was shown to be active in all lines of therapy. Particularly, although no complete response was observed, DCR was 73.1%, with no statistically significant difference between the different settings. At a median follow-up of 42 months, median PFS was 11.6, 9.7, and 7.5 months for patients treated with Exe-Eve as first, second, or third line of treatment, respectively. Median OS was 33.0 months; at a median follow-up of 67 months, median OS was 43.1, 31.7, and 27.9 months for patients treated with Exe-Eve as first, second or third line of treatment, respectively. No statistically significant difference in terms of PFS and OS between the different subgroups was detected. Our results confirmed the considerable activity and efficacy of Eve-Exe observed in BOLERO-2, although the safety profile of this combination remains debated. In the BOLERO-2 trial, the most commonly reported AEs, affecting at least one-third of patients in the Eve-Exe arm, were stomatitis, rash, fatigue, diarrhea, nausea, decreased appetite, and pneumonitis. While most AEs were low grade (G1-2), one-half of patients in the Eve-Exe arm experienced grade 3-4 toxicities vs. 27% of patients in the placebo plus Exe arm. The discontinuation rate due to AEs was higher with Eve-Exe (9%) compared with the control arm (3%); the most common toxiticies leading to treatment discontinuation in the experimental group included pneumonitis, stomatitis, dyspnea, and fatigue (19). Consistent with BOLERO-2 results, in our analysis, the most frequently described toxicities (all grades) were stomatitis (54.8%), fatigue (39.3%), rash (33.3%), and diarrhea (33.2%), which occurred in more than one third of patients. Treatment discontinuation was registered only in 5.7% of patients and the most common AEs leading to treatment discontinuation were pneumonitis, stomatitis, and diarrhea. In the Italian expanded-access, multicenter BALLET trial, permanent treatment discontinuation due to side effects was reported to be more frequent (17.1% of patients) with respect to our series and was mainly caused by non infectious pneumonitis (NIP), stomatitis, asthenia, and dyspnea. The majority of these toxicities occurred within the first 12 weeks of start of therapy, consistently across all clinical trials (20). Since 2012 approval, several retrospective trials have been carried out to assess the role of Eve-Exe combination in daily clinical practice, providing clinicians with valuable additional data to guide treatment decisions. To our knowledge, five large observational studies have strengthened the role of this combination in patients with HR+, HER2-MBC. With the exception of the Italian trial by Moscetti et al (21), the remaining studies were only presented as abstracts at scientific international conferences on breast cancer.\n\nThe Austrian non-interventional phase 4 STEPAUT study aimed at evaluating efficacy and safety of Eve-Exe according to clinical routine. The second interim analysis on 225 out of 300 enrolled patients was recently presented at San Antonio Breast Cancer Symposium in 2016. Overall, median PFS was 9.5 months, in line with our PFS data (9.1 months). A subgroup analysis was also performed according to Eve dosing and, interestingly, PFS was lower for the 5 mg-group compared to the 10-mg group (6.5 vs. 9.1 months, respectively). However, it should be noted that patients receiving the 5 mg starting dose had unfavorable prognostic factors as well as worse ECOG PS and more prior therapies. The safety profile was consistent with data previously reported in BOLERO-2 trial and, noteworthy, in accordance with our findings, occurrence of stomatitis did not negatively affect PFS. The EVEREXES phase IIIb trial investigated safety and tolerability profiles as primary endpoints and efficacy as a secondary objective. In this trial, 232 post-menopausal women affected by HR+, HER2-MBC were recruited in Eastern countries. The planned interim analysis presented at San Antonio Breast Cancer Symposium by Im et al in December 2015 showed a median PFS of 9.45 months, which is also consistent with our results. The majority of AEs were grade 1-2 and the most common G3-4 toxicities, as expected, included stomatitis, fatigue, hyperglycemia, and NIP. Therefore, this trial confirmed the role of Eve-Exe combination even for the treatment of patients from Asia, Africa and middle Est, a population poorly represented in BOLERO-2 (<10% of all series). Furthermore, a large, multicenter, non interventional study from Germany (BRAWO trial) including 3,000 patients provided data on the routine clinical use of Eve-Exe therapy. The second interim analysis of BRAWO, presented at the European Society of Medical Oncology (ESMO) in September 2014 by Fasching et al was carried out on 500 patients: A median PFS of 8 months was recorded, with a higher median PFS (10.1 months) for patients treated with Exe-Eve in the first-line setting. These data are still in accordance with our results as an increased PFS of 11.6 months was observed in patients receiving Eve-Exe as first line treatment, even though no statistically significant correlation in terms of risk of disease progression between the different lines of treatment was found. Of note, the third interim analysis of BRAWO study, presented at ESMO in 2015, showed a significantly longer duration of treatment in patients with younger age, better ECOG performance status, and no comorbidities. 4EVER is another German phase IIIb study evaluating the efficacy and safety of Eve-Exe in a broader patient population than that of BOLERO-2. The final efficacy analysis, calculated on 281 patients, was presented at the San Antonio Breast Cancer Symposium in 2015. Efficacy data were poorer compared with those from BOLERO-2, being the median PFS equal to 5.6 months. This may be due to the different patient population enrolled in this trial. In fact, unlike the BOLERO-2 trial, there were less limitations in enrollment criteria, including the number of previous CT lines, the prior use of Exe, or the time to progression after NSAI therapy. Finally, Moscetti et al (21) recently published an Italian retrospective trial assessing the safety of Eve-Exe combination and the possible association between toxicities and previous treatments in 181 unselected patients. On multivariate analysis, no association between the number of prior therapies and toxic events was found, which is in line with the real-life data of the Italian BALLETT-related cohort (20). In this study, a switch from 10 mg Eve starting dose to 5 mg, due to AEs, was reported in 27% of patients, which is a figure quite similar to that reported in BOLERO-2 and EAP. Conversely, in our series, Eve dosage was reduced to 5 mg in about 10% of patients only, perhaps due to the wide use of prophylactic measures and therapeutic interventions for stomatitis management.\n\nAnother important aspect to focus on is the correlation between adverse events and patient characteristics and response to treatment. In this regard, our multivariate analysis showed diabetes and previous chemotherapy for metastatic disease as the variables related to a worse outcome; conversely, the presence of mucositis correlated with long-term survival. Recently, a meta-analysis of data from seven randomized phase III trials of Eve assessing the clinical impact of stomatitis on efficacy in different solid tumors was published (22). Specifically, in BOLERO-2 study, the median PFS was 8.5 vs. 6.9 months for patients receiving Eve with or without stomatitis within 8 weeks, respectively. These results and those of the above mentioned STEPAUT trial are in accordance with our findings and suggest a careful and close monitoring of patients in the first weeks of treatment in order to better manage and prevent stomatitis. In this scenario, the SWISH trial demonstrated that a prophylactic use of a commercially available, non-expensive oral dexamethasone mouthwash resulted in a marked reduction in the incidence and severity of stomatitis in patients receiving Eve-Exe combination for treatment of HR+, HER2-MBC, when compared with data from BOLERO-2. On the basis of these findings, this measure can be considered as a new standard of oral care for BC patients receiving Eve and Exe therapy (23).\n\nIn conclusion, with the limitations due to the observational nature of our findings, addition of Eve to Exe is an effective therapeutic option for HR+, HER2-MBC patients after failure of NSAI therapy in the real word scenario. Patient characteristics, costs, and side effects have to be integrated in the treatment decision making process.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors' contributions\nFR and MO conceived and designed the study. GiuC, AD, CM, GiaC, RL, AF, FN, RA, OM and PI collected the data from the source. Analysis and interpretation of data was performed by FR. AD wrote the first draft for the manuscript. FC and SD performed data collection and critical revision of the article for important intellectual content. All authors approved the final manuscript.\n\nEthics approval and consent to participate\nThe Institutional Review Board at ‘F. Magrassi’ Department of Clinical and Experimental Medicine of ‘Luigi Vanvitelli’ University of Campania, Naples (Italy) approved the study. All patients provided written informed consent for the use of their data.\n\nPatient consent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. mPFS in the overall population. The mPFS in the overall population treated with Everolimus-Exemestane in combination was 9.1 months (95% confidence interval, 7.4-10.2). mPFS, median progression-free survival.\n\nFigure 2. mPFS according to the line of treatment. The mPFS was 11.6 (95% CI, 5.8-17.3), 9.7 (95% CI, 7.7-10.8) and 7.5 (95% CI, 6.0-9.8) months for patients treated with Exe-Eve as first, second or third line of treatment, respectively. mPFS, median progression-free survival; Eve-Exe, Everolimus-Exemestane; CI, confidence interval.\n\nFigure 3. mOS in the overall population. The mOS in the overall population treated with Everolimus-Exemestane in combination was 33.0 months (95% confidence interval 25.2-41.2) mOS, median overall survival.\n\nFigure 4. mOS according to the line of treatment. The mOS was 43.1 (95% CI, 23.1-53.2), 31.7 (95% CI, 23.5-44.1), and 27.9 months (95% CI, 22.7-38.9) for patients treated with Exe-Eve at first, second or third line of treatment, respectively. mOS, median overall survival; Eve-Exe, Everolimus-Exemestane; CI, confidence interval.\n\nTable I. Patient characteristics.\n\nCharacteristic\tExe-Eve as I line of ET (%)\tExe-Eve as II line of ET (%)\tExe-Eve as III line of ET (%)\tTotal (%)\tP-value\t\nTotal\t45\t115\t104\t264\t\t\nAge (years)\t\t\t\t\t0.091\t\n ≤48\t6 (13.3)\t31 (27.0)\t28 (26.9)\t65 (24.6)\t\t\n 49-64\t25 (53.3)\t65 (56.5)\t58 (55.8)\t147 (55.7)\t\t\n ≥65\t15 (33.3)\t19 (16.5)\t18 (17.3)\t52 (19.7)\t\t\nECOG PS\t\t\t\t\t0.724\t\n 0\t37 (82.2)\t100 (87.0)\t90 (86.5)\t227 (86)\t\t\n 1-2\t8 (17.8)\t15 (13.0)\t14 (13.5)\t37 (14.0)\t\t\nSurgery (primary tumor)\t\t\t\t\t0.082\t\n Quadrantectomy\t28 (62.2)\t56 (48.7)\t44 (42.3)\t128 (48.5)\t\t\n Mastectomy/biopsy\t17 (37.8)\t59 (51.3)\t60 (57.7)\t136 (51.5)\t\t\npT\t\t\t\t\t0.082\t\n 1.2\t17 (37.8)\t91 (79.1)\t72 (69.2)\t201 (76.1)\t\t\n 3.4.x\t7 (15.6)\t24 (20.9)\t32 (30.8)\t63 (23.9)\t\t\npN\t\t\t\t\t0.211\t\n 0\t18 (40.0)\t24 (20.8)\t18 (17.3)\t60 (22.7)\t\t\n 1\t10 (22.2)\t26 (22.6)\t26 (25.0)\t62 (23.5)\t\t\n 2\t8 (17.8)\t34 (29.5)\t29 (27.8)\t71 (26.9)\t\t\n 3\t5 (11.1)\t21 (18.2)\t20 (19.2)\t46 (17.4)\t\t\n X\t4 (8.8)\t10 (8.6)\t11 (6.7)\t25 (9.5)\t\t\nGrading\t\t\t\t\t0.510\t\n G1-G2\t17 (37.8)\t52 (45.2)\t50 (48.1)\t119 (45.1)\t\t\n G3\t28 (62.2)\t63 (54.8)\t54 (51.9)\t145 (54.9)\t\t\nER, median (IQR)\t80 (70-90)\t80 (70-90)\t80 (60-90)\t80 (70-90)\t0.252\t\nPgR, median (IQR)\t60 (30-80)\t60 (30-80)\t60 (20-80)\t60 (30-80)\t0.804\t\nKI67\t\t\t\t\t0.852\t\n ≤20%\t22 (48.9)\t56 (48.7)\t47 (45.2)\t125 (47.4)\t\t\n >20%\t23 (51.1)\t59 (51.3)\t57 (54.8)\t139 (52.7)\t\t\nAdjuvant chemotherapy\t\t\t\t\t0.641\t\n Yes\t35 (77.8)\t81 (70.4)\t76 (73.1)\t192 (72.7)\t\t\n No\t10 (22.2)\t34 (29.6)\t28 (26.9)\t72 (27.3)\t\t\nAdjuvant radiotherapy\t\t\t\t\t0.002\t\n Yes\t38 (84.4)\t64 (60)\t56 (53.9)\t163 (61.7)\t\t\n No\t7 (15.6)\t46 (40)\t48 (46.2)\t101 (38.3)\t\t\nAdjuvant ET\t\t\t\t\t0.015\t\n Yes\t45 (100)\t96 (83.5)\t88 (84.6)\t229 (86.7)\t\t\n No\t0 (0)\t19 (16.5)\t16 (15.4)\t35 (13.3)\t\t\nMedian duration of adjuvant ET, months (IQR)\t42 (21-60)\t38 (12-60)\t35.5 (16-60)\t36 (15-60)\t0.711\t\nDisease free interval (from surgery)\t42 (25-93)\t44 (18-84)\t48.5 (22-84)\t45 (21-85)\t0.710\t\n1st site of metastases\t\t\t\t\t0.005\t\n Liver/lung\t11 (24.4)\t13 (11.3)\t10 (9.6)\t34 (12.9)\t\t\n Skin/lymph nodes/peritoneo/pleura\t4 (8.9)\t21 (18.3)\t32 (30.8)\t57 (21.6)\t\t\n Bone\t30 (66.7)\t81 (70.4)\t62 (59.6)\t173 (65.5)\t\t\n2 site of metastases\t\t\t\t\t0.406\t\n No\t20 (44.4)\t61 (53.0)\t56 (53.9)\t137 (51.9)\t\t\n Liver, lung\t13 (28.9)\t20 (17.4)\t16 (15.4)\t49 (18.6)\t\t\n Other\t12 (26.7)\t34 (29.6)\t32 (30.8)\t78 (29.6)\t\t\n3 site of metastases\t\t\t\t\t0.999\t\n No\t41 (91.1)\t105 (91.3)\t95 (91.4)\t241 (91.3)\t\t\n Yes\t4 (8.9)\t10 (8.7)\t9 (8.7)\t23 (8.7)\t\t\n1st line CT for metastatic disease\t\t\t\t\t<0.001\t\n Yes\t3 (6.7)\t56 (48.7)\t69 (66.4)\t128 (48.5)\t\t\n No\t42 (93.3)\t59 (51.3)\t35 (33.7)\t136 (51.5)\t\t\nER, estrogen receptor; PgR, progesterone receptor; CT, computed tomography; ET, endocrine therapy; PS, performance status; IQR, interquartile range.\n\nTable II. Haematological and non-haematological toxicities.\n\nHaematological toxicities\tAll patients (%)\tFirst line (%)\tSecond line (%)\tThird line (%)\tP-valuea\t\nNeutropenia\t\t\t\t\t0.002\t\n G1-2\t36 (13.6)\t2 (4.4)\t12 (10.4)\t22 (21.1)\t\t\n G3-4\t6 (2.2)\t–\t2 (1.7)\t4 (3.8)\t\t\nAnemia\t\t\t\t\t0.788\t\n G1-2\t65 (24.6)\t13 (28.9)\t28 (24.3)\t24 (23.0)\t\t\n G3-G4\t13 (4.9)\t2 (4.4)\t4 (3.5)\t7 (6.7)\t\t\nThrombocytopenia\t\t\t\t\t0.010\t\n G1-2\t32 (12.1)\t–\t18 (15.6)\t14 (13.5)\t\t\n G3-4\t6 (2.28)\t–\t3 (2.6)\t3 (2.9)\t\t\nNon-haematological toxicities\t\t\t\t\t\t\nStomatitis\t\t\t\t\t0.828\t\n G1-2\t120 (45.4)\t15 (33.3)\t55 (47.8)\t50 (48.0)\t\t\n G3-4\t25 (9.5)\t4 (8.9)\t10 (8.7)\t11 (10.6)\t\t\nFatigue\t\t\t\t\t0.279\t\n G1-2\t95 (36.0)\t15 (33.3)\t39 (34.0)\t41 (39.4)\t\t\n G3-4\t9 (3.4)\t–\t3 (2.6)\t6 (5.8)\t\t\nRash\t\t\t\t\t0.778\t\n G1-2\t84 (31.8)\t16 (35)\t36 (31.3)\t32 (30.8)\t\t\n G3-G4\t4 (1.5)\t1 (2.2)\t1 (<0.1)\t2 (1.9)\t\t\nDiarrhea\t\t\t\t\t0.876\t\n G1-2\t76 (28.8)\t15 (33.3)\t29 (25.2)\t32 (30.7)\t\t\n G3-4\t12 (4.5)\t2 (4.0)\t4 (3.5)\t6 (5.7)\t\t\nNausea\t\t\t\t\t0.627\t\n G1-2\t76 (28.7)\t12 (26.7)\t32 (27.8)\t32 (30.8)\t\t\n G3-G4\t3 (1.1)\t–\t1 (<0.1)\t2 (1.9)\t\t\nDecreased appetite\t\t\t\t\t0.727\t\n G1-2\t73 (27.6)\t10 (22.2)\t28 (24.3)\t35 (33.6)\t\t\n G3-G4\t3 (1.1)\t–\t1 (<0.1)\t2 (1.9)\t\t\nAST increase\t\t\t\t\t0.781\t\n G1-2\t28 (10.6)\t5 (11.1)\t11 (9.6)\t12 (11.5)\t\t\n G3-4\t9 (3.4)\t1 (2.2)\t3 (2.6)\t5 (4.8)\t\t\nCough\t\t\t\t\t0.192\t\n G1-2\t31 (11.7)\t5 (11.1)\t12 (10.4)\t14 (13.5)\t\t\n G3-G4\t3 (1.1)\t–\t–\t3 (2.9)\t\t\nALT increase\t\t\t\t\t0.375\t\n G1-2\t24 (9.1)\t5 (11.1)\t10 (8.7)\t9 (8.6)\t\t\n G3-4\t7 (2.6)\t–\t3 (2.6)\t4 (3.8)\t\t\nHyperglicemia\t\t\t\t\t0.472\t\n G1-2\t17 (6.4)\t3 (6.7)\t8 (6.9)\t6 (5.8)\t\t\n G3-4\t5 (1.8)\t–\t2 (1.7)\t3 (2.9)\t\t\nPneumonitis/interstitial lung disease\t\t\t\t\t0.592\t\n G1-2\t13 (4.9)\t2 (4.4)\t4 (3.5)\t7 (6.7)\t\t\n G3-G4\t6 (2.3)\t–\t2 (1.7)\t4 (3.8)\t\t\na Assessed by the chi-squared test. ALT, alanine aminotransferase; AST, aspartate aminotransferase.\n==== Refs\nReferences\n1 Ferlay J Soerjomataram I Dikshit R Eser S Mathers C Rebelo M Parkin DM Forman D Bray F Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 Int J Cancer 136 E359 E386 2015 10.1002/ijc.29210 25220842 \n2 Anderson WF Chatterjee N Ershler WB Brawley OW Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database Breast Cancer Res Treat 76 27 36 2002 10.1023/A:1020299707510 12408373 \n3 Cardoso F Costa A Senkus E Aapro M André F Barrios CH Bergh J Bhattacharyya G Biganzoli L Cardoso MJ 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3) Ann Oncol 28 16 33 2017 10.1093/annonc/mdx036 28177437 \n4 National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology Breast Cancer Version 1.2018 https://www.nccn.org/professional/physician_gls/pdf/breast.pdf 4 6 2018 \n5 Osborne CK Schiff R Mechanisms of endocrine resistance in breast cancer Annu Rev Med 62 233 247 2011 10.1146/annurev-med-070909-182917 20887199 \n6 Bachelot T Bourgier C Cropet C Ray-Coquard I Ferrero JM Freyer G Abadie-Lacourtoisie S Eymard JC Debled M Spaëth D Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study J Clin Oncol 30 2718 2724 2012 10.1200/JCO.2011.39.0708 22565002 \n7 Baselga J Semiglazov V van Dam P Manikhas A Bellet M Mayordomo J Campone M Kubista E Greil R Bianchi G Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer J Clin Oncol 27 2630 2637 2009 10.1200/JCO.2008.18.8391 19380449 \n8 Boulay A Rudloff J Ye J Zumstein-Mecker S O'Reilly T Evans DB Chen S Lane HA Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer Clin Cancer Res 11 5319 5328 2005 10.1158/1078-0432.CCR-04-2402 16033851 \n9 Baselga J Campone M Piccart M Burris HA III Rugo HS Sahmoud T Noguchi S Gnant M Pritchard KI Lebrun F Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer N Engl J Med 366 520 529 2012 10.1056/NEJMoa1109653 22149876 \n10 Yardley DA Noguchi S Pritchard KI Burris HA III Baselga J Gnant M Hortobagyi GN Campone M Pistilli B Piccart M Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis Adv Ther 30 870 884 2013 10.1007/s12325-013-0060-1 24158787 \n11 Burris HA III Lebrun F Rugo HS Beck JT Piccart M Neven P Baselga J Petrakova K Hortobagyi GN Komorowski A Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial Cancer 119 1908 1915 2013 10.1002/cncr.28010 23504821 \n12 Turner NC Ro J André F Loi S Verma S Iwata H Harbeck N Loibl S Huang Bartlett C Zhang K Palbociclib in hormone-receptor-positive advanced breast cancer N Engl J Med 373 209 219 2015 10.1056/NEJMoa1505270 26030518 \n13 Cristofanilli M Turner NC Bondarenko I Ro J Im SA Masuda N Colleoni M De Michele A Loi S Verma S Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol 17 425 439 2016 10.1016/S1470-2045(15)00613-0 26947331 \n14 Hortobagyi GN Stemmer SM Burris HA Yap YS Sonke GS Paluch-Shimon S Campone M Blackwell KL André F Winer EP Ribociclib as first-line therapy for HR-positive, advanced breast cancer N Engl J Med 375 1738 1748 2016 10.1056/NEJMoa1609709 27717303 \n15 Sledge GW Jr Toi M Neven P Sohn J Inoue K Pivot X Burdaeva O Okera M Masuda N Kaufman PA MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 35 2875 2884 2017 10.1200/JCO.2017.73.7585 28580882 \n16 Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 6 14 2010 US Department of Health and Human Services. National Institutes of Health National Cancer Institute http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_Quick Reference_5×7.pdf 10 8 2017 \n17 Kaplan EL Meier P Nonparametric estimation from incomplete observations J Am Stat Assoc 53 457 481 1958 10.1080/01621459.1958.10501452 \n18 Piccart M Hortobagyi GN Campone M Pritchard KI Lebrun F Ito Y Noguchi S Perez A Rugo HS Deleu I Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Overall survival results from BOLERO-2 Ann Oncol 25 2357 2362 2014 10.1093/annonc/mdu456 25231953 \n19 Rugo HS Pritchard KI Gnant M Noguchi S Piccart M Hortobagyi G Baselga J Perez A Geberth M Csoszi T Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: Insights from BOLERO-2 Ann Oncol 25 808 815 2014 10.1093/annonc/mdu009 24615500 \n20 Jerusalem G Mariani G Ciruelos EM Martin M Tjan-Heijnen VC Neven P Gavila JG Michelotti A Montemurro F Generali D Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: Primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET) Ann Oncol 27 1719 1725 2016 10.1093/annonc/mdw249 27358383 \n21 Moscetti L Vici P Gamucci T Natoli C Cortesi E Marchetti P Santini D Giuliani R Sperduti I Mauri M Safety analysis, association with response and previous treatments of everolimus and exemestane in 181 metastatic breast cancer patients: A multicenter Italian experience Breast 29 96 101 2016 10.1016/j.breast.2016.07.005 27476084 \n22 Rugo HS Hortobagyi GN Yao J Pavel M Ravaud A Franz D Ringeisen F Gallo J Rouyrre N Anak O Motzer R Meta-analysis of stomatitis in clinical studies of everolimus: Incidence and relationship with efficacy Ann Oncol 27 519 525 2016 10.1093/annonc/mdv595 26759276 \n23 Rugo HS Seneviratne L Beck JT Glaspy JA Peguero JA Pluard TJ Dhillon N Hwang LC Nangia C Mayer IA Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative metastatic breast cancer using dexamethasone mouthwash (SWISH): A single-arm, phase 2 trial Lancet Oncol 18 654 662 2017 10.1016/S1470-2045(17)30109-2 28314691\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2049-9450", "issue": "9(3)", "journal": "Molecular and clinical oncology", "keywords": "endocrine therapy; everolimus; metastatic breast cancer; real-life experience", "medline_ta": "Mol Clin Oncol", "mesh_terms": null, "nlm_unique_id": "101613422", "other_id": null, "pages": "255-263", "pmc": null, "pmid": "30155246", "pubdate": "2018-09", "publication_types": "D016428:Journal Article", "references": "25220842;27358383;24158787;22149876;28314691;27476084;27717303;19380449;26759276;12408373;26947331;25231953;28580882;26030518;28177437;23504821;16033851;20887199;24615500;22565002", "title": "Exemestane and Everolimus combination treatment of hormone receptor positive, HER2 negative metastatic breast cancer: A retrospective study of 9 cancer centers in the Campania Region (Southern Italy) focused on activity, efficacy and safety.", "title_normalized": "exemestane and everolimus combination treatment of hormone receptor positive her2 negative metastatic breast cancer a retrospective study of 9 cancer centers in the campania region southern italy focused on activity efficacy and safety" }

[ { "companynumb": "IT-MYLANLABS-2018M1067006", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "EXEMESTANE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "203315", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EXEMESTANE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BREAST CANCER METASTATIC", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "EVEROLIMUS." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Neutropenia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "RICCARDI F, COLANTUONI G, DIANA A, MOCERINO C, CARTENI G, LAURIA R, ET AL. EXEMESTANE AND EVEROLIMUS COMBINATION TREATMENT OF HORMONE RECEPTOR POSITIVE, HER2 NEGATIVE METASTATIC BREAST CANCER: A RETROSPECTIVE STUDY OF 9 CANCER CENTERS IN THE CAMPANIA REGION (SOUTHERN ITALY) FOCUSED ON ACTIVITY, EFFICACY AND SAFETY. MOL?CLIN?ONCOL 2018?9(3):255?263.", "literaturereference_normalized": "exemestane and everolimus combination treatment of hormone receptor positive her2 negative metastatic breast cancer a retrospective study of 9 cancer centers in the campania region southern italy focused on activity efficacy and safety", "qualification": "1", "reportercountry": "IT" }, "primarysourcecountry": "IT", "receiptdate": "20180912", "receivedate": "20180912", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 15374516, "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" } ]

{ "abstract": "Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log¹⁰ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV-specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.", "affiliations": "Transplantation Virology, Institute for Medical Microbiology, Department of Biomedicine, University of Basel Internal Medicine, University Hospital of Basel, Switzerland.", "authors": "Egli|A|A|;Helmersen|D S|DS|;Taub|K|K|;Hirsch|H H|HH|;Johnson|A|A|", "chemical_list": "D007555:Isoxazoles; D063065:Organophosphonates; D003596:Cytosine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077339:Leflunomide; D009173:Mycophenolic Acid; D000077404:Cidofovir; D011241:Prednisone; D016559:Tacrolimus", "country": "United States", "delete": false, "doi": "10.1111/j.1600-6143.2010.03265.x", "fulltext": null, "fulltext_license": null, "issn_linking": "1600-6135", "issue": "10(10)", "journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "keywords": null, "medline_ta": "Am J Transplant", "mesh_terms": "D000328:Adult; D000368:Aged; D000077404:Cidofovir; D003596:Cytosine; D005260:Female; D006801:Humans; D007555:Isoxazoles; D007674:Kidney Diseases; D000077339:Leflunomide; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D063065:Organophosphonates; D027601:Polyomavirus Infections; D011241:Prednisone; D051437:Renal Insufficiency; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus", "nlm_unique_id": "100968638", "other_id": null, "pages": "2324-30", "pmc": null, "pmid": "20840474", "pubdate": "2010-10", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Renal failure five years after lung transplantation due to polyomavirus BK-associated nephropathy.", "title_normalized": "renal failure five years after lung transplantation due to polyomavirus bk associated nephropathy" }

[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2019-08051", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "091249", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1500 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1500", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MYCOPHENOLATE MOFETIL." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TACROLIMUS" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TACROLIMUS." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "7.5 MILLIGRAM, QD", "drugenddate": null, "drugenddateformat": null, "drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY", "drugintervaldosagedefinition": "804", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "7.5", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "40", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "BK virus infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Polyomavirus-associated nephropathy", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Transplant rejection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "EGLI A, HELMERSEN DS, TAUB K, HIRSCH HH, ET AL.. RENAL FAILURE FIVE YEARS AFTER LUNG TRANSPLANTATION DUE TO POLYOMAVIRUS BK-ASSOCIATED NEPHROPATHY. AMERICAN JOURNAL OF TRANSPLANTATION. 2010?10(10):2324-2330", "literaturereference_normalized": "renal failure five years after lung transplantation due to polyomavirus bk associated nephropathy", "qualification": "3", "reportercountry": "CH" }, "primarysourcecountry": "JP", "receiptdate": "20191227", "receivedate": "20191227", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17205892, "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": "BACKGROUND\nEpidural steroid injections are frequently used to treat back and extremity pain. The procedure is generally safe, with a low rate of adverse events, including intrathecal entry, pneumocephalus, and chemical meningitis.\n\n\nMETHODS\nWe report a case of a 45-year-old woman who presented to the emergency department (ED) with headache, nausea, vomiting, and photophobia after a lumbar epidural steroid injection. She was afebrile and had an elevated white blood cell count. A non-contrast computed tomography scan of the head revealed pneumocephalus within the subarachnoid space and lateral ventricles. The patient was admitted to the ED observation unit for pain control and subsequently developed a marked leukocytosis and worsening meningismus. A lumbar puncture was performed yielding cerebrospinal fluid (CSF) consistent with meningitis (1,000 total nucleated cells, 89% neutrophils, 85 mg/dL total protein, and no red blood cells). Gram stain revealed no bacteria. The patient was admitted on empiric vancomycin and ceftriaxone. Antibiotics were discontinued at 48 h when CSF cultures remained negative and the patient was clinically asymptomatic. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should consider intrathecal entry and pneumocephalus in patients who present with a headache after an epidural intervention. The management of pneumocephalus includes supportive therapies, appropriate positioning, and supplemental oxygen. These symptoms can be accompanied by fever, leukocytosis, and markedly inflammatory CSF findings consistent with bacterial or chemical meningitis. Empiric treatment with broad-spectrum antibiotics should be initiated until CSF culture results are available.", "affiliations": "Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.;Department of Anesthesiology, Penn State Milton S. Hershey Medical Center and Penn State College of Medicine, Hershey, Pennsylvania.;Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.", "authors": "Shah|Aakash Kaushik|AK|;Bilko|Andrey|A|;Takayesu|James Kimo|JK|", "chemical_list": "D013256:Steroids", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0736-4679", "issue": "51(3)", "journal": "The Journal of emergency medicine", "keywords": "chemical meningitis; epidural intervention; epidural steroid injection; headache; intrathecal injection; pneumocephalus", "medline_ta": "J Emerg Med", "mesh_terms": "D005260:Female; D006801:Humans; D007268:Injections, Epidural; D007278:Injections, Spinal; D008581:Meningitis; D008875:Middle Aged; D011007:Pneumocephalus; D013256:Steroids", "nlm_unique_id": "8412174", "other_id": null, "pages": "265-8", "pmc": null, "pmid": "27381953", "pubdate": "2016-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Epidural Steroid Injection Complicated by Intrathecal Entry, Pneumocephalus, and Chemical Meningitis.", "title_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis" }

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EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. J-EMERG-MED 2016;51(3):265-268.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170105", "receivedate": "20170105", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13088867, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-B. 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"drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "019830", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ODANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "MORPHINE SULFATE" }, "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": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "4", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "MORPHINE SULFATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "VANCOMYCIN HYDROCHLORIDE" }, "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, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "VANCOMYCIN HCL" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Photophobia", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "19.1", "reactionoutcome": null }, { "reactionmeddrapt": "Headache", "reactionmeddraversionpt": "19.1", "reactionoutcome": null } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO, A AND TAKAYESU, JK. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS AND CHEMICAL MENINGITIS. THE JOURNAL OF EMERGENCY MEDICINE, VOL. 51, NO. 3, PP. 265-268, 2016", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170207", "receivedate": "20170207", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13194090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-TEVA-726860USA", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "0.5%, 2ML", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "88497", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INFUSION", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. J-EMERG-MED 2016;51(3):265-268.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170106", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13093930, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" }, { "companynumb": "US-PFIZER INC-2016456906", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "011856", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "POWDER FOR SOLUTION FOR INJECTION", "drugdosagetext": "80 MG, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE SODIUM SUCCINATE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO MILLILITERS OF A 0.5%", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, SINGLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "20.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" }, { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "20.1", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH, A.. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS.. JOURNAL OF EMERGENCY MEDICINE. 2016;51 (3):265-268", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20171027", "receivedate": "20161003", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 12804140, "safetyreportversion": 5, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180320" }, { "companynumb": "PHHY2016US179288", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "12 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "LOCAL ANAESTHESIA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": "40719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SUSPENSION FOR INJECTION", "drugdosagetext": "80 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "SOLUTION FOR INJECTION", "drugdosagetext": "2 ML, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK.. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. JOURNAL OF EMERGENCY MEDICINE. 2016;51(3):265-8.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170104", "receivedate": "20170104", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13086135, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-FRESENIUS KABI-FK201700200", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "BETAMETHASONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADICULAR PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "006488", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADICULAR PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "2", "drugstructuredosageunit": "012", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE (MANUFACTURER UNKNOWN)" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "008", "drugauthorizationnumb": "040583", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN", "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "RADICULAR PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "80", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)" } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis aseptic", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Product use issue", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Procedural complication", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH A,BILKO A,TAKAYESU J. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS. THE JOURNAL OF EMERGENCY MEDICINE 2016;3:265-268.", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170106", "receivedate": "20170106", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13093935, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170428" }, { "companynumb": "US-GLENMARK PHARMACEUTICALS-2017GMK026061", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 L, BOLUS", "drugenddate": null, "drugenddateformat": null, "drugindication": null, "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "011", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SALINE /00075401/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "LIDOCAINE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "TWO ML MILLILITERS OF A 0.5% LIDOCAINE SOLUTION CONTAINING 80 MG METHYLPREDNISOLONE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "LIDOCAINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "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": "SALINE /00075401/" }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "INJECTION", "drugdosagetext": "TWO ML MILLILITERS OF A 0.5% LIDOCAINE SOLUTION CONTAINING 80 MG METHYLPREDNISOLONE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "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": "BETAMETHASONE DIPROPIONATE" }, "drugadditional": "3", "drugadministrationroute": "037", "drugauthorizationnumb": "078930", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "12 MG, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "BACK PAIN", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "12", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BETAMETHASONE DIPROPIONATE." } ], "patientagegroup": null, "patientonsetage": "45", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Incorrect route of drug administration", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Pneumocephalus", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Meningitis chemical", "reactionmeddraversionpt": "19.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "SHAH AK, BILKO A, TAKAYESU JK.. EPIDURAL STEROID INJECTION COMPLICATED BY INTRATHECAL ENTRY, PNEUMOCEPHALUS, AND CHEMICAL MENINGITIS.. JOURNAL OF EMERGENCY MEDICINE. 2016;51(3):265-268", "literaturereference_normalized": "epidural steroid injection complicated by intrathecal entry pneumocephalus and chemical meningitis", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170130", "receivedate": "20170130", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13162531, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20170428" } ]

{ "abstract": "BACKGROUND\nA single injection of pegfilgrastim has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, whereas the experiences with pegfilgrastim in mobilization of peripheral blood progenitor cells (PBPCs) are limited.\n\n\nMETHODS\nForty unselected patients with lymphoma or multiple myeloma were treated with different chemotherapy regimens followed by 6 mg of pegfilgrastim for mobilization of autologous PBPCs. Patients with an inadequate mobilization (blood CD34+ cells <or= 10/microL after nadir) were given additional daily doses of 10 microg per kg unconjugated filgrastim.\n\n\nRESULTS\nA median blood CD34+ peak concentration of 81 per microL (range, 10-565/microL) was found in 30 patients, who had only received pegfilgrastim, compared to 13 per microL (median, range 4-71/microL; p < 0.001) in 10 poor mobilizing patients with additional filgrastim. The median yield of CD34+ cells was 9.8 x 10(6) per kg (range, 1.5-88.1) after pegfilgrastim only versus 2.5 x 10(6) (range, 1.7-7.0) in poor mobilizers. Patients who needed additional cytokine administration were those with a more extensive previous antineoplastic treatment and mobilizing regimens containing PBPC toxic agents.\n\n\nCONCLUSIONS\nThe results confirm the efficacy and feasibility of PBPC mobilization with chemotherapy and single-dose pegfilgrastim in patients with lymphoproliferative malignacies. In less heavily pretreated patients, 6 mg of pegfilgrastim after chemotherapy induced an adequate mobilization, whereas dose and schedule in patients after numerous cytotoxic regimens need further investigation.", "affiliations": "1st Medical Department, University Hospital Dresden, Dresden, Germany. [email protected]", "authors": "Kroschinsky|Frank|F|;Hölig|Kristina|K|;Platzbecker|Uwe|U|;Poppe-Thiede|Kirsten|K|;Ordemann|Rainer|R|;Blechschmidt|Matthias|M|;Oelschlaegel|Uta|U|;Schaich|Markus|M|;Hänel|Mathias|M|;Bornhäuser|Martin|M|;Ehninger|Gerhard|G|", "chemical_list": "D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D005047:Etoposide; D003907:Dexamethasone; D000069585:Filgrastim; D008558:Melphalan; D002330:Carmustine", "country": "United States", "delete": false, "doi": "10.1111/j.1537-2995.2006.00911.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1132", "issue": "46(8)", "journal": "Transfusion", "keywords": null, "medline_ta": "Transfusion", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine; D003561:Cytarabine; D003907:Dexamethasone; D005047:Etoposide; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008223:Lymphoma; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D036102:Peripheral Blood Stem Cell Transplantation; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012074:Remission Induction; D014182:Transplantation, Autologous; D016896:Treatment Outcome", "nlm_unique_id": "0417360", "other_id": null, "pages": "1417-23", "pmc": null, "pmid": "16934080", "pubdate": "2006-08", "publication_types": "D016430:Clinical Trial; D016428:Journal Article", "references": null, "title": "Efficacy of single-dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma.", "title_normalized": "efficacy of single dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma" }

[ { "companynumb": "DE-AMGEN-DEUSP2020018797", "fulfillexpeditecriteria": "2", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUPOGEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": "125031", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "6 MILLIGRAM, (48 HOURS AFTER CHEMOTHERAPY)", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEULASTA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Multiple organ dysfunction syndrome", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Infection", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Aplasia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Febrile neutropenia", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Non-Hodgkin^s lymphoma recurrent", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Bone pain", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PLATZBECKER U. EFFICACY OF SINGLE-DOSE PEGFILGRASTIM AFTER CHEMOTHERAPY FOR THE MOBILIZATION OF AUTOLOGOUS PERIPHERAL BLOOD STEM CELLS IN PATIENTS WITH MALIGNANT LYMPHOMA OR MULTIPLE MYELOMA. TRANSFUSION. 2006?46:1417-1423", "literaturereference_normalized": "efficacy of single dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17394556, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": 1, "transmissiondate": "20200409" }, { "companynumb": "DE-AMGEN-DEUSP2020018810", "fulfillexpeditecriteria": "2", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "103353", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEUPOGEN" }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "PEGFILGRASTIM" }, "drugadditional": null, "drugadministrationroute": "058", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "UNKNOWN FORMULATION", "drugdosagetext": "6 MILLIGRAM, AFTER CHEMO", "drugenddate": null, "drugenddateformat": null, "drugindication": "HAEMATOPOIETIC STEM CELL MOBILISATION", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "6", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "NEULASTA" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective for unapproved indication", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "22.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "PLATZBECKER U. EFFICACY OF SINGLE-DOSE PEGFILGRASTIM AFTER CHEMOTHERAPY FOR THE MOBILIZATION OF AUTOLOGOUS PERIPHERAL BLOOD STEM CELLS IN PATIENTS WITH MALIGNANT LYMPHOMA OR MULTIPLE MYELOMA. TRANSFUSION. 2006?46:1417-1423", "literaturereference_normalized": "efficacy of single dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma", "qualification": "1", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20200210", "receivedate": "20200210", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17397411, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20200409" } ]

{ "abstract": "BACKGROUND\nDrug hypersensitivity is classically divided into IgE mediated and non-IgE mediated disease. We report a rare case of consequent IgE mediated and non-IgE mediated reactions within the beta lactam class of antibiotics.\n\n\nMETHODS\nAn 84-year-old man developed toxic epidermal necrolysis (TEN) due to ceftriaxone, a third generation cephalosporin, involving 72% of the body surface area. The patient recovered but within weeks subsequently developed an acute IgE mediated allergic reaction to piperacillin/tazobactam, an extended spectrum penicillin. Further IgE RAST revealed positive results to penicillin major determinant.\n\n\nCONCLUSIONS\nThis case demonstrates the complexity of drug hypersensitivity reactions. While it is accepted that IgE mediated penicillin allergy is a predisposition to cephalosporin allergy, this case displays an unusual correlation between drug hypersensitivity and drug class. There have been few studies that evaluate the cross reactivity with penicillin or other beta-lactams in subjects with primary hypersensitivity to cephalosporins. This clinical scenario emphasizes the need of more studies on cephalosporin allergy in particular as shown by this case of sequential non-IgE mediated cephalosporin induced TEN reaction pursuant by an IgE mediated penicillin allergy.", "affiliations": "UCLA West Los Angeles VA Medical Center 90073, USA. [email protected]", "authors": "Lam|Amanda|A|;Randhawa|Inderpal|I|;Klaustermeyer|William|W|", "chemical_list": "D002511:Cephalosporins; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin", "country": "England", "delete": false, "doi": "10.2332/allergolint.C-07-55", "fulltext": null, "fulltext_license": null, "issn_linking": "1323-8930", "issue": "57(3)", "journal": "Allergology international : official journal of the Japanese Society of Allergology", "keywords": null, "medline_ta": "Allergol Int", "mesh_terms": "D000369:Aged, 80 and over; D002511:Cephalosporins; D004342:Drug Hypersensitivity; D005076:Exanthema; D006801:Humans; D008297:Male; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D013262:Stevens-Johnson Syndrome", "nlm_unique_id": "9616296", "other_id": null, "pages": "281-4", "pmc": null, "pmid": "18566552", "pubdate": "2008-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem.", "title_normalized": "cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem" }

[ { "companynumb": "US-LUPIN PHARMACEUTICALS INC.-2022-07120", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065125", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "2 GRAM (EVERY 4 HOURS)", "drugenddate": null, "drugenddateformat": null, "drugindication": "Sepsis", "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": "1", "activesubstance": { "activesubstancename": "CEFTRIAXONE" }, "drugadditional": "1", "drugadministrationroute": "042", "drugauthorizationnumb": "065125", "drugbatchnumb": "Unknown", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK (WAS MISTAKENLY DOSED WITH CEFTRIAXONE AGAIN)", "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" } ], "patientagegroup": null, "patientonsetage": "84", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Toxic epidermal necrolysis", "reactionmeddraversionpt": "25.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "Lam A, Randhawa I, Klaustermeyer W. Cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem. Allergology International. 2008;57(3):281-287", "literaturereference_normalized": "cephalosporin induced toxic epidermal necrolysis and subsequent penicillin drug exanthem", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20220517", "receivedate": "20220517", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 20838094, "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": "BACKGROUND\nWe report a case of fungal endophthalmitis which developed after subtenon injections of triamcinolone acetonide (TA).\n\n\nMETHODS\nA 63-year-old man had Graves' ophthalmopathy. He had received subtenon injections of TA in his left eye. He was admitted to Kimura Eye & Internal Medicine Hospital because of a subconjunctival abscess with inflammatory cells in the anterior chamber. Although we treated it as a suspected bacterial infection at the first visit, it deteriorated rapidly. Because prolonged antibiotics and antifungal therapy seemed ineffective, we performed diagnostic surgery. The lower sclera around the subtenon injections of TA was hard and thick, and a white spotty lesion and retinal detachment were seen on the lower retina. A culture of the Tenon sac showed filamentous fungus. After the surgery the subconjunctival abscess recurred because intravenous antifungal therapy had been discontinued. A culture of the abscess identified Alternaria sp. The subconjunctival abscess, thickened sclera, and retinal exudate were limited to the region of the sub-Tenon injection of TA, We conclude that the sclera had been permeated by hyphae of Alternaria sp.\n\n\nCONCLUSIONS\nIn this case, critical infection was caused by the sub-Tenon injections of TA.", "affiliations": "Kimura Eye & Internal Medicine Hospital, Hiroshima, Japan. [email protected]", "authors": "Isshiki|Yoshihiko|Y|;Kimura|Tohru|T|;Yokoyama|Mitsunobu|M|;Kimura|Wataru|W|;Syoge|Keisuke|K|;Ryu|Momoyoshi|M|;Uchida|Yoshiko|Y|;Yoshiki|Hiroka|H|;Suzuki|Takashi|T|", "chemical_list": "D014222:Triamcinolone Acetonide", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0029-0203", "issue": "111(9)", "journal": "Nippon Ganka Gakkai zasshi", "keywords": null, "medline_ta": "Nippon Ganka Gakkai Zasshi", "mesh_terms": "D000528:Alternaria; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D049970:Graves Ophthalmopathy; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D014222:Triamcinolone Acetonide", "nlm_unique_id": "7505716", "other_id": null, "pages": "741-4", "pmc": null, "pmid": "17907469", "pubdate": "2007-09", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Case of fungal endophthalmitis developed after subtenon injections of triamcinolone acetonide.", "title_normalized": "case of fungal endophthalmitis developed after subtenon injections of triamcinolone acetonide" }

[ { "companynumb": "JP-ALKEM LABORATORIES LIMITED-JP-ALKEM-2018-01056", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRIAMCINOLONE ACETONIDE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "207651", "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": "TRIAMCINOLONE ACETONIDE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Alternaria infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Infective scleritis", "reactionmeddraversionpt": "21.0", "reactionoutcome": "2" } ], "summary": null }, "primarysource": { "literaturereference": "ISSHIKI Y, KIMURA T, YOKOYAMA M, KIMURA W AND ET AL.. CASE OF FUNGAL ENDOPHTHALMITIS DEVELOPED AFTER SUBTENON INJECTIONS OF TRIAMCINOLONE ACETONIDE. NIPPON GANKA GAKKAI ZASSHI.. 2007?111:741?4", "literaturereference_normalized": "case of fungal endophthalmitis developed after subtenon injections of triamcinolone acetonide", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20180306", "receivedate": "20180306", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14601969, "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": "Clinically available targeted agents to treat advanced renal cell carcinoma (RCC) include sunitinib, sorafenib and temsirolimus. Sorafenib and sunitinib have been associated with bleeding in selected trials, but clinical and endoscopic characteristics of gastrointestinal bleeding are not well described. Herein, we report four cases of advanced RCC in which endoscopic hemostasis effectively resolved high-grade, life-threatening gastrointestinal bleeding that occurred during targeted therapy. Although stomatitis and mucositis have occurred during targeted therapies, life-threatening gastrointestinal bleeding is less common. In these four patients, the origins of gastrointestinal bleeding were identified, and complete endoscopic hemostasis was achieved. Endoscopies revealed variable characteristics including angiodysplasia, multiple gastric ulcers and oozing bleeding of the normal mucosa. Although the most effective diagnostic and treatment strategies are disputed, endoscopic examinations are best performed before starting targeted therapies. Additionally, these patients should be monitored even for rare life-threatening events.", "affiliations": "Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.;Department of Urology, Tottori Red Cross Hospital, Tottori 680-8517, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.;Department of Urology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan.;Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kagawa 761-0793, Japan.", "authors": "Fujihara|Shintaro|S|;Mori|Hirohito|H|;Kobara|Hideki|H|;Nishiyama|Noriko|N|;Ayaki|Maki|M|;Ohata|Ryo|R|;Ueda|Nobufumi|N|;Sugimoto|Mikio|M|;Kakehi|Yoshiyuki|Y|;Masaki|Tsutomu|T|", "chemical_list": null, "country": "Greece", "delete": false, "doi": "10.3892/ol.2015.3671", "fulltext": null, "fulltext_license": null, "issn_linking": "1792-1074", "issue": "10(5)", "journal": "Oncology letters", "keywords": "argon plasma coagulation; gastrointestinal bleeding; sorafenib; sunitinib; targeted therapy; temsirolimus", "medline_ta": "Oncol Lett", "mesh_terms": null, "nlm_unique_id": "101531236", "other_id": null, "pages": "2895-2898", "pmc": null, "pmid": "26722259", "pubdate": "2015-11", "publication_types": "D016428:Journal Article", "references": "8778606;21251188;23841849;22235142;14673156;17538086;22056247;22206873;19615940;11057898;17519900;19767240;19470934", "title": "Uncommon gastrointestinal bleeding during targeted therapy for advanced renal cell carcinoma: A report of four cases.", "title_normalized": "uncommon gastrointestinal bleeding during targeted therapy for advanced renal cell carcinoma a report of four cases" }

[ { "companynumb": "JP-MYLANLABS-2016M1000702", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SUNITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "201275", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "37.5MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SUNITINIB" }, { "actiondrug": "1", "activesubstance": { "activesubstancename": "AXITINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "10MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AXITINIB" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "200MG/DAY", "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": "SORAFENIB" }, { "actiondrug": "2", "activesubstance": { "activesubstancename": "SORAFENIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "INITIALLY 800MG/DAY, LATER DOSE REDUCED TO 200MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "METASTASES TO LIVER", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SORAFENIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Gastrointestinal haemorrhage", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" }, { "reactionmeddrapt": "Anaemia", "reactionmeddraversionpt": "19.0", "reactionoutcome": "2" }, { "reactionmeddrapt": "Fatigue", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Interstitial lung disease", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Loss of consciousness", "reactionmeddraversionpt": "19.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "FUJIHARA S, MORI H, KOBARA H, NISHIYAMA N, AYAKI M, OHATA R, ET AL. UNCOMMON GASTROINTESTINAL BLEEDING DURING TARGETED THERAPY FOR ADVANCED RENAL CELL CARCINOMA: A REPORT OF FOUR CASES. ONCOL-LETT 2015?10(5):2895-2898.", "literaturereference_normalized": "uncommon gastrointestinal bleeding during targeted therapy for advanced renal cell carcinoma a report of four cases", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160111", "receivedate": "20160111", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11908570, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": 1, "seriousnessother": null, "transmissiondate": "20160526" } ]

{ "abstract": "BACKGROUND\nBeyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation.\n\n\nMETHODS\nWe retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children's Hospital from 2009 to 2018 and analyzed survival using the Kaplan-Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated.\n\n\nRESULTS\nMedian age at diagnosis was 10.9 years (18 months-18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG.\n\n\nCONCLUSIONS\nOur single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.", "affiliations": "Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA.;Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA.;Department of Radiation Oncology, University of Washington, Seattle, WA, USA.;Department of Laboratories, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Department of Laboratory Medicine, Genetics and Solid Tumor Diagnostics Laboratory, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.;Department of Laboratory Medicine, Genetics and Solid Tumor Diagnostics Laboratory, University of Washington and Seattle Children's Hospital, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.;Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA. [email protected].", "authors": "Crotty|Erin E|EE|;Leary|Sarah E S|SES|;Geyer|J Russell|JR|;Olson|James M|JM|;Millard|Nathan E|NE|;Sato|Aimee A|AA|;Ermoian|Ralph P|RP|;Cole|Bonnie L|BL|;Lockwood|Christina M|CM|;Paulson|Vera A|VA|;Browd|Samuel R|SR|;Ellenbogen|Richard G|RG|;Hauptman|Jason S|JS|;Lee|Amy|A|;Ojemann|Jeffrey G|JG|;Vitanza|Nicholas A|NA|http://orcid.org/0000-0002-3966-4985", "chemical_list": "D000068258:Bevacizumab; D000077146:Irinotecan; D000077204:Temozolomide", "country": "United States", "delete": false, "doi": "10.1007/s11060-020-03558-w", "fulltext": null, "fulltext_license": null, "issn_linking": "0167-594X", "issue": "148(3)", "journal": "Journal of neuro-oncology", "keywords": "Bevacizumab; Diffuse intrinsic pontine glioma; Irinotecan; Pediatric high-grade glioma; Temozolomide", "medline_ta": "J Neurooncol", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D020295:Brain Stem Neoplasms; D002648:Child; D002675:Child, Preschool; D000080443:Diffuse Intrinsic Pontine Glioma; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma; D006801:Humans; D007223:Infant; D000077146:Irinotecan; D008297:Male; D060787:Neoplasm Grading; D012189:Retrospective Studies; D015996:Survival Rate; D000077204:Temozolomide", "nlm_unique_id": "8309335", "other_id": null, "pages": "607-617", "pmc": null, "pmid": "32556862", "pubdate": "2020-07", "publication_types": "D016428:Journal Article", "references": "28966033;28821206;27157931;30445539;28161497;29280457;31207154;16265674;19147777;21858607;17932894;23592571;17278121;17293590;17031553;26092413;21345842;21339192;19897538;21038110;11051264;24189654;32123717;30833574;30766509;26626490;24050762;29412784;23017588;29763623;25433556;22735884;21666852;27020328;25757751", "title": "Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children's Hospital experience.", "title_normalized": "children with dipg and high grade glioma treated with temozolomide irinotecan and bevacizumab the seattle children s hospital experience" }

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METER, EVERY 2 WEEKS", "drugenddate": null, "drugenddateformat": null, "drugindication": "GLIOMA", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "2", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "1", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "125", "drugstructuredosageunit": "009", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "IRINOTECAN HYDROCHLORIDE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "ONDANSETRON" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "NAUSEA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ONDANSETRON" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG TMP/KG/DAY BIW", "drugenddate": null, "drugenddateformat": null, "drugindication": "ANTIFUNGAL PROPHYLAXIS", "drugintervaldosagedefinition": "803", "drugintervaldosageunitnumb": "1", "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": "2", "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "SULFAMETHOXAZOLE (+) TRIMETHOPRIM" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": "5", "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": "3", "drugadministrationroute": "048", "drugauthorizationnumb": "021029", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": "CAPSULE", "drugdosagetext": "200 MG/M2/DAY FOR THE FIRST 5 DAYS OF 28 CDAYS CYCLE", "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "TEMODAR" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "DIPHENHYDRAMINE" }, "drugadditional": null, "drugadministrationroute": null, "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": "DIPHENHYDRAMINE." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "BEVACIZUMAB" }, "drugadditional": null, "drugadministrationroute": "042", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, 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"primarysource": { "literaturereference": "CROTTY EE, LEARY SES, GEYER JR, OLSON JM, MILLARD NE, SATO AA, ET AL.. CHILDREN WITH DIPG AND HIGH?GRADE GLIOMA TREATED WITH TEMOZOLOMIDE, IRINOTECAN, AND BEVACIZUMAB: THE SEATTLE CHILDREN^S HOSPITAL EXPERIENCE. 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null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." }, { "actiondrug": null, "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "BRAIN STEM GLIOMA", "drugintervaldosagedefinition": null, 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"drugstartdateformat": null, "drugstructuredosagenumb": "10", "drugstructuredosageunit": "007", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "BEVACIZUMAB." } ], "patientagegroup": "3", "patientonsetage": null, "patientonsetageunit": null, "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombocytopenia", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Nausea", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Product administered to patient of inappropriate age", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Vomiting", "reactionmeddraversionpt": "23.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "CROTTY EE, LEARY SES, GEYER JR, OLSON JM, MILLARD NE, SATO AA, ET AL.. CHILDREN WITH DIPG AND HIGH?GRADE GLIOMA TREATED WITH TEMOZOLOMIDE, IRINOTECAN, AND BEVACIZUMAB: THE SEATTLE CHILDREN^S HOSPITAL EXPERIENCE. JOURNAL OF NEURO?ONCOLOGY. 2020", "literaturereference_normalized": "children with dipg and high grade glioma treated with temozolomide irinotecan and bevacizumab the seattle children s hospital experience", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20200704", "receivedate": "20190521", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 16335532, "safetyreportversion": 3, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20201102" } ]

{ "abstract": "Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.", "affiliations": "Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.;Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens' Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy.;Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens' Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy.;Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy.;Dialysis and Transplantation Unit, Pediatric Nephrology, Department of Woman's and Child's Health, University Hospital of Padua, 35128 Padua, Italy.;Medical Genetics Unit, Department of Medical and Surgical Science, S. Orsola-Malpighi Hospital_Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy.;Medical Genetics Unit, DIMEC, University of Bologna, 40138 Bologna, Italy.;\"Lalla Seràgnoli\", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.;Pediatric Radiology Unit, Department of Diagnostic and Preventive Medicine, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy.;Immunology Research Area-Unit of Diagnostic Immunology, Unit of B-cell Pathophysiology, Department of Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy.;Pediatric Unit, Department of Woman, Child and Urologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.;\"Lalla Seràgnoli\", Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy.", "authors": "Bertulli|Cristina|C|;Marzollo|Antonio|A|0000-0003-2177-8500;Doria|Margherita|M|0000-0001-5533-0304;Di Cesare|Silvia|S|0000-0002-9912-7997;La Scola|Claudio|C|0000-0002-2644-7447;Mencarelli|Francesca|F|;Pasini|Andrea|A|;Affinita|Maria Carmen|MC|;Vidal|Enrico|E|0000-0003-3963-0803;Magini|Pamela|P|;Dimartino|Paola|P|;Masetti|Riccardo|R|0000-0002-1264-057X;Greco|Laura|L|0000-0002-3914-8614;Palomba|Patrizia|P|;Conti|Francesca|F|0000-0002-3665-8926;Pession|Andra|A|", "chemical_list": "C000620371:IL7R protein, human; D053699:Interleukin-7 Receptor alpha Subunit; C412482:SMARCAL1 protein, human; D004265:DNA Helicases", "country": "Switzerland", "delete": false, "doi": "10.3390/ijms21228604", "fulltext": "\n==== Front\nInt J Mol Sci\nInt J Mol Sci\nijms\nInternational Journal of Molecular Sciences\n1422-0067 MDPI \n\n33203071\n10.3390/ijms21228604\nijms-21-08604\nArticle\nExpanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells\nBertulli Cristina 1† https://orcid.org/0000-0003-2177-8500Marzollo Antonio 2† https://orcid.org/0000-0001-5533-0304Doria Margherita 3 https://orcid.org/0000-0002-9912-7997Di Cesare Silvia 3 https://orcid.org/0000-0002-2644-7447La Scola Claudio 1 Mencarelli Francesca 1 Pasini Andrea 1 Affinita Maria Carmen 2 https://orcid.org/0000-0003-3963-0803Vidal Enrico 4 Magini Pamela 5 Dimartino Paola 6 https://orcid.org/0000-0002-1264-057XMasetti Riccardo 7 https://orcid.org/0000-0002-3914-8614Greco Laura 8 Palomba Patrizia 9 https://orcid.org/0000-0002-3665-8926Conti Francesca 10*‡ Pession Andrea 710‡ 1 Nephrology and Dialysis Unit, Department of Pediatrics, S. Orsola-Malpighi Hospital Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy; [email protected] (C.B.); [email protected] (C.L.S.); [email protected] (F.M.); [email protected] (A.P.)\n2 Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, 35128 Padua, Italy; [email protected] (A.M.); [email protected] (M.C.A.)\n3 Unit of Primary Immunodeficiency, Academic Department of Pediatrics (DPUO), Bambino Gesù Childrens’ Hospital-Scientific Institute for Research and Healthcare (IRCCS), 00165 Rome, Italy; [email protected] (M.D.); [email protected] (S.D.C.)\n4 Dialysis and Transplantation Unit, Pediatric Nephrology, Department of Woman’s and Child’s Health, University Hospital of Padua, 35128 Padua, Italy; [email protected]\n5 Medical Genetics Unit, Department of Medical and Surgical Science, S. Orsola-Malpighi Hospital_Scientific Institute for Research and Healthcare (IRCCS), 40138 Bologna, Italy; [email protected]\n6 Medical Genetics Unit, DIMEC, University of Bologna, 40138 Bologna, Italy; [email protected]\n7 “Lalla Seràgnoli”, Hematology-Oncology Unit, Department of Pediatrics, University of Bologna, 40138 Bologna, Italy; [email protected] (R.M.); [email protected] (A.P.)\n8 Pediatric Radiology Unit, Department of Diagnostic and Preventive Medicine, S. Orsola-Malpighi Hospital, 40138 Bologna, Italy; [email protected]\n9 Immunology Research Area—Unit of Diagnostic Immunology, Unit of B-cell Pathophysiology, Department of Laboratories, IRCCS Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy; [email protected]\n10 Pediatric Unit, Department of Woman, Child and Urologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy\n* Correspondence: [email protected] or [email protected]; Tel.: +39-(51)-2144666† These authors contributed equally to the manuscript.\n\n‡ These authors contributed equally to the manuscript.\n\n\n15 11 2020 \n11 2020 \n21 22 860423 9 2020 11 11 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype–genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD—both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.\n\ncongenitalhereditaryneonatal diseases and abnormalitiesconsanguinityDNA methylationimmune system diseases\n==== Body\n1. Introduction\nSchimke immuno-osseous dysplasia (SIOD) (OMIM 242900) is a rare autosomal recessive multisystemic disorder characterized by spondyloepiphyseal dysplasia, growth retardation, renal impairment, and T-cell dysfunction [1,2,3]. Cerebrovascular events, premature atherosclerosis, hypothyroidism, ectodermal abnormalities such as altered tooth development have been described. Patients with SIOD are at increased risk of developing cancer, mainly osteosarcoma, undifferentiated carcinoma, and non-Hodgkin lymphoma [4,5,6,7,8,9]. Early death is common and is mainly related to opportunistic infection or end-stage renal disease.\n\nSchimke immuno-osseous dysplasia is caused by biallelic variants in SMARCAL1, encoding the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A-like protein-1 (SMARCAL-1) from the SWI2/SNF2 family of ATP-dependent chromatin remodeling proteins [10,11,12]. Disease severity inversely correlates with residual SMARCAL1 activity—mild and severe forms of SIOD are associated with missense and predicted loss-of-function (LOF) variants (nonsense, frameshift, or splicing), respectively [13]. SMARCAL1 plays an important role in DNA stabilization and its deficiency leads to the impairment of cellular function due to the accumulation of DNA damage, resulting in a progressive systemic disease. It is still not clear how functional impairment of SMARCAL1 causes such a specific SIOD phenotype represented by alterations in the bones, kidney, and immune system, however it has been shown that proteins encoded by SMARCAL1 orthologs buffer fluctuations in gene expression and that alterations in gene expression contribute to SIOD manifestations [14,15,16]. Cell-mediated immune defects have been partially explained by the lack of IL7Rα expression and IL-7 responsiveness due to hypermethylation of the IL7R promoter in SIOD T cells thus representing a hallmark of T-cell immunodeficiency in SIOD [17].\n\nWe describe two brothers born from consanguineous Moroccan parents, with different clinical courses of SIOD, due to the same homozygous c.1682G>A (p.Arg561His) variant in SMARCAL1.\n\n2. Results\n2.1. Clinical Report\n2.1.1. Patient 1 (P1)\nThe index case was born from consanguineous Moroccan parents (first cousins) at 32 weeks of gestation with a weight and length below the 3rd centile and with a prenatal diagnosis of multiple malformations, including a single umbilical artery, duplication of the choroid plexuses with mild lateral ventriculomegaly, a hypoplastic corpus callosum and cerebellar vermis, cardiovascular anomalies, abdominal calcifications, hyperechogenic bowel, and rocker-bottom feet. After birth liver calcifications, a right ectopic kidney, an atrial septal defect type II, and asymmetric ventriculomegaly were found. Persistent leukopenia and lymphopenia led to the diagnosis of combined immunodeficiency (CID) and the introduction of cotrimoxazole prophylaxis. After birth a right-sided hemiparesis was noted. Cerebral MRI performed at 4 months showed a malacic area located at the lentiform nucleus and external left capsule, with dilatation of the subarachnoid spaces of the insula and left lateral ventricle, consistent with a previous cerebral ischemic event. The exam was repeated 2 years later showing the same alterations (Figure 1).\n\nDuring infancy he suffered from several upper respiratory tract infections and one episode of intestinal amebiasis caused by Entamoeba histolytica. Severe episodes of migraine-like headaches were reported and psychomotor and growth retardation was observed. At the age of four, he attended kindergarten with school support, he had not attained sphincter control and language skills were almost absent; on clinical examination, he presented growth retardation (weight and height below the 3rd centile) and some dysmorphic features—microcephaly, sparse eyebrows, epicanthus, telecanthus, wide nasal root, blue sclerae, prominent metopic, and protruding ears with a thin helix. At the age of five, he presented with steroid-resistant nephrotic syndrome which progressed to chronic kidney disease and was managed with conservative treatment. Detection of hypogammaglobulinemia led to the initiation of intravenous immunoglobulin (IVIg) replacement therapy. The clinical features of the patient associated with the typical skeletal abnormalities (left convex thoracic scoliosis, abnormal femoral heads, and dismorphic vertebrae), led to the suspicion of Schimke immuno-osseous dysplasia (SIOD) (Table 1).\n\n2.1.2. Patient 2 (P2)\nThe younger brother, carrying the same homozygous variant in SMARCAL1, was born at 31 weeks of gestation, with a prenatal diagnosis of intrauterine growth restriction, multicystic left kidney, and a neoformation on the right kidney. Furthermore, hyperpigmented macules on the right arm were reported at birth and oral levothyroxine was started for congenital hypothyroidism. Leukopenia and persistent lymphopenia were detected with an immunological phenotype consistent with a diagnosis of combined immunodeficiency (CID). Moreover, ecochardiography revealed an interatrial defect with pulmonary stenosis. An abdominal MRI scan confirmed the presence of a multicystic left kidney (MCDK) and a mass on the right kidney which was hard to distinguish from the overall kidney parenchyma (Figure 2).\n\nOpen surgical biopsy of the lesion was consistent with classical-type congenital mesoblastic nephroma (CMN). Molecular detection of the ETV6-NTRK3 gene fusion was negative, thus excluding a possible congenital cause of the tumors. The right renal mass associated with the left MCDK caused progressive chronic kidney disease (maximum sCr 2.09 mg/dL) with the presence of residual diuresis. Given the patient’s low body weight, the residual renal function maintained only on a small portion of functional right kidney (not infiltrated by the tumor) and the benign nature of the CMN, warranted a ‘wait-and-see’ approach. Five months later, the nephroma had increased in size to 11 cm causing respiratory distress and reduced oral tolerance with failure to thrive. Chemotherapy with vincristine was started (0.05 mg/kg/dose weekly for 6 weeks), with the aim of reducing the CMN in order to perform nephron-sparing surgery. The treatment successfully reduced the tumor volume to 4.5 cm, but unacceptable toxicity (prolonged grade 4 neutropenia and repeated sepsis), associated with severe psychomotor delay and growth retardation, led to treatment interruption. Therefore, an attempt of surgical removal of the mass was attempted which resulted in a partial debulking only and the patient developed end-stage kidney disease requiring kidney replacement therapy. Unfortunately, the tumor progressed a month later. Thus, vincristine treatment was resumed and 9 weekly doses were administered during the period in which the patient was being treated with IVIg, antifungal mold-active and antiviral prophylaxis. The treatment was well-tolerated, however the tumor continued to expand and infiltrate contiguous structures. Palliative treatment was administered until death at 15 months of age.\n\n2.2. WES Findings\nWES analysis was performed on P1. A mean coverage of 145X was obtained and 98.3% of bases were covered >20X. Two homozygous variants survived the prioritization process (Table 2), but only the p.Arg561His in SMARCAL1 emerged as the most prominent candidate, with a CADD score of 32 and affecting a disease gene causing a clinical condition similar to that presented by the two siblings, Schimke immunoosseous dysplasia (MIM 242900). The homozygous SMARCAL1 variant was also present in P2 and both parents were heterozygous carriers (Figure 3).\n\nThis missense change, mapping in a run of homozygosity (ROH) of about 5 Mb, involved a highly-conserved residue; it was classified as likely pathogenic by Varsome (https://varsome.com/), according to the American College of Medical Genetics (ACMG) guidelines [18], and it had been previously reported in two patients with clinically-diagnosed Schimke immuno-osseous dysplasia (SIOD), in a compound heterozygous state with another variant (c.3G>A, p.Met1Ile) in one case [19] and in a homozygous state in the other one [20,21] (Table 1).\n\n2.3. P1 and P2 Showed a Combined Immunodeficiency Phenotype\nImmunophenotyping of the peripheral blood mononuclear cells (PBMCs) revealed that both patients had significant T-cell lymphopenia characterized by low naïve CD4+ T-cell (CD4+CD45RA+) and CD8+ T-cell (CD8+CD45RA+) counts (Table 3). The frequencies of B cells (CD19+) and NK cells (CD3-CD56+CD16+) were close to those of age-matched controls. P1 and P2 B phenotype showed normal subset distribution compared to age-matched values except for an increased percentage of transitional B cells (CD38++IgM++). After stimulation with CpG oligonucleotide in vitro, B cell proliferation was reduced (Figure 4A) and differentiation into plasmablasts was abolished (Figure 4B). Accordingly, no immunoglobulin production was found in the supernatant (Figure 4C).\n\nThe immunoglobulin levels in both patients’ sera showed a reduction of IgG with normal levels of IgA and IgM. IL-7Rα (CD127) expression on P1 T lymphocytes was severely reduced on total CD3+ and CD4+ cells and almost absent on CD8+ T cells, while the mother’s CD4+ and CD8+ T lymphocytes showed only a slightly decreased CD127 expression (Figure 5).\n\nThe NK-cell compartment was further analyzed in P1 showing a strong expansion of the CD56bright NK-cell subset [45.2% vs. 13.6% (12.9, 15.6), median % (interquartile range, IQR) of Healthy Donors (HDs)], at the expense of CD56dim cells (46.0% vs. median 65.8% (60.0, 69.2) of HDs) (Figure 6A,B). The majority of CD56bright cells in the SIOD patient did not express CD16 and had an immature phenotype, with an overall expansion of CD56brightCD16−NKG2A+NKG2C−CD57− cells (29.7% vs. 13.7% (12.8, 16.2) of HDs; Figure 6C), which has been previously described in children with X-linked severe combined immunodeficiency (X-SCID) [25]. A further analysis of the NK-cell phenotype showed that the patient presented a normal pattern of expression of the NKG2A and KIR inhibitory receptors and DNAM-1 and NKG2D activating receptors (Figure 6D shows comparison with a representative HD). On the other hand, the intracellular levels of perforin, which is highly expressed by virtually all CD56dim cells in HDs, were reduced by 3-fold in the patient’s CD56dim cells (Figure 6E). Moreover, we found that IL-7Rα (CD127) expression, which is typically restricted to the CD56bright subset within NK cells, was present on the patient’s CD56bright cells albeit reduced by 4-fold (Figure 6E). Next, we analyzed the cytotoxicity of the patient’s NK cells against K562 cell targets by measuring the expression of the CD107a degranulation marker. Figure 6F shows that the cytotoxic activity of the patient’s NK cells was strongly reduced when compared with cells of HDs.\n\n3. Discussion\nWe describe two brothers with SIOD carrying the same missense homozygous variant in SMARCAL1, with different clinical manifestations and degrees of severity. P1 presented with growth retardation, stroke, skeletal anomalies, developmental delay (especially language), cardiac and renal malformation and immunodeficiency since birth and he developed severe nephrotic syndrome at 5 years of age. Despite the presence of a combined immunodeficiency, he did not experience any severe infections. P2 presented with MCDK, a clinically-aggressive classical type CMN, growth retardation, hypothyroidism, and combined immunodeficiency. Even though an unclear genotype–phenotype correlation was previously supposed, suggesting milder effects for missense variants and severe consequences for LOF molecular events, the observation of intra- and inter-familial clinical variability revealed that disease severity or outcome cannot be predicted by SMARCAL1 genotype [2,26,27]. Nonetheless, the available literature suggests that missense variants seem to allow for some residual SMARCAL1 function, causing a mild SIOD phenotype, while nonsense, frameshift or splicing variants consistent with a loss-of-function (LOF) mechanism cause the more severe form [2,26]. Both siblings developed a severe SIOD phenotype (onset of disease symptoms in the first year of life, growth failure, nephropathy, abnormal thyroid function, severe infections, and cerebrovascular symptoms). In addition to the well-known SIOD signs and symptoms, they had atypical clinical features, including congenital right ectopic kidney in P1 and MCDK affecting the left kidney associated with nephroma in P2 as well as an atrial septal defect and cerebral anomalies (ventriculomegaly and hypoplasia of the corpus callosum) in P1 and interatrial defect and pulmonary stenosis in P2. Within the spectrum of congenital anomalies of the kidneys and of the urinary tract (CAKUT), ectopic kidney and MCDK have never been reported as a manifestation of SIOD to date. The homozygous p.Arg561His variant has already been described in a patient with early-onset SIOD, who developed non-Hodgkin lymphoma [28]. In this previous study, the SIOD patient, despite immunodeficiency, did not experience recurrent infections or ischemic events, supporting a milder phenotype compared to the siblings presented herein. Moreover, no congenital kidney, heart, or brain anomalies were observed in that patient. A similar mild form of SIOD was described in a patient with a different homozygous change at the same residue (p.Arg561Cys). Severe clinical manifestations were reported in a boy carrying the p.Arg561His variant in the compound heterozygous state with the c.3G>A (p.Met1Ile) change, causing a start loss and generating a predicted truncated protein missing the nuclear location signal [20]. Clinical features of SIOD patients with variants involving the Arg561 residue are summarized in Table 1. The Arg561 residue lies within the helicase ATP-binding domain (amino acids 445–600, Uniprot database, https://www.uniprot.org/) and its substitution with a histidine could interfere with DNA binding and/or ATP hydrolyzation, potentially leading to a LOF effect. All these findings indicate that variants of Arg561 residue are likely responsible for SIOD with variable severity, depending on the resulting amino acid, on the type of alteration on the other allele, and on the individual genomic background. We searched for additional WES pathogenic variants contributing to the complex phenotype of P1, especially to extra-SIOD features. No homozygous variants in disease genes, except the SMARCAL1 variant, were known or predicted to be pathogenic or were previously associated with congenital kidney and heart defects. The evaluation of heterozygous variants excluded the co-occurrence of dominant or recessive (through compound heterozygosity) genetic diseases modifying the typical SIOD phenotype. Unfortunately, the impossibility of extending WES analysis to P2 due to technical issues, prevented us from investigating additional genetic variants underlying his atypical manifestations, especially the congenital mesoblastic nephroma. CMN is a rare tumor in children representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically–classical, cellular, and mixed. Treatment consists of nephrectomy or nephron-sparing surgery at birth. Preoperative chemotherapy with actinomycin and vincristin can be administered [29]. Biological target therapy can be considered in the presence of ETV6-NTRK3 gene fusions [30]. Even though malignancies are reported in SIOD patients, nephroma has never been observed. In a review of 71 patients, two developed Epstein–Barr virus (EBV)-positive, non-Hodgkin lymphoma, one EBV-negative non-Hodgkin lymphoma, and one osteosarcoma [14]; a case of undifferentiated carcinoma has also been reported [5]. Literature regarding the relationship between SMARCAL1 and neoplasia is poor. EBV-driven lymphomas can be attributed to immunodeficiency, but other malignancies reported in SIOD patients are less clearly associated with immune system disorders. SIOD is not currently considered a cancer predisposition syndrome and the incidence of malignancy in these patients is not well described, due to the limited number of cases and short life expectancy. However, members of the SWI/SNF2 family of ATPases are frequently mutated in human cancer, behaving as tumor suppressors, and the function of SMARCAL1 in DNA transcription, replication, and repair could play a role in the development of malignancy if the gene is mutated [31].\n\nRegardless of a possible pathogenetic link, in the study, we describe the first classical-type mesoblastic nephroma in a patient with SIOD (P2) with implications for cancer treatment. In our patient, the tumor showed an unusually aggressive course with transient response to chemotherapy and failure of surgical treatment. It is well known that patients with SIOD are hypersensitive to DNA-damaging agents, so chemotherapy should be administered with caution, and even in the case of a transplant (kidney or bone marrow) a reduced-intensity conditioning must be adopted [14]. Both patients showed a combined immunodeficiency as proven by a profound lymphopenia, a lack of thymic output, and defective IL7Rα expression on lymphocytes. These results are consistent with data already reported in the literature [17]. We also show that B cells have a reduced ability to proliferate and differentiate into plasmablasts in vitro resulting in a lack of immunoglobulin in the supernatant (Figure 4). As IL7 is not necessary for the development of B cells and their response to CpG [32] impaired epigenetic remodeling may explain the altered B cell function [33]. Furthermore, we have characterized the NK-cell compartment of a SIOD patient for the first time, highlighting phenotypic and functional abnormalities. In particular, P1 presented a relative increment of the CD56bright cell subset at the expense of CD56dim cells. In addition, the patient’s NK cells displayed a normal phenotype with the exception of a strong down-modulation of IL-7Rα on CD56bright cells and intracellular perforin in CD56dim cells. In a healthy condition, the highly cytotoxic CD56dim cells represent the vast majority of peripheral NK cells, whereas CD56bright consist in a small percentage of NK cells that are considered to be immature precursors of CD56dim cells, but yet can release large amounts of cytokines and exert immunoregulatory functions (e.g., killing of activated immune cells) [34]. The significance of the increased CD56bright cell frequency that is found in various pathologic settings such as chronic viral infection, cancer, and autoimmunity, is not clear, as yet, and a potential immunosuppressive role has been suggested [26,35]. One possible leading mechanism for accumulation of CD56bright cells is a decreased rate differentiation towards mature CD56dim cells, hence it is possible that the SMARCAL-1 mutation in P1 had a negative impact on NK cell development, although not as dramatic as for T cells. Of note, IL-7Rα expression in our patient was nearly absent on T cells, a previously-reported hallmark of SIOD patients that may restrict T-cell development [17], while it was present, albeit reduced, on CD56bright NK cells. This suggests that the mechanisms controlling IL-7Rα expression are distinct in T and NK cells and that residual IL-7 signalling in the patient’s CD56bright cells is sufficient for their homeostasis. Importantly, IL-7Rα down-modulation on CD56bright NK cells occurring in chronic Hepatitis C Virus (HCV) and HIV infection has been shown to impair IL-7-dependent NK-cell activation and effector functions [36], a phenomenon that deserves to be investigated in SIOD patients as well. Finally, we found an overall impairment of NK cell cytotoxicity, possibly due to the reduced frequency and low perforin content of CD56dim cells, which contribute to the immunological dysfunction and increased risk of developing tumors or severe infections in the SIOD patient.\n\nTaken together these results led us to consider these patients as leaky-SCID and thus evaluable for hematopoietic stem cell transplantation as a therapeutic option to treat the immunodeficiency. In the literature few cases have been reported with poor outcomes for this procedure. Only one affected individual has been successfully treated with bone marrow transplantation (BMT) [14,37] thus this procedure should be considered for the severe phenotype only. Factors described as a possible cause for a poor outcome were a debilitated state of the patient and the potential role of SMARCAL1 in cell hypersensitivity to genotoxic agents. However, the low number of bone marrow transplants and the heterogeneity of the patients’ genotypes and phenotype as well as the diversity of the procedures do not shed light on any specific predictors of outcome. Our knowledge about SIOD is still limited and, considering the rarity of the disease, multicentric studies are necessary in order to identify the best management of these patients.\n\n4. Materials and Methods\n4.1. Subjects and Families/Collection of Samples and Informed Consent \nThe parents of the two siblings with SIOD gave written informed consent for the clinical evaluations and genetic analyses, in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The clinical data for the patients were obtained from questionnaires completed by the attending physician as well as from medical records. Ethics Committee approval was obtained along with written informed consent for data collection (protocol n. 138/2017/U/Tess approved date: 12 December 2017).\n\n4.2. Whole Exome Sequencing/Sanger Sequencing\nGenomic DNA purified from whole peripheral blood samples of P1 was enriched for whole exome sequences through the Roche SeqCap EZ MedExome Kit and sequenced as 100 bp paired-end reads on the Illumina NextSeq 500 system. Quality check for the generated reads was performed with FastQC (http://www.bioinformatics.babraham.ac.uk/ publications.html). Reads were aligned with Burrows-Wheeler Aligner (BWA) to the University of California Santa Cruz (UCSC) reference genome, hg19. Local realignment and base quality score recalibration was performed with Genome Analysis ToolKit (GATK) and duplicate removal with PicardTools (http://picartools.sourceforge.net). SAMtools and GATK were used to collect alignment statistics. Variants passing quality filters were annotated against Ensembl (http://www.ensembl.org/). Since the pedigree suggested a likely recessive disease (two affected siblings born from consanguineous healthy parents), we focused on biallelic, especially homozygous variants. Runs of homozygosity (ROHs) were detected from WES data through the H3M2 algorithm [38].\n\nNovel or very rare homozygous variants (MAF < 0.001) within ROHs > 1.5 Mb were considered for further analyses when they caused predicted loss-of-function alterations or when PhyloP and pathogenicity prediction scores indicated conserved nucleotides and probably damaging affected amino acids for missense changes. The same filtering parameters (frequency, conservation, and functional-prediction scores) were used to identify candidate heterozygous variants potentially contributing to atypical clinical manifestations through a dominant or a recessive (compound heterozygosity) mechanism.\n\nThe quality and amount of the available DNA sample of P2 were not adequate for WES analysis.\n\nSanger sequencing was performed to validate filtered variants and to verify segregation in the healthy parents and affected brother (P2).\n\n4.3. Flow Cytometry Analysis\n4.3.1. Immunophenotype and IL7Ra Membrane Expression\nAfter red blood cell lysis with ammonium chloride of peripheral blood samples, lymphocytes were surface stained for T and B cell analysis. The following previously-titrated monoclonal antibodies were employed to surface stain the lymphocytes: CD3 PerCP (clone BW264/56, Miltenyi Biotec, Bergisch Gladbach, Germany), CD4 APC (clone OKT4, Becton Dickinson, Franklin Lakes, NJ, USA), CD8 PE-Cy7 (clone RPA-T8, Becton Dickinson, USA), TCR alpha-beta APC (clone T10B9, Becton Dickinson), TCR gamma-delta FITC (11F3, Miltenyi Biotec, DE), CD45RA APC-H7 (clone T6D11, Miltenyi Biotec, DE), CCR7 PE (clone 3D12, Ebioscience, San Diego, CA, USA), CD127 PE-CY7 (clone eBioRDR5, eBiosciences), CD16 PE (clone 3G8), CD56 PE (clone NCAM16.2), CD19 PE-CY7 (clone SJ25C1, Becton Dickinson), CD27 FITC (clone M-T271, Becton Dickinson). \n\nNK cell studies were performed on cryopreserved lymphocytes previously isolated through Ficoll density gradient and stained with NKG2A(CD159a) FITC (clone REA110, Miltenyi Biotec), NKG2C (CD159c) PE (clone REA205, Miltenyi Biotec); NKG2D(CD314) PE (clone 1D11, eBioscience), CD3 APC (clone UCHT1, eBioscience), CD16/APC-eFluor780 (clone CB16, eBioscience), CD57/PECy7 (clone TB01, eBioscience); CD3/AlexaFluor700 (clone UCHT1, Becton Dickinson), CD56/PerCpCy5.5 (clone B159, Becton Dickinson), CD16/BV510 (clone 3G8, Becton Dickinson), Perforin/BV421 (clone delta g9, Becton Dickinson), conjugated mouse IgG for isotype control staining (BD Pharmingen); CD56/PerCp (MEM-188) from Thermo Fisher Scientific (Waltham, MA, USA); CD107a/FITC (H4A3), DNAM-1(CD226)/FITC (11A8), NKp46/PE-Cy7 (9E2), KIR2DL1/S1/S3/S5/APC (HP-MA4), and KIR2DL2/L3/S2/APC (DX27) from Biolegend (San Diego, CA, USA). Cells were incubated with the appropriate antibody cocktail for 30 min at 4 °C, washed with PBS and suspended in PBS. For intracellular perforin staining, cells were reacted with FOXP3 Fix/Perm Buffer Set (Biolegend, USA) as recommended by the manufacturer. At least 50,000 events in the lymphocyte live gate were acquired on a FACSCANTO II (BD Biosciences, San Diego, CA, USA) or Cytoflex (Beckman Coulter, Brea, CA, USA) and analyzed with FlowJo (Tree Star Inc, version 9.3.2, Ashland, OR, USA) or Kaluza (Beckman Coulter, Brea, CA, USA) software.\n\n4.3.2. NK-cell Degranulation Assay\nA flow cytometry-based cytotoxicity assay was performed using the patient’s PBMCs as effectors (E) and K562 cells as targets (T) at an E:T ratio of 10:1 and measuring the frequency of CD107a+ cells within gated NK cells, as previously described [19].\n\n4.4. Cell Preparation and B Cell Proliferation Assay\nPBMCs were isolated by Ficoll PaqueTM Plus (Amersham Pharmacia Biotech) density-gradient centrifugation. Lymphocytes were washed in PBS (1×) and before stimulation, peripheral blood mononuclear cells were labelled with Carboxyfluorescein succinimidyl ester (CFSE, Invitrogen) at a final concentration of 0.1 µg/mL (ThermoFisher Scientific) and cultured at 5 × 105 cells per well in 96-well plates in complete Roswell Park Memorial Institute medium (RPMI) 1640 (Euroclone) supplemented with 10% FBS (Hyclone Laboratories, Logan, UT, USA) in the presence or absence of 2.5 µg/mL of CpG oligodeoxynucleotide (ODN 2006, Hycult Biotechnology, Uden, The Netherlands). Cell proliferation was measured on day 7 by flow cytometry.\n\n4.4.1. Flow Cytometric Analysis\nTo evaluate the proliferation and differentiation of B cells after stimulation with CpG, cells were stained with the appropriate combination of fluorochrome-conjugated Abs to identify B cell subsets: CD19 BB700 (clone SJ25C1 Becton Dickinson), CD27 PE (clone M-T271 Becton Dickinson), CD38 BV421 (clone HIT2, Becton Dickinson), and IgM Alexafluor647 (conjugated Affinipure F(ab’)2, Jackson ImmunoResearch Laboratories, West Grove, PA, USA). Dead cells were excluded from analysis by side/forward scatter gating. All analyses were performed on a LSRFortessaX-20 (Becton Dickinson, San Jose, CA, USA) interfaced to a FACSDiva software (BD Biosciences, San Jose, CA, USA). Fifty thousand gated events on living cells were analyzed, whenever possible, for each sample.\n\n4.4.2. ELISA Immunoassay for IgM, IgA, and IgG\nELISA immunoassay was employed to quantify plasma Igs and secreted Igs after stimulation with CpG. 96-well plates (Corning) were coated overnight with purified anti-human IgA, IgG, and IgM (Jackson ImmunoResearch Laboratories, PA, USA). Plates were washed with PBS/0.1% Tween and blocked with PBS/1% gelatin. Subsequently, two incubation steps for 1 h at 37 °C, first with culture supernatants and second with peroxidase-conjugated goat anti-human IgA, IgG, or IgM Abs (Jackons ImmunoResearch Laboratories, PA, USA) were performed. The chromogene substrate employed to developed the assay was o-phenylen-diamine solution (Sigma-Aldrich, St. Louis, MO, USA). Measurement of the absorbance at 450 nm and calculation of Ig concentrations by interpolation from the standard curve were performed lastly.\n\nAcknowledgments\nWe thank for their valuable contribution to this work Simona Ferrari, Giovanni Innella, Fraia Melchionda, Arcangelo Prete, Caterina Cancrini, Simona Cascioli, Rita Carsetti and Alexandra Teff.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor Contributions\nC.B. and A.M. conceptualized the article, participated in the visualization and prepared the original draft. M.D., S.D.C., P.P. participated in the investigation, performed the immunological experiments and the formal analysis of the article. C.L.S., F.M., M.C.A., E.V., R.M., F.M., and L.G. participated in data curation and resources. A.P. (Andrea Pasini) and A.P. (Andra Pession) participated in the validation of the article. P.M., and P.D. participated in the investigation and performed the genetic analysis and the formal analysis of the article. F.C. and A.P. (Andra Pession) participated in the project administration, supervised the work, and reviewed and edited the article. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research was funded by Fondazione Città della Speranza ONLUS (http://cittadellasperanza.org/, to AM), “Fondazione del Monte”, grant for the identification of genetic causes of congenital malformations and intrauterine fetal demise through whole exome sequencing (ID ROL: FDM/6360, to MS), and by the Italian Ministry of Health, Ricerca Corrente from Bambino Gesù Childrens’ Hospital, Rome, Italy to MD.\n\nConflicts of Interest\nThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nFigure 1 Cerebral MRI of Patient 1 (P1, index case). (A) Malacic area located at the lentiform nucleus and external left capsule and dilatation of the subaracnoid spaces of the insula and (B) Dilatation of the left lateral ventricle and T2-weighted hypointense lesion compatible with hemoglobin degradation.\n\nFigure 2 Computerized tomography (CT) urogramof Patient 2 (P2) (performed after vincristine therapy and before surgery). (A) Mesoblastic nephroma located in the right kidney (arrow), (B) contrast-enhanced portion of the functioning right kidney located in the superior pole of the nephroma (arrow) without a cleavage plane, and (C) multicystic left kidney (arrow).\n\nFigure 3 Pedigree and family segregation of SMARCAL1 variant (c.1682G>A; p.Arg561His).\n\nFigure 4 Stimulation with CpG. (A) The histograms represent B cell proliferation in a healthy control and P1. B cells were loaded with CFSE dye. The intensity of fluorescence decreased with cell division. The numbers indicate the percentage of B cells that had proliferated. (B) CD27 and IgM expression is determined in P1 and in a healthy donor with or without the addition of CpG (untreated, UNT). Different B cell populations can be recognized—CD27- mature/naive B cells, IgM+CD27+ memory B cells, IgM-CD27+ switched-memory B cells, and CD27bright plasmablasts (either IgM+ or IgM−, arrows). Percentages of these subpopulations in the CD19+ B cells gate are indicated. Black arrows indicate plasmablasts. (C) IgM (white columns), IgA (grey columns), and IgG (black) concentration (µg/mL) in the supernatants after 7 days of stimulation with CpG in a healthy control and in P1.\n\nFigure 5 IL7Rα (CD127) surface expression on T-cell subsets from a healthy donor, P1, and the patient’s mother. (A) Grey histogram plots represent signals from isotype control staining. Note that total CD3+, total CD4+, and total CD8+ uniformly express reduced IL7Rα in P1 and are slightly reduced in the mother. (B,C) IL7Rα (CD127) surface expression of T-cell subsets of a healthy donor, the mother, and P1. Grey histogram plots represent signals from isotype control staining. Note that total CD4+, naive CD4+ cells (CD4+CD27+CD45RA+), central memory CD4+ cells (CD4+CD27+CD45RA and effector memory (CD4+CD45RA-CD27-) uniformly express reduced IL7Rα in P1 and are slightly reduced in the mother. (C) Note that total CD8+, naive CD8+ cells (CD8+CCR7+CD45RA+), central memory CD8+ cells (CD8+-CCR7+CD45RA−), effector memory (CD8+-CCR7-CD45RA−) and terminal effector memory CD45RA+ (CD8+-CCR7-CD45RA+) uniformly express severely-reduced IL7Rα in P1 and are slightly reduced in the mother. Grey numbers represent mean fluorescence intensities (MFI) of the isotype control staining and black numbers represent mean fluorescence intensities of the specific CD127 staining on the different T cell subsets.\n\nFigure 6 Phenotypic and functional alterations of NK cells in the P1 SIOD patient. (A–C) peripheral blood mononuclear cells (PBMCs) of P1 and of age-matched healthy donors (HDs) were analyzed by flow cytometry to measure the frequency of NK-cell subsets, the phenotype of gated CD56bright and CD56dim NK cells (D,E), and the NK-cell cytotoxicity (F). (A) The gating strategy used to identify CD56bright, CD56dim, and CD56neg NK cell subsets is shown for a representative HD and the SIOD patient, (B) Median and range of CD56bright and CD56dim cell frequencies among NK cells of the patient and four HDs is shown; (C) Median and range of CD56bright cell percentage with a CD16-NKG2A+ NKG2C- CD57- immature phenotype among NK cells of P1 and three HDs is depicted, (D) Filled black histograms show the cell surface expression of NKG2A, KIR (KIRmix: KIR2DL1/S1/S3/S5 and KIR2DL2/L3/S2), DNAM-1, NKG2D, and CD127 as well as intracellular perforin expression of gated CD56bright and CD56dim NK cells of P1 and a representative HD. Filled gray histograms represents staining with isotype control IgG. The mean fluorescence intensity (MFI) values for both NK marker labeling (black) and control IgG (gray), as well as the percentage of positive cells are indicated, (E) The values of perforin MFI (left) and CD127 MFI (right) divided by their control IgG MFI values (ratio) measured on CD56bright and CD56dim cells as shown in (D) are reported, (F) Bar plots represent pattern of CD107a expression measured by flow cytometry on gated NK cells of the patient and age-matched (n = 2, circles) and adult (n = 7, triangles) HDs following 6-h culture of PBMCs with and without (not stimulated, ns) K562 cell targets. The mean ± SD is reported.\n\nijms-21-08604-t001_Table 1Table 1 Comparison of clinical features among the two siblings and previously-published cases with at least one mutation involving the same SMARCAL1 residue (p.Arg561).\n\nClinical and Genetic Features\tP1\n(6 Years)\tP2\n(18 Months)\tBasiratnia 2011 \n(8 Years)\tYue 2010 (8 Years)\tBökenkamp 2005 \n(12 Years)\t\n\n\tSMARCAL1 genotype\t\np.Arg561His/\n\n\np.Arg561His\n\t\np.Arg561His/\n\n\np.Arg561His\n\t\np.Arg561His/\n\n\np.Arg561His\n\t\np.Arg561His/\n\n\np.Met1Ile\n\t\np.Arg561Cys/\n\n\np.Arg561Cys\n\t\nClinical features\t\n\t\nGrowth\tIUGR\t+\t+\tNR\t+\t−\t\nShort stature \t+\t+\t+\t+\t+\t\nSkeletal features\tShort neck\t+\t+\t+\t+\t+\t\nShort trunk\t+\t+\tNR\t+\t+\t\nThoracic scoliosis\t+\tNR\tNR\t\n\t+ (kyphosis)\t\nLumbar lordosis\t−\t−\tNR\tNR\t+\t\nDysmorphic vertebrae\t+\t−\t+\t+\t+\t\nHypoplastic pelvis\t−\t−\tNR\tNR\tNR\t\nAbnormal femoral heads\t+\t−\t+\tNR\t+\t\nMicrocephaly\t+\t+\tNR\tNR\tNR\t\nOsteopenia\t−\t−\t+\t+\tNR\t\nRenal disease and malformations\tProteinuria or nephropathy\t+\t+\t+\t+\t+\t\nFSGS\t−\t−\tNR\t+\t+\t\nEctopic kidney\t+\t−\tNR\tNR\tNR\t\nMulticystic kidney\t−\t+\tNR\tNR\tNR\t\nHeart defects\tAtrial septal defects\t+\t+\tNR\tNR\tNR\t\nPulmonary valve stenosis\t−\t+\tNR\tNR\tNR\t\nCerebral anomalies\tVentriculomegaly\t+\t−\tNR\tNR\tNR\t\nHypoplasia corpus callosum\t+\t−\tNR\tNR\tNR\t\nPhysical features \tBroad nasal tip\t−\t−\tNR\t+\tNR\t\nWide and depressed nasal bridge\t−\t−\tNR\t+\t+\t\nProtruding abdomen\t−\t+\t+\t+\t+\t\nPigmented macules\t−\t+\tNR\t+\tNR\t\nUnusual hair\t−\t−\tNR\tNR\tNR\t\nMicrodontia\t−\t−\tNR\tNR\tNR\t\nCorneal opacities\t+\t−\tNR\tNR\tNR\t\nDevelopment\tNeuro-developmental delay\t+\t+\tNR\t−\t−\t\nLanguage development delay\t+\t−\tNR\t−\t−\t\nVasculature\tHeadaches\t+\t−\tNR\tNR\t−\t\nTIAs\t−\t−\tNR\tNR\t−\t\nStrokes\t+\t−\tNR\tNR\t−\t\nOther \tHypothyroidism\t−\t+\t+\t−\t−\t\nNon−Hodgkin lymphoma\n\t−\t−\t+\tNR\tNR\t\nRecurrent infections\t+\t+\t−\t+\t−\t\nMesoblastic nephroma\t−\t+\t−\tNR\tNR\t\nExtremity edema\t−\t−\t+\t+\t+ (minimal)\t\nHypertension\t−\t−\t+\tNR\tNR\t\nNR: Not Reported. +: feature present; −: feature absent.\n\nijms-21-08604-t002_Table 2Table 2 Analysis of WES: potentially interesting variants associated with clinical phenotype.\n\nGenomic Position (hg19)\tcDNA/\nProtein Position\tGene\tROH Size (Mb)\tGnomAD Frequency\tPhyloP100way\nVertebrate\tCADD\tDisease\t\nchr2:\tNM_001127207.2:c.1682G>A/ p.Arg561His\t\nSMARCAL1\n\t5.081\t0.00001593\t7.994\t32\tSIOD\t\n217303180\t\nchr11:\tNM_001198810.2:c.1471G>A/\np.Ala491Thr\t\nSLC43A1\n\t14.523\t0.00003184\t7.537\t23.2\t/\t\n57254630\t\nijms-21-08604-t003_Table 3Table 3 Immunological features of patients P1 and P2.\n\n\n\tP1\tP2\t\n\nSex\n\tMale\tMale\t\n\nAge\n\t7 years\tDied (15 months of age)\t\n\nAge at diagnosis\n\t5 years 6 month\t1 year\t\n\nWhite blood cells, 103/μL\n\t3.04\t4.1\t\n\nHemoglobin, g/L\n\t10.5\t7.4\t\n\nPlatelets, 103/μL\n\t305\t49\t\n\nNeutrophils, 103/μL\n\t2.06\t2.92\t\n\nLymphocytes, 103/μL\n\t0.57\t0.55\t\n(1.2–4.7)\t(3.2–12.3)\t\n\nCD3+ (PAN T), % (cells/µL)\n\t64.2% (0.36)\t30% (0.16)\t\n(0.77–4.0)\t(2.4–8.3)\t\n\nCD3+/α+β\n\t86.60%\t75.40%\t\n\nCD3+/γ+σ+\n\t12.70%\t24.6% \t\n\nCD3+CD4-CD8-, %\n\t1.70%\t27%\t\n\nCD4, % (cells/µL)\n\t24.6% (0.14)\t14% (0.16)\t\n(0.4–2.5) \t(1.3–7.1)\t\n\nCD4+CD45 RA+ (naïve), %\n\t2.40%\t17%\t\n(46–99)\t(77–96)\t\n\nCD4+CD45 RA-CCR7+ (central memory), %\n\t55.60%\tND\t\n(0.35–100)\t\n\nCD4+CD45 RA-CCR7- (effector memory), %\n\t39.40%\tND\t\n(0.27–18)\t\n\nCD4+CD45 RA+CCR7- (terminal effector memory), %\n\t2.37%\tND\t\n(0.0031–1.8)\t\n\nCD3+CD4+CD31+CD45 RA+ (recent thymic emigrant) %\n\t2%\tND\t\n(41–81)\t\n\nCD8, % (cells/µL)\n\t26.6% (0.15)\t10% (0.05)\t\n(0.2–1.7)\t(0.4–4.1)\t\n\nCD8+CD45 RA+ (naïve), %\n\t2%\tND\t\n(16–100)\t\n\nCD8+CD45 RA-CCR7+ (central memory), %\n\t1.57%\tND\t\n(1–6)\t\n\nCD8+CD45 RA-CCR7- (effector memory), %\n\t80%\tND\t\n(5–100)\t\n\nCD8+CD45 RA+CCR7- (terminal effector memory), %\n\t16.50%\tND\t\n(15–41)\t\n\nCD56+16+CD3- (NK), % (cells/µL)\n\t15% (0.08)\t26% (0.14)\t\n(0.012–0.34)\t(0.0075–0.33)\t\n\nCD19 (PAN B), % (cells/µL)\n\t18.4% (0.1)\t42% (0.23)\t\n(0.10–0.80)\t(0.11–7.7)\t\n\nCD19+IgD+CD27- (B naïve)\n\t85%\t94%\t\n(47.3–77.0)\t(76.5–94.7)\t\n\nCD19+IgD+CD27+ (B memory)\n\t8.80%\t1%\t\n(5.2–20.4)\t(3.0–10.7)\t\n\nCD19+IgD-CD27+ (switched B memory)\n\t6.16%\t1.8%\t\n(4.7–21.2)\t(1.4–11.9)\t\n\nCD19+CD21+CD38- (B CD21+low)\n\t0.80%\tND\t\n(5.9–25.8)\t\n\nCD19+IgM++CD38++ (B transitional)\n\t18.40%\t30%\t\n(4.6–8.3)\t(3.6–12.7)\t\n\nCD19+IgM-+CD38++ (B plasmablast)\n\t0.10%\t1%\t\n(0.6–5.3)\t(0.4–5.5)\t\n\nIgM\n\t0.10 g/L\t0.56 g/L\t\n(0.03-0.20) \t(0.02–0.18)\t\n\nIgA\n\t0.10 g/L\t0.10 g/L\t\n(0.02–0.20)\t(0.02–0.15)\t\n\nIgG\n\t0.64 g/L *\t1.16 g/L *\t\n(0.52–1.49)\t(0.42-1-1)\t\nFISH, fluorescence in situ hybridization; ND, not done; PHA, phyto hemagglutinin; TCR, T-cell receptor; WBC, white blood cell. 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Successful renal transplantation following prior bone marrow transplantation in pediatric patients Pediatr. Transplant. 2004 8 507 512 10.1111/j.1399-3046.2004.00208.x 15367289 \n38. Magi A. Tattini L. Palombo F. Benelli M. Gialluisi A. Giusti B. Abbate R. Seri M. Gensini G.F. Romeo G. H3M2: Detection of runs of homozygosity from whole-exome sequencing data Bioinformatics 2014 30 2852 2859 10.1093/bioinformatics/btu401 24966365\n\n", "fulltext_license": "CC BY", "issn_linking": "1422-0067", "issue": "21(22)", "journal": "International journal of molecular sciences", "keywords": "DNA methylation; congenital; consanguinity; hereditary; immune system diseases; neonatal diseases and abnormalities", "medline_ta": "Int J Mol Sci", "mesh_terms": "D019943:Amino Acid Substitution; D001161:Arteriosclerosis; D004265:DNA Helicases; D005260:Female; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit; D007668:Kidney; D007694:Killer Cells, Natural; D008297:Male; D020125:Mutation, Missense; D018201:Nephroma, Mesoblastic; D009404:Nephrotic Syndrome; D010009:Osteochondrodysplasias; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism; D014551:Urinary Tract; D000073336:Whole Genome Sequencing", "nlm_unique_id": "101092791", "other_id": null, "pages": null, "pmc": null, "pmid": "33203071", "pubdate": "2020-11-15", "publication_types": "D002363:Case Reports; D016430:Clinical Trial; D016428:Journal Article", "references": "29286563;28400540;11113849;19793861;20179009;28769923;15367289;16419127;23630135;23644491;10857751;23359635;16562781;28124468;21815909;28826739;10653321;18805831;15880370;19796992;22699664;16237566;21914180;28796785;11799392;24966365;25741868;29703886;20533385;22888040;2066860;27859047;26499378;17676601;19278419;4282260;18356746", "title": "Expanding Phenotype of Schimke Immuno-Osseous Dysplasia: Congenital Anomalies of the Kidneys and of the Urinary Tract and Alteration of NK Cells.", "title_normalized": "expanding phenotype of schimke immuno osseous dysplasia congenital anomalies of the kidneys and of the urinary tract and alteration of nk cells" }

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{ "abstract": "We describe a case of acquired monosomy 7 myelodysplastic syndrome (MDS) in a boy with congenital adrenocortical insufficiency, genital anomalies, growth delay, skin hyperpigmentation, and chronic lung disease. Some of his clinical manifestations were suggestive of dyskeratosis congenita (DC), while other features resembled IMAGe association. DC has been linked to mutations in telomere maintenance genes. The genetic basis of IMAGe association is unknown, although mice harboring a mutation in a telomere maintenance gene, Tpp1, have adrenal hypoplasia congenita. We considered the possibility that this patient has a defect in telomere function resulting in features of both DC and IMAGe association.", "affiliations": "Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. [email protected]", "authors": "McDonald|Sharon|S|;Wilson|David B|DB|;Pumbo|Elena|E|;Kulkarni|Shashikant|S|;Mason|Philip J|PJ|;Else|Tobias|T|;Bessler|Monica|M|;Ferkol|Thomas|T|;Shenoy|Shalini|S|", "chemical_list": "C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; C509186:TERT protein, human; D019098:Telomerase; C000717267:TPP1 protein, human", "country": "United States", "delete": false, "doi": "10.1002/pbc.22283", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "54(1)", "journal": "Pediatric blood & cancer", "keywords": null, "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D019871:Dyskeratosis Congenita; D006801:Humans; D008297:Male; D009006:Monosomy; D009154:Mutation; D009190:Myelodysplastic Syndromes; D012880:Skin Pigmentation; D019098:Telomerase; D000091346:Tripeptidyl-Peptidase 1", "nlm_unique_id": "101186624", "other_id": null, "pages": "154-7", "pmc": null, "pmid": "19760774", "pubdate": "2010-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and IMAGe association.", "title_normalized": "acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and image association" }

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ACQUIRED MONOSOMY 7 MYELODYSPLASTIC SYNDROME IN A CHILD WITH CLINICAL FEATURES SUGGESTIVE OF DYSKERATOSIS CONGENITA AND IMAGE ASSOCIATION.. 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"medicinalproduct": "METHOTREXATE." } ], "patientagegroup": null, "patientonsetage": "6", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Lower respiratory tract infection", "reactionmeddraversionpt": "21.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "MCDONALD S, WILSON DB, PUMBO E, KULKARNI S, MASON PJ, ELSE T, ET AL. ACQUIRED MONOSOMY 7 MYELODYSPLASTIC SYNDROME IN A CHILD WITH CLINICAL FEATURES SUGGESTIVE OF DYSKERATOSIS CONGENITA AND IMAGE ASSOCIATION. PEDIATR-BLOOD-CANCER 2010?54(1):154-157.", "literaturereference_normalized": "acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and image association", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180509", "receivedate": "20180509", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14870691, "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": "We present a case report of a 31-year-old female patient who presented to us with a 1 day history of acute bilateral eye pain, blurred vision and headache. She was found to have a myopic shift, raised intraocular pressure (IOP) and shallow anterior chambers in both eyes. She had been commenced on oral topiramate 1 week previously. A number of investigations, including anterior segment optical coherence tomography (AS-OCT) were done and a diagnosis of topiramate induced bilateral acute angle closure (TiAAC) was made. Topiramate was discontinued and she was managed with topical and oral antiglaucoma medications, topical steroids and cyclopegics. Her symptoms subsided dramatically at the next follow-up. The AS-OCT documentation revealed lucidly the improvement in her anterior chamber depth and anterior chamber angle parameters. Her IOP decreased, her myopic shift showed reversal and her AS-OCT findings revealed gross improvement in all the parameters angle opening distance, trabecular iris space area and scleral spur angle. This case report clearly shows with AS OCT documentation the changes which occur in the anterior segment in a case of TiAAC.", "affiliations": "Department of Glaucoma, Aravind-Ziess Centre for Excellence in Glaucoma, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu, India.", "authors": "Mitra|Arijit|A|;Ramakrishnan|R|R|;Kader|Mohideen Abdul|MA|", "chemical_list": "D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose", "country": "India", "delete": false, "doi": "10.4103/0301-4738.129784", "fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Medknow Publications & Media Pvt Ltd India 24881612IJO-62-61910.4103/0301-4738.129784Brief CommunicationsAnterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure Mitra Arijit Ramakrishnan R Kader Mohideen Abdul Department of Glaucoma, Aravind-Ziess Centre for Excellence in Glaucoma, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu, IndiaCorrespondence to: Dr. Arijit Mitra, Aravind-Ziess Centre for Excellence in Glaucoma, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli - 627 001, Tamil Nadu, India. E-mail: [email protected] 2014 62 5 619 622 19 4 2013 25 12 2013 Copyright: © Indian Journal of Ophthalmology2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case report of a 31-year-old female patient who presented to us with a 1 day history of acute bilateral eye pain, blurred vision and headache. She was found to have a myopic shift, raised intraocular pressure (IOP) and shallow anterior chambers in both eyes. She had been commenced on oral topiramate 1 week previously. A number of investigations, including anterior segment optical coherence tomography (AS-OCT) were done and a diagnosis of topiramate induced bilateral acute angle closure (TiAAC) was made. Topiramate was discontinued and she was managed with topical and oral antiglaucoma medications, topical steroids and cyclopegics. Her symptoms subsided dramatically at the next follow-up. The AS-OCT documentation revealed lucidly the improvement in her anterior chamber depth and anterior chamber angle parameters. Her IOP decreased, her myopic shift showed reversal and her AS-OCT findings revealed gross improvement in all the parameters angle opening distance, trabecular iris space area and scleral spur angle. This case report clearly shows with AS OCT documentation the changes which occur in the anterior segment in a case of TiAAC.\n\nAnterior segment optical coherence tomographyangle opening distanceangle recess areamyopic shiftshallow anterior chambertopiramate induced bilateral acute angle closuretrabecular iris space area\n==== Body\nAcute bilateral angle-closure glaucoma and myopia has been reported widely after the use of topiramate and the condition is usually reversible when the drug is discontinued. However, even though there have been case reports of topiramate induced bilateral acute angle closure (TiAAC) in the past, to the best of our knowledge no published Indian case report shows documented anterior segment optical coherence tomography (OCT) evidence of the change in the anterior segment parameters pre- and post-treatment.\n\nCase Report\nThis was a case of a 31-year-old female patient who presented to us with a 1 day history of acute bilateral eye pain, blurred vision and headache. Her headache was similar in nature to her chronic daily headaches for which she and been commenced on tablet epimate (25 mg) (topiramate) OD orally by her neurologist 1 week prior to presentation.\n\nAt presentation, she was found to have blurred vision with an unaided visual acuity of 4/60 in both eyes. On refraction, a myopic shift in a previously emmetropic individual was established. Her vision was improving to 6/6 (P) with a correction of-3.25 D Spherical and-1.0 D Cylinder at 180° in both eyes. Keratometry was within normal limits. Circumciliary congestion was present along with mild corneal edema [Fig. 1a, b and 2a–d] and shallow anterior chambers in both eyes [Fig. 3a and b]. Gonioscopy showed closed angles in both eyes [Fig. 4a and b]. There was 360° of iridocorneal apposition but no peripheral anterior synechiae on indentation. A raised intraocular pressure (IOP) of 28 and 32 mm of Hg in right and left eye respectively was noted. Anterior segment OCT was done and it corroborated the Gonioscopic findings showing 360° iridocorneal apposition with grossly reduced anterior segment parameters [Fig. 5a and b]. The AS-OCT pictures confirmed shallow anterior chamber depth, narrow angles and forward movement of the lens iris diaphragm with increased convexity of the iris profile. The AS-OCT parameters seen at presentation are shown in Table 1.\n\nFigure 1 (a) Slit lamp photo of right eye showing marked shallowing of the anterior chamber. (b) Slit lamp photo of left eye showing marked shallowing of the anterior chamber\n\nFigure 2 (a) and (c) Clinical photographs showing congestion in the right eye along with shallow anterior chamber, (b) and (d) Clinical photographs showing congestion in the left eye along with shallow anterior chamber\n\nFigure 3 (a) Slit lamp photograph showing the marked shallowing of the anterior chamber in right eye, (b) Slit lamp photograph showing the marked shallowing of the anterior chamber in left eye\n\nFigure 4 (a) Gonioscopy of right eye showing closed angles. There was 360° of iridocorneal apposition but no peripheral anterior synechia on indentation, (b) Gonioscopy of left eye showing closed angles. There was 360° of iridocorneal apposition but no peripheral anterior synechia on indentation\n\nFigure 5 (a) Anterior segment optical coherence tomography of right eye at presentation showing reduced anterior chamber depth, occludable angles with reduced anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle), (b) Anterior segment optical coherence tomography of left eye at presentation showing reduced anterior chamber depth, occludable angles with reduced anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle)\n\nTable 1 AS-OCT parameters of the right and left eye at presentation\n\nTiAAC was diagnosed and she was started treatment with Dexamethasone eye drops 0.1% 6 times per day, Atropine 1% eye drops BD, Timolol Maleate eye drops (0.5% BD) and tablet Acetazolamide (250 mg) 1 tablet TDS. The following day her IOP had dropped to 14 mm of Hg in the right eye and 12 mm of Hg in the left eye. Slit-lamp examination revealed bilateral mild conjunctival congestion, clear corneas, mild anterior chamber reaction with occasional cells and Grade I flare and markedly shallow anterior chambers both centrally and peripherally. Both optic discs had a cup: disc ratio of 0.5 with healthy neuroretinal rims. Since the IOP had come down, only Timolol was continued along with dexamethasone and atropine eye-drops. Tablet acetazolamide was deliberately withheld.\n\nBy the 4th day, her IOP was 12 mmHg in both eyes. There was no evidence of congestion and the anterior chambers of both eyes were deep and quiet. Gonioscopy showed 360° open angles with grade 4 (Shaffer's) in all quadrants of both eyes with no evidence of PAS. All topical medications were discontinued and the patient was reassured.\n\nThe AS-OCT done on this follow-up visit showed that all the anterior chamber angle parameters had increased [Fig. 6a and b] and that the angles were wide open in both eyes [Table 2].\n\nFigure 6 (a) Anterior segment optical coherence tomography of right eye showing improvement in the anterior chamber depth and anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle) post-treatment, (b) Anterior segment optical coherence tomography of left eye showing improvement in the anterior chamber depth and anterior chamber parameters (angle opening distance, trabecular iris space area and scleral spur angle) post-treatment\n\nTable 2 AS-OCT parameters of the right and left eye post-treatment\n\nThus this case report shows very clearly with AS-OCT documentation the changes which occur in the anterior segment in a case of TiAAC.\n\nDiscussion\nTopiramate, a sulfamate-substituted monosaccharide, is used to treat epilepsy in children and adults. It was however originally used as an anticonvulsant. Psychiatrists have used topiramate to treat bipolar disorder, to augment psychotropics, or to counteract the weight gain associated with numerous antidepressants.\n\nIt is FDA approved for and most frequently prescribed for the prevention of migraine due to the effect it has on the blood vessels in the brain.[1] It is used as a preventative for atypical migraine sufferers. It widens the blood vessels in the brain which become restricted by increased serotonin levels.\n\nBanta et al. first reported a case of uveal effusion and secondary angle-closure glaucoma associated with topiramate use in July 2001.[2] In September 2001, Ortho-McNeil Pharmaceuticals sent out a “Dear Healthcare Professional” letter, indicating 21 cases of acute angle-closure glaucoma had been reported to their safety division and physicians should be aware of this adverse drug reaction. The FDA released a case series with an overview of the package insert[3] and a case report from Rhee et al. described a 43-year-old patient with topiramate associated glaucoma that included high-frequency ultrasound evidence of ciliary process swelling and forward displacement of the lens iris diaphragm.[4] Since, then many case reports have appeared in the literature.[56]\n\nThe largest series reported by Fraunfelder et al. in 2004 described the ocular side-effects of topiramate in 115 patients.[6] There were seven cases of permanent vision loss reported indicating that if unrecognized as a drug related event there was the potential for a serious adverse outcome. Other reported side-effects included retinal vascular occlusions, visual field defects, peri-orbital edema, scleritis, blepharospasm, oculogyric crisis, nystagmus and diplopia. In contrast to primary AAC, which is rare under 40 years of age, secondary AAC associated with topiramate has been reported in pediatric patients as well as adults,[7] with an age range from 3 years to 70 years and a mean of 34 years. The condition has predominantly been reported in females (80%).\n\nThe presentation of TiAAC is usually within the first 2 weeks (range 1-49 days) of commencing this drug for the 1st time or within hours of doubling the dose, although there appears to be no relationship with the dose of topiramate taken. Absorption of topiramate is rapid, reaching peak plasma concentrations1-4 h following an oral dose. Typically the presenting symptoms include blurred vision, ocular pain, headache, nausea and vomiting. The clinical signs associated with this syndrome are shallowing of the anterior chamber, occluded angles, papillary changes, significantly elevated IOP, suprachoroidal effusion, ciliary body edema, forward displacement of the crystalline lens and acute myopia.\n\nAcute myopia up to -9.0 diopters can occur in a matter of hours after starting topiramate, but might take weeks to fully resolve. There are several cases in the literature of topiramate-associated transient myopia without secondary angle closure.[8] Transient myopia is a well-known complication of other oral sulfa medications and their derivatives like acetazolamide.[9]\n\nMyopia in TiAAC may be due to a disturbance of the osmotic state of the lens and concomitant alteration of the refractive index.\n\nThe first published TiAAC using AS-OCT for documentation was by van Issum et al. in 2011.[10] To the best of our knowledge, no Indian case report on TiAAC using AS-OCT has yet been published. Thus, this case report is unique and it suggests AS-OCT documentation of all cases of TiAAC for proper quantification and understanding of the disease process.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Silberstein SD Lipton RB Dodick DW Freitag FG Ramadan N Mathew N Efficacy and safety of topiramate for the treatment of chronic migraine: A randomized, double-blind, placebo-controlled trial Headache 2007 47 170 80 17300356 \n2 Banta JT Hoffman K Budenz DL Ceballos E Greenfield DS Presumed topiramate-induced bilateral acute angle-closure glaucoma Am J Ophthalmol 2001 132 112 4 11438067 \n3 Thambi L Kapcala LP Chambers W Nourjah P Beitz J Chen M Topiramate-associated secondary angle-closure glaucoma: A case series Arch Ophthalmol 2002 120 1108 12149075 \n4 Rhee DJ Goldberg MJ Parrish RK Bilateral angle-closure glaucoma and ciliary body swelling from topiramate Arch Ophthalmol 2001 119 1721 3 11709030 \n5 Chen TC Chao CW Sorkin JA Topiramate induced myopic shift and angle closure glaucoma Br J Ophthalmol 2003 87 648 9 12714417 \n6 Fraunfelder FW Fraunfelder FT Keates EU Topiramate-associated acute, bilateral, secondary angle-closure glaucoma Ophthalmology 2004 111 109 11 14711721 \n7 Lin J Fosnot J Edmond J Bilateral angle closure glaucoma in a child receiving oral topiramate J AAPOS 2003 7 66 8 12690373 \n8 Sen HA O’Halloran HS Lee WB Case reports and small case series: Topiramate-induced acute myopia and retinal striae Arch Ophthalmol 2001 119 775 7 11346412 \n9 Bovino JA Marcus DF The mechanism of transient myopia induced by sulfonamide therapy Am J Ophthalmol 1982 94 99 102 6979937 \n10 van Issum C Mavrakanas N Schutz JS Shaarawy T Topiramate-induced acute bilateral angle closure and myopia: Pathophysiology and treatment controversies Eur J Ophthalmol 2011 21 404 9 21058272\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "0301-4738", "issue": "62(5)", "journal": "Indian journal of ophthalmology", "keywords": null, "medline_ta": "Indian J Ophthalmol", "mesh_terms": "D000208:Acute Disease; D000328:Adult; D000869:Anterior Eye Segment; D004282:Documentation; D005260:Female; D005632:Fructose; D015812:Glaucoma, Angle-Closure; D006068:Gonioscopy; D006801:Humans; D007429:Intraocular Pressure; D018696:Neuroprotective Agents; D041623:Tomography, Optical Coherence; D000077236:Topiramate", "nlm_unique_id": "0405376", "other_id": null, "pages": "619-22", "pmc": null, "pmid": "24881612", "pubdate": "2014-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "6979937;12690373;12714417;14711721;17300356;11346412;21058272;11438067;11709030;12149075", "title": "Anterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure.", "title_normalized": "anterior segment optical coherence tomography documentation of a case of topiramate induced acute angle closure" }

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{ "abstract": "BACKGROUND\nWe describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).\n\n\nMETHODS\nWe identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.\n\n\nRESULTS\nTwo percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.\n\n\nCONCLUSIONS\nTwo percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.", "affiliations": "*Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; †Department of Medicine, Weill Cornell Medical College; ‡Department of Pathology; and §Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY.", "authors": "Varghese|Anna M|AM|;Zakowski|Maureen F|MF|;Yu|Helena A|HA|;Won|Helen H|HH|;Riely|Gregory J|GJ|;Krug|Lee M|LM|;Kris|Mark G|MG|;Rekhtman|Natasha|N|;Ladanyi|Marc|M|;Wang|Lu|L|;Berger|Michael F|MF|;Pietanza|M Catherine|MC|", "chemical_list": "D000970:Antineoplastic Agents; D002864:Chromogranins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C509186:TERT protein, human; D019098:Telomerase; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C067419:CBL protein, human", "country": "United States", "delete": false, "doi": "10.1097/JTO.0000000000000142", "fulltext": null, "fulltext_license": null, "issn_linking": "1556-0864", "issue": "9(6)", "journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer", "keywords": null, "medline_ta": "J Thorac Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D002864:Chromogranins; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs; D005784:Gene Amplification; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D016160:Retinoblastoma Protein; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma; D012907:Smoking; D015996:Survival Rate; D019098:Telomerase; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins", "nlm_unique_id": "101274235", "other_id": null, "pages": "892-6", "pmc": null, "pmid": "24828667", "pubdate": "2014-06", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "19652623;22941189;21361067;22941188;19096304;21430269;22228640;16049312;23470965;18403609;11030152;17601631;16837691;15737014;23407558", "title": "Small-cell lung cancers in patients who never smoked cigarettes.", "title_normalized": "small cell lung cancers in patients who never smoked cigarettes" }

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SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915967, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "US-MYLANLABS-2015M1008032", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "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": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915968, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "US-MYLANLABS-2015M1008029", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915970, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" }, { "companynumb": "US-MYLANLABS-2015M1008030", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "091002", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "drugenddate": null, "drugenddateformat": null, "drugindication": "LUNG NEOPLASM MALIGNANT", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": "3", "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ERLOTINIB" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Small cell lung cancer extensive stage", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Drug resistance", "reactionmeddraversionpt": "18.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "VARGHESE AM, ZAKOWSKI MF, YU HA, WON HH, RIELY GJ, KRUG LM, ET AL. SMALL-CELL LUNG CANCERS IN PATIENTS WHO NEVER SMOKED CIGARETTES. J-THORAC-ONCOL 2014; 9(6):892-896.", "literaturereference_normalized": "small cell lung cancers in patients who never smoked cigarettes", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20150316", "receivedate": "20150316", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 10915971, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20150721" } ]

{ "abstract": "BACKGROUND\nPrevious randomized controlled trials evaluating the efficacy of mycophenolate mofetil (MMF) in patients with immunoglobulin A nephropathy (IgAN) have produced varying results.\n\n\nMETHODS\nDouble-blind placebo-controlled randomized controlled trial.\n\n\nMETHODS\n52 children, adolescents, and adults with biopsy-proven IgAN in 30 centers in the United States and Canada. Entry criteria: age older than 7 to younger than 70 years; urine protein-creatinine ratio (UPCR), ≥0.6g/g (males) or ≥0.8g/g (females); and estimated glomerular filtration rate ≥ 50mL/min/1.73m(2) (≥40mL/min/1.73m(2) if receiving angiotensin-converting enzyme inhibitor). Mean age, 32±12 (SD) years; 62% men; and 73% white.\n\n\nMETHODS\nLisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor [Pronova Biocare]) was given to 94 patients for 3 months; 52 of the patients with persistent UPCR≥0.6g/g (males) and ≥0.8g/g (females) were randomly assigned to MMF or placebo (target dose, 25-36mg/kg/d) in addition to lisinopril/losartan plus Omacor.\n\n\nRESULTS\nChange in UPCR after 6 and 12 months treatment with MMF/placebo and 12 months after the end of treatment.\n\n\nMETHODS\nUPCR measured on 24-hour urine samples. Glomerular filtration rate estimated with the Schwartz (age < 18 years) or Cockcroft-Gault (age ≥ 18 years) formula.\n\n\nRESULTS\n44 patients completed 6 months of treatment with MMF (n=22) or placebo (n=22). The trial was terminated early at the recommendation of the Data Monitoring Committee because of the lack of benefit. No patient achieved a complete remission (UPCR<0.2g/g). Mean UPCRs at randomization and after 6 months were 1.45 (95% CI, 1.16-1.75) and 1.40 (95% CI, 1.09-1.70) for MMF and 1.41 (95% CI, 1.17-1.65) and 1.58 (95% CI, 1.13-2.04) for placebo, respectively. The mean difference in UPCR change between these groups (MMF minus placebo) was -0.22 (95% CI, -0.75 to 0.31; P=0.4). Adverse events were rare apart from nausea (MMF, 8.7%; placebo, 3.7%); one of these MMF patients withdrew.\n\n\nCONCLUSIONS\nLow patient enrollment and short follow-up.\n\n\nCONCLUSIONS\nMMF did not reduce proteinuria significantly in patients with IgAN who had persistent proteinuria after lisinopril/losartan plus Omacor.", "affiliations": "Baylor Scott and White Healthcare, Temple, TX. Electronic address: [email protected].;A.T. Still University, Mesa, AZ.;University of North Carolina at Chapel Hill, NC.;Stanford University, Stanford, CA.;Dallas Nephrology Associates, Dallas, TX.;Mayo Clinic, Rochester, MN.;Columbia University, New York, NY.;Toronto General Hospital, Toronto, Ontario, Canada.;Kidney and Hypertension, Cincinnati, OH.;BC Children's Hospital, Vancouver, British Columbia, Canada.;Capital Dist Renal Physicians, Albany, NY.;Kidney Specialists of Central Oklahoma, Oklahoma City, OK.;St. Paul's Hospital, Vancouver, British Columbia, Canada.;Texas Tech University Health Science Center, El Paso, TX.;University of Michigan, Ann Arbor, MI.;University of Tennessee Health Science Center, Memphis, TN.", "authors": "Hogg|Ronald J|RJ|;Bay|R Curtis|RC|;Jennette|J Charles|JC|;Sibley|Richard|R|;Kumar|Sumit|S|;Fervenza|Fernando C|FC|;Appel|Gerald|G|;Cattran|Daniel|D|;Fischer|Danny|D|;Hurley|R Morrison|RM|;Cerda|Jorge|J|;Carter|Brad|B|;Jung|Beverly|B|;Hernandez|German|G|;Gipson|Debbie|D|;Wyatt|Robert J|RJ|", "chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D003404:Creatinine; C405603:Omacor; D017706:Lisinopril; D009173:Mycophenolic Acid; D019808:Losartan", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0272-6386", "issue": "66(5)", "journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation", "keywords": "IgA nephropathy (IgAN); MEST scores; Mycophenolate mofetil (MMF); proteinuria; randomized controlled trial (RCT); remission; urinary protein-creatinine ratio (UPCR)", "medline_ta": "Am J Kidney Dis", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002648:Child; D003404:Creatinine; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D015118:Eicosapentaenoic Acid; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA; D006801:Humans; D007166:Immunosuppressive Agents; D017706:Lisinopril; D019808:Losartan; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011507:Proteinuria; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "8110075", "other_id": null, "pages": "783-91", "pmc": null, "pmid": "26209543", "pubdate": "2015-11", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Randomized controlled trial of mycophenolate mofetil in children, adolescents, and adults with IgA nephropathy.", "title_normalized": "randomized controlled trial of mycophenolate mofetil in children adolescents and adults with iga nephropathy" }

[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP005331", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "90055", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "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": null, "activesubstance": { "activesubstancename": "OMEGA-3-ACID ETHYL ESTERS" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "2", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "1 G PER DAY, UNK", "drugenddate": null, "drugenddateformat": null, "drugindication": "IGA NEPHROPATHY", "drugintervaldosagedefinition": null, "drugintervaldosageunitnumb": null, "drugrecurreadministration": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "1", "drugstructuredosageunit": "002", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OMACOR" } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" }, { "reactionmeddrapt": "Therapy partial responder", "reactionmeddraversionpt": "20.1", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "HOGG RJ, BAY RC, JENNETTE JC, SIBLEY R, KUMAR S, FERVENZA FC, ET AL. RANDOMIZED CONTROLLED TRIAL OF MYCOPHENOLATE MOFETIL IN CHILDREN, ADOLESCENTS, AND ADULTS WITH IGA NEPHROPATHY. AM J KIDNEY DIS. 2015;66(5):783-91", "literaturereference_normalized": "randomized controlled trial of mycophenolate mofetil in children adolescents and adults with iga nephropathy", "qualification": "1", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20170724", "receivedate": "20170724", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 13781208, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20171127" } ]

{ "abstract": "OBJECTIVE\nTo estimate the prevalence of gestational trophoblastic disease (GTD) in the western region of Saudi Arabia, and to evaluate the success of treatment and the effect of age and risk group on survival.\n\n\nMETHODS\nBetween January 2001 and December 2010, all patients treated for GTD were identified from the King Abdulaziz University Hospital database. Patients with persistent disease were evaluated according to their clinical treatment outcomes.\n\n\nRESULTS\nIn total, 122 cases of GTD were identified in the database. Of these, 77 (63%) cases were diagnosed and received initial treatment at the study centre, resulting in an incidence of 1.26 cases per 1000 deliveries. The mean (±standard deviation) age of the study participants was 31.52 ± 10.8 years, mean gestational age at diagnosis was 12.42 ± 3.2 weeks, and mean follow-up for each patient was 24 months. There were 20 cases (26%) of persistent GTD after treatment. The majority of patients with low-risk disease were treated with single-agent methotrexate, with an overall success rate of 83%. The overall 5-year survival rate for all patients was 98%. Using the Wilcoxon (Gehan) test, risk group and age (cut-off 40 years) were not found to be significantly associated with survival (p=0.69).\n\n\nCONCLUSIONS\nThis single-institute study reports the first survival data for GTD for Saudi Arabia. However, the overall incidence of GTD in Saudi Arabia will be defined by establishment of a GTD registry.", "affiliations": "Scientific chair of prof. Abdullah Hussain Basalamah for Gynecological Cancer, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.;Scientific chair of prof. Abdullah Hussain Basalamah for Gynecological Cancer, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Electronic address: [email protected].;Scientific chair of prof. Abdullah Hussain Basalamah for Gynecological Cancer, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.", "authors": "Anfinan|Nisrin|N|;Sait|Khalid|K|;Sait|Hesham|H|", "chemical_list": "D000970:Antineoplastic Agents; D003609:Dactinomycin; D008727:Methotrexate", "country": "Ireland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0301-2115", "issue": "180()", "journal": "European journal of obstetrics, gynecology, and reproductive biology", "keywords": "Incidence; Survival rate; Trophoblastic disease", "medline_ta": "Eur J Obstet Gynecol Reprod Biol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000970:Antineoplastic Agents; D002822:Choriocarcinoma; D003609:Dactinomycin; D005260:Female; D031901:Gestational Trophoblastic Disease; D006801:Humans; D006828:Hydatidiform Mole; D008175:Lung Neoplasms; D008727:Methotrexate; D008875:Middle Aged; D011247:Pregnancy; D015995:Prevalence; D011379:Prognosis; D012529:Saudi Arabia; D014594:Uterine Neoplasms; D055815:Young Adult", "nlm_unique_id": "0375672", "other_id": null, "pages": "8-11", "pmc": null, "pmid": "24972119", "pubdate": "2014-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Gestational trophoblastic disease in the western region of Saudi Arabia (single-institute experience).", "title_normalized": "gestational trophoblastic disease in the western region of saudi arabia single institute experience" }

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{ "abstract": "Hoyeraal-Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after successful HSCT. We present an HHS patient with an X-linked recessive DKC1 c.1058C > T; Ala353Val mutation who successfully underwent unrelated HSCT at 5 years of age. After months of early infections and organ toxicities immediately post-transplant, he had more than two years of excellent quality of life with correction of bone marrow failure and immunodeficiency. However, episodic massive variceal bleeding and progressive respiratory insufficiency, which were secondary to non-cirrhotic portal hypertension and pulmonary arteriovenous shunts, respectively, developed over 2 years after HSCT and resulted in his death from respiratory failure 4 years after HSCT. This outcome suggests that while HSCT can correct bone marrow failure and immunodeficiency, it may fail to prevent or even aggravate other fatal processes, such as portal hypertension and pulmonary arteriovenous shunting.", "affiliations": "Department of Pediatric Hematology and Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 11259, Taiwan. [email protected].;Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.;Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan. [email protected].", "authors": "Chen|Rong-Long|RL|;Lin|Kuanyin K|KK|;Chen|Liuh-Yow|LY|0000-0002-9857-068X", "chemical_list": "D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins", "country": "Switzerland", "delete": false, "doi": "10.3390/ijms20133261", "fulltext": "\n==== Front\nInt J Mol SciInt J Mol SciijmsInternational Journal of Molecular Sciences1422-0067MDPI 10.3390/ijms20133261ijms-20-03261Case ReportComplications for a Hoyeraal–Hreidarsson Syndrome Patient with a Germline DKC1 A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation Chen Rong-Long 1*Lin Kuanyin K 2https://orcid.org/0000-0002-9857-068XChen Liuh-Yow 2*1 Department of Pediatric Hematology and Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei 11259, Taiwan2 Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan* Correspondence: [email protected] (R.-L.C.); [email protected] (L.-Y.C.); Tel.: +886-2-2897-0011 (R.-L.C. & L.-Y.C.)02 7 2019 7 2019 20 13 326105 6 2019 01 7 2019 © 2019 by the authors.2019Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Hoyeraal–Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after successful HSCT. We present an HHS patient with an X-linked recessive DKC1 c.1058C > T; Ala353Val mutation who successfully underwent unrelated HSCT at 5 years of age. After months of early infections and organ toxicities immediately post-transplant, he had more than two years of excellent quality of life with correction of bone marrow failure and immunodeficiency. However, episodic massive variceal bleeding and progressive respiratory insufficiency, which were secondary to non-cirrhotic portal hypertension and pulmonary arteriovenous shunts, respectively, developed over 2 years after HSCT and resulted in his death from respiratory failure 4 years after HSCT. This outcome suggests that while HSCT can correct bone marrow failure and immunodeficiency, it may fail to prevent or even aggravate other fatal processes, such as portal hypertension and pulmonary arteriovenous shunting.\n\ndyskeratosis congenitaHoyeraal–Hreidarsson syndromeportal hypertensionpulmonary arteriovenous shuntsreduced intensity conditioningtelomeropathyunrelated peripheral blood stem cell transplantationvascular aging\n==== Body\n1. Introduction\nHoyeraal–Hreidarsson syndrome (HHS, OMIM 500545)—a severe variant of dyskeratosis congenita (DC, OMIM 305000) involving very short leukocyte telomere length—is characterized by intrauterine growth retardation and cerebellar hypoplasia, in addition to the classical mucocutaneous DC triad (nail dystrophy, skin hyperpigmentation, oral leukoplakia), with early life-threatening presentations related to immunodeficiency and bone marrow failure (BMF) [1]. Germline variants resulting from different gene mutations—namely DKC1, TINF2, TERC, TERT, NOP10, NHP2, CTC1, WRAP53, ACD, RTEL1, and PARN—have been implicated in HHS and other DC variants. These variants have been documented as mainly perturbing telomeric functions, with the most severe disease forms presenting significantly shorter telomeres than milder forms [2]. Among affected gene variants, X-linked recessive male patients with the DKC1 c.1058C > T; Ala353Val missense mutation present with a diverse clinical phenotype, ranging from late-onset DC without BMF to lethal HHS [2]. Given the high rate of early mortality due to BMF and/or immunodeficiency in HHS patients, there are very few reports in the literature on HHS patients with variable genetic variants that have received hematopoietic stem cell transplantation (HSCT) [3,4,5,6,7]. Herein, we report our experience of treating an HHS patient with a characterized DKC1 mutation, who successfully recovered from early life-threatening complications after receiving a reduced intensity conditioning (RIC) preparation, followed by unrelated peripheral blood stem cell transplantation (PBSCT). However, regrettably, vascular aging events continued to evolve and resulted in mortality four years after HSCT.\n\n2. Case Reports\nThe patient, a boy, suffered oligohydramnios during pregnancy and was born prematurely in December 2009, with a gestational age of 33 weeks and a birth body weight of 1318 g. Growth and developmental delay requiring rehabilitation were noted from early infancy. In addition, progressive skin hyperpigmentation, nail dysplasia, and leukoplakia of the tongue were also noted. In January 2011, aged 1 year, he was first noted to have cytopenia (leukocytes 5.22 × 109/L, hemoglobin 8.1 mg/dL, platelet count 18 × 109/L). He was treated with intravenous immunoglobulins and prednisolone, but the pancytopenia worsened. He required increasingly frequent transfusions and treatment for infections and, by late 2014, he had a neutrophil count of around 0.5 × 109/L, hemoglobin ranging from 6 to 7 mg/dL, and a platelet count of less than 10 × 109/L.\n\nSevere aplastic anemia was confirmed by bone marrow studies in November 2014. In addition, he presented with severe immunodeficiency; very low CD16+56+ natural killer cell (0.013, reference 0.16–0.57 × 109/L) and CD19+ B cell (0.001, reference 0.43–1.27 × 109/L) counts were recorded. Moderate T-lymphopenia was also diagnosed; cell counts of CD3+ T cells = 0.415 (reference 1.58–3.71) × 109/L, CD4+ T cells = 0.253 (reference 0.87–2.14) × 109/L, and CD8+ T cells = 0.138 (reference 0.47–1.11) × 109/L. Levels of immunoglobulins G, A, and M were within normal ranges for his age (data not shown). HHS arising from recurrent X-linked recessive DKC1 c.1058C > T; Ala353Val mutation with extremely short telomeres was diagnosed (Figure 1). Phenotypes of this mutant variant include intrauterine growth retardation, severe lymphopenia, cerebellar hypoplasia (Figure 2), and the characteristic DC mucocutaneous triad of nail dystrophy, skin hyperpigmentation, and oral leukoplakia (Figure 3). He also had non-cirrhotic non-icteric hepatic biochemical abnormalities, but without evidence of pulmonary fibrosis or other lung pathologies.\n\nAs HLA-identical sibling donors were unavailable, a decision was made to pursue unrelated HSCT as salvage therapy. The conditioning consisted of alemtuzumab (a total of 1 mg/kg given from day −10 to day −6) and fludarabine (30 mg/m2 daily from day −8 to day −3), kindly provided by Boston Children’s Hospital [8]. For prophylaxis against graft-versus-host disease (GVHD), the patient received cyclosporine and mycophenolate mofetil. On 10 March 2015 (day 0), he received PBSCs from an unrelated donor comprising 45 × 108 total nucleated cells/kg and 23 × 106 CD34+ cells/kg. The patient and the donor were HLA-8/8 matched (A 1101/2402, B 4001/4601, Cw 0102/0702, DR 0809/0901) and ABO-matched (B to B). Neutrophil engraftment was documented on day +11. The patient did not require any transfusion after day +18. Chimerism analyses were performed from bone marrow (nine months post-transplantation) and from peripheral blood (repeatedly from day +27), all of which showed 100% donor chimerism.\n\nThe initial course was complicated by an episode of Hickman catheter-related Kocuria rosea sepsis and stage 2 skin acute GVHD. Concurrently with the development of skin GVHD, phimosis progressed with the appearance of an erythematous and bullous-like foreskin lesion. The lesion partially regressed following treatment with oral valacyclovir and prednisolone. In addition, diarrhea arose, with stool content changing from loose to watery then bloody, and was associated with cramping abdominal pain and intermittent fever. He required a long admission from day +51 to day +167, with complications including cytomegalovirus (CMV) reactivation, severe enterocolitis, buccal mucositis/cellulitis, and parotitis. He required parenteral nutritional support for nearly two months and developed Wernicke encephalopathy during this period that was responsive to thiamine treatment. Finally, these complications were alleviated and he was discharged under on-going prednisolone and cyclosporine treatment. \n\nHowever, he still experienced repeated CMV reactivation, episodes of diarrhea with or without fever, Escherichia coli urinary tract infection, Clostridium difficile-associated diarrhea, Salmonella group E enteric fever, and influenza during the first year post-transplantation. He also underwent circumcision because of a difficulty urinating, which was secondary to progressive obstructive phimosis at nine months post-transplantation. Steroid and cyclosporine treatments were discontinued 9 months and 1 year post-transplantation, respectively. Recovery of bone marrow hematopoiesis was documented (Figure 4). Moreover, the frequency of serious infections markedly decreased over the course of the second year post-transplantation, so the boy returned to school.\n\nAt the early post-transplantation stage, the patient’s hepatic abnormalities remained stationary, with mildly elevated transaminase levels, though hepatic ultrasonography revealed heterogeneous echotexture with multiple tiny hypoechoic nodules. He gradually gained body weight purely by oral intake from 12.4 kg before HSCT to 15.9 kg in November 2016. He had become transfusion-independent by 21 November 2016, with a neutrophil count of 2.69 × 109/L, hemoglobin of 10.6 mg/dL, and a platelet count of 128 × 109/L. A lymphocyte subset analysis in November 2016 revealed normal counts of CD16+56+ natural killer cells (0.184, reference 0.12–0.48 × 109/L) and CD19+ B cells (0.390, reference 0.28–0.64 × 109/L). The extent of T-lymphopenia had also decreased with CD3+ T, CD4+ T, and CD8+ T cell counts of 0.803 (reference 1.24–1.21), 0.272 (0.65–1.52), and 0.392 (0.37–0.95) × 109/L, respectively.\n\nHowever, massive upper gastrointestinal bleedings happened after respiratory tract infections in late April 2017 when portal hypertension complicated with esophago-gastric varices was diagnosed by emergency endoscopy and computerized tomography (Figure 5). In addition, he was noted to have persistent hypoxemia, with the arterial partial pressure of oxygen always less than 50 mmHg after treatment for a documented influenza episode in May 2017. The patient had very severe hepatopulmonary syndrome, with a calculated alveolar-arterial oxygen gradient of 70 mmHg at sitting and 75 mmHg at supine positions, respectively. Pulmonary arteriovenous shunting was documented by a lung perfusion scan in August 2017 (Figure 6). Only palliative management was considered thereafter. The patient was still able to enjoy school and home life under regular oxygen supplementation, although intermittent admissions were required to manage severe upper gastrointestinal bleeding or aggravated respiratory symptoms in his final days. Ultimately, he passed away in February 2019, primarily due to respiratory compromise.\n\n3. Discussion\nWe have characterized herein the lifelong events of an HHS patient with DKC1 A353V and extremely short telomeres. Despite the presence of perinatal intrauterine growth restriction and developmental delay, HHS was not diagnosed until the patient suffered from complications related to rapidly progressive BMF and immunodeficiency when the characteristic mucocutaneous DC triad and cerebral hypoplasia were noted.\n\nHSCT is the first consideration for treatment when DC-associated BMF develops and a matched-sibling donor is available [9,10]. Until recently, HSCT for DC has been associated with an inferior outcome, mainly owing to early and late post-transplantation complications including graft failure, GVHD, sepsis, and, in particular, the increased propensity to develop pulmonary failure [11]. The largest cohort (n = 94) of non-myeloablative HSCT for DC still showed the crude mortality rate of 41%, with about one-third of deaths resulting from late complications such as organ damage and secondary malignancies [12]. For unrelated donor HSCT in DC, the risks are even higher, though RIC preparative regimens have been suggested as being more successful [8,13].\n\nInstances of HSCT treatment for genotype-determined HHS are rarely reported. One of two sibling HHS with homozygous TERT mutation had early engraftment after HLA-9/10 unrelated bone marrow transplantations. However, another died one month after post-matched unrelated cord blood transplantation (CBT) [5]. Two HHS patients with the RTEL mutation were successfully rescued: one by haploidentical PBSCT and the other by unrelated CBT [6,7]. Another HHS patient with the DKC1 mutation had delayed marrow reconstitution after an unrelated bone marrow transplant [3]. In contrast, our HHS patient (with the DKC1 mutation) had prompt and complete donor engraftment, as well as steady immune recovery, after unrelated PBSCT following a novel radiation/alkylator-free RIC regimen [8]. Our patient gradually attained abilities to overcome mild and brief GVHD/infections.\n\nThe previously reported HHS patient with the DKC1 mutation developed severe gastrointestinal problems that required chronic steroid therapy, long-term total parenteral nutrition, and jejunostomy feeding following an unrelated bone marrow transplant [3]. Another HHS patient with the RTEL mutation also required total parenteral nutrition at home for 2 years after CBT [7]. Protracted enterocolitis was also the most troublesome early post-transplantation complication in our patient, which has caused significant morbidities elsewhere [14]. We emphasize that the increased propensity of HHS patients to develop telomere-mediated intestinal disease (as reviewed by Jonassaint et al. [14]) should be highlighted as an early and life-threatening post-transplantation complication, even after RIC preparation.\n\nThe early success of HSCT in our patient failed to prevent (and may have even aggravated) as yet uncharacterized vascular aging processes that particularly affected the liver and lungs, causing severe non-cirrhotic portal hypertension and pulmonary arteriovenous shunting that resulted in death four years after HSCT. This scenario contrasts with those of germline telomerase mutations that predispose cirrhosis formation and familial idiopathic pulmonary fibrosis but, in general, do not result in the expression of classical DC phenotypes [15,16,17]. The vascular changes in our patient are similar to the setting of chronic liver diseases leading to hepatopulmonary syndrome, in which dilatation of pulmonary pre-capillary and capillary vessels is the striking pathological feature, and with some patients exhibiting a few pleural/pulmonary shunts as well as portopulmonary venous anastomoses [18]. Recently, pulmonary arteriovenous malformations, with or without hepatopulmonary syndrome, have been characterized as a pulmonary phenotype of DC, with 77% of such patients undergoing HSCT [19]. Among the 13 such cases reported, germline mutations were documented in twelve including TINF2 (six), TERT (two), RTEL1 (two), PARN (one), and DKC1 T408I (one). We now add a case of a germline DKC1 A353V HHS patient having pulmonary arteriovenous malformations with hepatopulmonary syndrome 2 years after HSCT.\n\nIn conclusion, a boy with characteristics of HHS caused by an X-linked recessive DKC1 mutation developed life-threatening BMF and severe lymphopenia. These complications were successfully ameliorated over time through unrelated PBSCT using a novel radiation/alkylator-free RIC regimen with manageable early complications. He was subsequently able to return to school, but ultimately developed severe portal hypertension and fatal hepatopulmonary syndrome.\n\n4. Materials and Methods\n4.1. Whole Exome Sequencing (WES)\nTo identify genetic variants in the patient, genomic DNA from leukocytes of the subject was subjected to WES. The sequence data was aligned to a reference genome (hg19) to identify genetic variants. Analysis of the variants in genes associated with dyskeratosis congenita led to the identification of the DKC1 c.1058C>T mutation. Sanger sequencing was carried out to verify the DKC1 mutation. A fragment of DNA containing the DKC1 mutation site was amplified by PCR using oligonucleotide primers 5′-tgagctgcaagcctgttatg-3′ and 5′-caaatccccctctgtgagaa-3′, which were also used for direct sequencing. Our results confirmed the DKC1 mutation in the patient and revealed the mother to be a carrier with wild-type and mutant DKC1 alleles. Written informed consent was obtained from all the participants for public release of the survey results.\n\n4.2. Telomere Length Analysis\nLeukocyte telomere length was analyzed by telomere restriction fragment assay, as previously described [20]. Briefly, leukocyte genomic DNA was digested by Rsa I and Hinf I restriction enzymes and resolved by agarose gel electrophoresis. Telomeric DNA was detected by in gel hybridization using a [32P]-labeled telomeric probe.\n\n4.3. Tecnetium-99m MAA Lung and Brain Scanning\nA technetium-99m-labeled macroaggregated albumin lung perfusion scan was performed according to a previous report [21]. The extrapulmonary shunt fraction, assuming that 13% of the cardiac output is delivered to the brain, was calculated using the geometric mean of technetium (GMT) counts around the brain and lung according to the following formula: (GMTbrain/0.13)/ ((GMTbrain/0.13) + GMTlung).\n\nAcknowledgments\nWe would like to thank Suneet Agarwal for assistance in clinical management of the patient.\n\nAuthor Contributions\nR.-L.C. and L.-Y.C. designed the study. R.-L.C., K.K.L., and L.-Y.C. carried out the experiments and performed the data analysis. R.-L.C and L.-Y.C. wrote the manuscript.\n\nFunding\nThis study was supported by Career Development Award CDA-105-L01 from Academia Sinica and grants from the Ministry of Science and Technology (105-2311-B-001-055-MY3).\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nFigure 1 (A) Pedigree of the affected family. Solid symbol represents the affected patient and open symbols represent unaffected relatives. Squares indicate males and circle indicates a female subject. (B) Sanger DNA sequencing of DKC1 exon 11 on chromosome X from peripheral blood cells taken from subjects of the studied pedigree. Wild-type (S1), patient (P1), carrier (M1). (C) Telomere length analysis (by terminal restriction fragment assay) of DNA from leukocytes of the patient (P1), an age-matched control (Ctrl), a carrier (M1), and from HT1080 fibrosarcoma cancer cells. The patient (P1) had exceedingly shortened and heterogeneous telomeres compared to the control (Ctrl).\n\nFigure 2 Brain magnetic resonance imaging of the patient in December 2014 showing characteristic cerebellar hypoplasia.\n\nFigure 3 Pre-transplant photographs of the patient showing nail dysplasia (A), abnormal skin pigmentation (B), and tongue leukoplakia (white arrowhead) (C).\n\nFigure 4 H&E-stained micrographs (40× A,C; 400× B,D) showing the severe hypocellularity with scanty hematopoiesis of bone marrow obtained pre-hematopoietic stem cell transplantation (HSCT) in February 2015 (A,B) compared to much more cellular material with abundant hematopoiesis obtained in December 2015 (i.e., nine months post-HSCT) (C,D).\n\nFigure 5 Enhanced computerized tomography scans showing esophageal (A) and gastric (B) varices.\n\nFigure 6 Technetium-99m-labeled macroaggregated albumin (Tc-99m MAA) dynamic perfusion imaging and total-body scans showing abnormal increased uptake in the brain immediately after Tc-99m MAA injection, with calculated intrapulmonary right-to-left shunts of 57.6%. LT, left; RT, right; R+L, right plus left; WB, whole body.\n==== Refs\nReferences\n1. Hreidarsson syndrome, a complex telomere biology disorder Br. J. Haematol. 2015 170 457 471 10.1111/bjh.13442 25940403 \n2. Vulliamy T.J. Marrone A. Knight S.W. Walne A. Mason P.J. Dokal I. Mutations in dyskeratosis congenita: Their impact on telomere length and the diversity of clinical presentation Blood 2006 107 2680 2685 10.1182/blood-2005-07-2622 16332973 \n3. Knight S.W. Heiss N.S. Vulliamy T.J. Aalfs C.M. McMahon C. Richmond P. Jones A. Hennekam R.C. Poustka A. Mason P.J. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1 Br. J. Haematol. 1999 107 335 339 10.1046/j.1365-2141.1999.01690.x 10583221 \n4. Coman D. Herbert A. McGill J. Lockwood L. Hallahan A. Unrelated cord blood transplantation in a girl with Hoyeraal-Hreidarsson syndrome Bone Marrow Transpl. 2008 42 293 294 10.1038/bmt.2008.163 18560411 \n5. Gramatges M.M. Qi X. Sasa G.S. Chen J.J. Bertuch A.A. A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal-Hreidarsson syndrome Blood 2013 121 3586 3593 10.1182/blood-2012-08-447755 23538340 \n6. Bhattacharyya R. Tan A.M. Chan M.Y. Jamuar S.S. Foo R. Iyer P. TCR-αβ and CD19-depleted haploidentical stem cell transplant with reduced intensity conditioning for Hoyeraal–Hreidarsson syndrome with RTEL1 mutation Bone Marrow Transpl. 2016 51 753 754 10.1038/bmt.2015.352 \n7. Moriya K. Niizuma H. Rikiishi T. Yamaguchi H. Sasahara Y. Kure S. Novel compound heterozygous RTEL1 gene mutations in a patient with Hoyeraal-Hreidarsson syndrome Pediatr. Blood Cancer 2016 63 1683 1684 10.1002/pbc.26030 27128385 \n8. Lehmann L.E. Williams D.A. London W.B. Agarwal S. Full donor myeloid engraftment with minimal toxicity in dyskeratosis congenita patients undergoing allogeneic bone marrow transplantation without radiation or alkylating agents Blood 2014 124 2941 \n9. Savage S.A. Dokal I. Armanios M. Aubert G. Cowen E.W. Domingo D.L. Giri N. Greene M.H. Orchard P.J. Tolar J. Dyskeratosis congenita: The first NIH clinical research workshop Pediatr. Blood Cancer 2009 53 520 523 10.1002/pbc.22061 19415736 \n10. Ayas M. Nassar A. Hamidieh A.A. Kharfan-Dabaja M. Othman T.B. Elhaddad A. Seraihy A. Hussain F. Alimoghaddam K. Ladeb S. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure Bone Marrow Transpl. 2013 48 1168 1172 10.1038/bmt.2013.35 \n11. Gadalla S.M. Sales-Bonfim C. Carreras J. Alter B.P. Antin J.H. Ayas M. Bodhi P. Davis J. Davies S.M. Deconinck E. Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita Biol. Blood Marrow Transpl. 2013 19 1238 1243 10.1016/j.bbmt.2013.05.021 23751955 \n12. Fioredda F. Iacobelli S. Korthof E.T. Knol C. van Biezen A. Bresters D. Veys P. Yoshimi A. Fagioli F. Mats B. Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita Br. J. Haematol. 2018 183 110 118 10.1111/bjh.15495 29984823 \n13. Dietz A.C. Orchard P.J. Baker K.S. Giller R.H. Savage S.A. Alter B.P. Tolar J. Disease-specific hematopoietic cell transplantation: Nonmyeloablative conditioning regimen for dyskeratosis congenita Bone Marrow Transpl. 2011 46 98 104 10.1038/bmt.2010.65 20383216 \n14. Jonassaint N.L. Guo N. Califano J.A. Montgomery E.A. Armanios M. The gastrointestinal manifestations of telomere-mediated disease Aging Cell 2013 12 319 323 10.1111/acel.12041 23279657 \n15. Calado R.T. Brudno J. Mehta P. Kovacs J.J. Wu C. Zago M.A. Chanock S.J. Boyer T.D. Young N.S. Constitutional telomerase mutations are genetic risk factors for cirrhosis Hepatology 2011 53 1600 1607 10.1002/hep.24173 21520173 \n16. Hartmann D. Srivastava U. Thaler M. Kleinhans K.N. N’kontchou G. Scheffold A. Bauer K. Kratzer R.F. Kloos N. Katz S.F. Telomerase gene mutations are associated with cirrhosis formation Hepatology 2011 53 1608 1617 10.1002/hep.24217 21520174 \n17. Armanios M.Y. Chen J.J. Cogan J.D. Alder J.K. Ingersoll R.G. Markin C. Lawson W.E. Xie M. Vulto I. Phillips J.A. III Telomerase mutations in families with idiopathic pulmonary fibrosis N. Engl. J. Med. 2007 356 1317 1326 10.1056/NEJMoa066157 17392301 \n18. Rodríguez-Roisin R. Krowka M.J. Hepatopulmonary syndrome—A liver-induced lung vascular disorder N. Engl. J. Med. 2008 358 2378 2387 10.1056/NEJMra0707185 18509123 \n19. Khincha P.P. Bertuch A.A. Agarwal S. Townsley D.M. Young N.S. Keel S. Shimamura A. Boulad F. Simoneau T. Justino H. Pulmonary arteriovenous malformations: An uncharacterized phenotype of Dyskeratosis Congenita and related Telomere Biology Disorders Eur. Respir. J. 2017 49 1601640 10.1183/13993003.01640-2016 27824607 \n20. Chen L.Y. Majerská J. Lingner J. Molecular basis of telomere syndrome caused by CTC1 mutations Genes Dev. 2013 27 2099 2108 10.1101/gad.222893.113 24115768 \n21. Krowka M.J. Wiseman G.A. Burnett O.L. Spivey J.R. Therneau T. Porayko M.K. Wiesner R.H. Hepatopulmonary syndrome: A prospective study of relationships between severity of liver disease, PaO2 response to 100% oxygen, and brain uptake after 99m Tc MAA lung scanning Chest 2000 118 615 624 10.1378/chest.118.3.615 10988181\n\n", "fulltext_license": "CC BY", "issn_linking": "1422-0067", "issue": "20(13)", "journal": "International journal of molecular sciences", "keywords": "Hoyeraal–Hreidarsson syndrome; dyskeratosis congenita; portal hypertension; pulmonary arteriovenous shunts; reduced intensity conditioning; telomeropathy; unrelated peripheral blood stem cell transplantation; vascular aging", "medline_ta": "Int J Mol Sci", "mesh_terms": "D018797:Cell Cycle Proteins; D002675:Child, Preschool; D019871:Dyskeratosis Congenita; D005317:Fetal Growth Retardation; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008831:Microcephaly; D009687:Nuclear Proteins; D036102:Peripheral Blood Stem Cell Transplantation; D017354:Point Mutation", "nlm_unique_id": "101092791", "other_id": null, "pages": null, "pmc": null, "pmid": "31269755", "pubdate": "2019-07-02", "publication_types": "D002363:Case Reports", "references": "10583221;10988181;16332973;17392301;18509123;18560411;19415736;20383216;21520173;21520174;23279657;23538340;23542225;23751955;24115768;25940403;26808564;27128385;27824607;29984823", "title": "Complications for a Hoyeraal-Hreidarsson Syndrome Patient with a Germline DKC1 A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation.", "title_normalized": "complications for a hoyeraal hreidarsson syndrome patient with a germline dkc1 a353v variant undergoing unrelated peripheral blood stem cell transplantation" }

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{ "abstract": "The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM.", "affiliations": "Department of Neurosurgery, Ankara Ataturk Education and Research Hospital, Ankara, Turkey.;Department of Neurosurgery, Ankara Bayındır Hospital, Ankara, Turkey.", "authors": "Kazanci|Atilla|A|;Tekkök|İsmail Hakkı|İH|", "chemical_list": null, "country": "Korea (South)", "delete": false, "doi": "10.3340/jkns.2015.58.2.163", "fulltext": "\n==== Front\nJ Korean Neurosurg SocJ Korean Neurosurg SocJKNSJournal of Korean Neurosurgical Society2005-37111598-7876The Korean Neurosurgical Society 10.3340/jkns.2015.58.2.163Case ReportPhenytoin Induced Erythema Multiforme after Cranial Radiation Therapy Kazanci Atilla M.D.1Tekkök İsmail Hakkı M.D.21 Department of Neurosurgery, Ankara Ataturk Education and Research Hospital, Ankara, Turkey.2 Department of Neurosurgery, Ankara Bayındır Hospital, Ankara, Turkey.\nAddress for reprints: Atilla Kazanci, M.D. Department of Neurosurgery, Ankara Ataturk Education and Research Hospital, Ankara 06810, Turkey. Tel: +00905057793149, Fax: +90 312 291 27 26, [email protected] 2015 28 8 2015 58 2 163 166 25 8 2014 11 1 2015 14 1 2015 Copyright © 2015 The Korean Neurosurgical Society2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The prophylactic use of phenytoin during and after brain surgery and cranial irradiation is a common measure in brain tumor therapy. Phenytoin has been associated with variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis. EM associated with phenytoin and cranial radiation therapy (EMPACT) is a rare specific entity among patients with brain tumors receiving radiation therapy while on prophylactic anti-convulsive therapy. Herein we report a 41-year-old female patient with left temporal glial tumor who underwent surgery and then received whole brain radiation therapy and chemotherapy. After 24 days of continous prophylactic phenytoin therapy the patient developed minor skin reactions and 2 days later the patient returned with generalized erythamatous and itchy maculopapuler rash involving neck, chest, face, trunk, extremities. There was significant periorbital and perioral edema. Painful mucosal lesions consisting of oral and platal erosions also occurred and prevented oral intake significantly. Phenytoin was discontinued gradually. Systemic admistration of corticosteroids combined with topical usage of steroids for oral lesions resulted in complete resolution of eruptions in 3 weeks. All cutaneous lesions in patients with phenytoin usage with the radiotherapy must be evoluated with suspicion for EM.\n\nCranial RadiotherapyErythema MultiformePhenytoin\n==== Body\nINTRODUCTION\nTreatment of intracranial malignancies includes prophylactic anti-convulsant and steroid medication in addition to a combination of surgery, radiation therapy and chemotherapy. Phenytoin as a anti-convulsant therapy has been known for variety of adverse skin reactions including urticaria, erythroderma, erythema multiforme (EM), Stevens-Johnson syndrome, and toxic epidermal necrolysis for a long time246101113). Erythema multiforme (EM) is a skin reaction that ranges from self-limited cutaneous eruption to a progressive mucocutaneous disease145891315). EM typically presents with self-limited targetoid lesions on the extensor surfaces of extremities and is often associated with underlying infection (commonly herpes simplex) or a hypersensitivity reaction to a variety of medications like sulfonamides, penicillines, quinolones and anti-convulsants124611).\n\nHypersensitivity reaction mechanism caused by anti-convulsant drugs is not clear however, it has been proposed that toxic metabolite of aromatic anti-convulsants could bind the cellular macromolecules causing a secondary immunological response3). In patients receiving phenytoin as a prophylactic anti-convulsant who have also treated with radiotherapy, anti-eppileptics must be administered with caution, and all cutaneous reactions developing subsequently within the radiation site must be promptly evaluated with a high index of suspicion for erythema multiforme.\n\nHerein we report the case of a patient who developed EM after administration of cranial irradiation and phenytoin treatment.\n\nCASE REPORT\nA 41-year-old female patient with left temporal lobe WHO grade IV glioblastome multiforme underwent surgery on the first day after admitting to our hospital (Fig. 1). The patient was given 300 mg/day of phenytoin and 16 mg/day dexamethasone before the surgery. Upon initial diagnosis of glioblastoma multiforme (GBM) after maximal surgical resection the patient underwent radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. She continued taking phenythoin and tapering dosage of dexamethasone. She subsequently underwent whole brain radiation therapy and was given a total dose of 6000 cGy over 5 days per week in doses of 2.0 Gy fractions spaced over 6 weeks. The patient underwent chemotherapy with temozolomide 130 mg/day for 42 days. After 1 month without chemotherapy she was given 6 cycles of 300 mg/day temozolomide for 5 days.\n\nAfter completing radiation therapy and tapering of dexamethasone on the 24th day of continous prophylactic phenytoin therapy the patient developed minor skin reactions on the scalp within the radiation field especially on left temporal side. The maculopappular eruption generalized within a few days to involve the neck, face, trunk and extremities (Fig. 2). Edema on the lips, mucosal lesions consisting of oral erosions, conjunctival suffusion and periorbital edema also evolved. Laboratory serology included a normal blood cell differential with 12% monocytes, 1.9% eosinophils. Transaminase levels were midly elevated-aspartate aminotransferase 49 U/L and alanine aminotransferase 57 U/L. Anti-nuclear antibody (ANA), anti-double stranded DNA (Anti-dsDNA), anti-extractable nuclear antigen (Anti-ENA), anti-neutrophil cytoplasmic antibody (ANCA) were negative and serum immunoglobulin levels were normal. The was no clinical and/or laboratory evidence of a infection or an autoimmune disease.\n\nDermatological consultation was sought and a diagnosis of phenytoin induced EM was considered. Phenytoin was discontinued and patient received intravenous corticosteroid that was tapered over 4 days. The patient was also given topical corticosteroid for oral ulcerations. On the 6th day of discontinuation of phenytoin patient had temporal lobe seizure and levetiracetam 2000 mg/day and carbamezapine 400 mg/day was initiated for seizure prophylaxis. Over the following 1 week resolution of the mucocutaneous lesions occured and the patient completely recovered within 3 weeks after stopping phenytoin.\n\nDISCUSSION\nEM is a mucocutaneous reaction associated with several precipitating factors that include infections and various drugs such as sulfonamides, penicilinle, anti-convulsants, allopurinol and anti-inflammotory drugs1347810). EM typically presents with self-limited targetoid lesions on the extensor surfaces of extremities but skin lesions range from skin rashes to a progressive mucocutaneous disease145891315).\n\nPhenytoin is commonly prescribed as a prophylactic anti-convulsant in patients with intracranial malignancies. Phenytoin induced skin reactions ranging from urticaria to toxic epidermal necrolysis has been reported several times12346891112131415). Skin reactions associated with anti-convulsant therapy mainly occur during the first few days to 8 weeks of anti-convulsant drug administration81011). As in our case skin lesions occured 24 days after continous prophylactic phenytoin therapy.\n\nA generalized hypersensitivity has also been described in approximately 10% of patients receiving phenytoin that consists of fever, arthralgias, peripheral eosinophilia, generalized lymphadenopathy and hepatosplenomegaly1378). This hypersensitivity reaction frequently associated with aromatic anti-convulsants such as phenytoin, phenobarbital and carbamezapine. Anti-convulsants are converted to reactive metabolites and induce cytochrome P450 3A and produce oxidative reactive intermediates that may be implicated in hypersensitivity reactions and then these metabolites excreted from kidney via another hepatic enzyme epoxide hydrolase23589101113). Imbalance between the formation of metabolites and enzymatic detoxification leads to accumulation of metabolites causes them to bind with celluler macromoleculles resulting in a toxic role in type 4 hypersensitivity reactions135810). Baba et al.3) suggested that hypersensitivity reactions developed after craniotomy and surgical trauma could have been involved in decreasing activity of hepatic enzymes due to exposure to anaesthetic agents3). Thus this is a clinical phenomenon that occurs with unusual frequency in patients with brain tumor who undergo radiation therapy while taking phenytoin or other anticonvulsants such as phenobarbital and carbamazepine8). Both carbamazepine and barbiturates have shown cross-sensitivity with phenytoin\n\nRecently management of glioblastoma multiforme progressively changed to maximal surgical resection with postoperative radiotherapy and concurrent chemotherapy. In our case after maximal surgical resection the patient underwent radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide. Several reports in literature suggest the existance of a phenomenon in which EM, Stevens-Johnson syndrome or toxic epidermal necrolysis may ocur in patients with brain tumors treated with radiation therapy and anti-convulsant drugs and it was concluded that radiation therapy was responsible because reinstitution of the drugs did not result in recurrence of the reaction. As in our case the clinical picture differed from the classic form of EM in that the erythema began on the scalp and spread to the extremities, progressing to extensive bullous formation16810). As a well recognized phenomenon cutaneous reactions with radiation therapy is usually dose dependent and consists of erythema limited to the radiation field14610). Irradiation can enhance a primary antibody response and impairs T suppressor cells and radiation therapy might promote the development of a hypersensitivity reaction to phenytoin that may be more evident patients receive a tapering dosage of steroids8).\n\nAhmed et al.1) recently used definition EMPACT (E : erythema M : multiforme associated with P : phenytoin and C : cranial radiation T : therapy) to best describe this disorder. Ahmed et al. reviewed 24 patients which had taken phenytoin for variable time periods (mean 40 days) the lesions developed within the port site during the radiation treatments or soon after its completion. In literature many cases, as in our case, the skin rashes and eruptions first ocur in the irradiation area which may resulted in misdiagnosis as a normal radiation reaction and this may cause delaying the diagnosis of EM lesions and more severe syndromes246810). In literature as in our case not only skin eruptions but EM lesions on the irradiation area with pheytoin treatment was described as diagnostic criteria for EMPACT1). It is also reported that the incidence of this syndrome is much more frquent in cases where phenytoin was administered less than 2 months prior to start of radiotherapy, compared to cases where treatment commenced more then 2 months before irradiation1013).\n\nThe optimal treatment for EM is not well defined. Phenytoin should be discontinued immediatelly and high dose intravenous steroid application resolves dermal lesions. For the oral mucosal lesions topical steroid is necessarry8101113). If the lesions are more severe like Stevens-Johnson syndrome or toxic epidermal necrolysis sympthomatic treatment should be applied similiar to that used for burns. Metabolic and electrolyte imbalance should be corrected by replacement of intravenous fluids.\n\nCONCLUSION\nThe prophylactic use of anti-convulsants after brain surgery or during cranial irradiation is very common. In patients receiving phenytoin as a prophylactic anti-convulsant who have also treated with radiotherapy EM is a relatively rare adverse situation. The physician must be aware of the anti-convulsant hypersensitivity syndrome when combined with radiotherapy and all cutaneous reactions developing subsequently within the radiation field must be evaluated with the suspicion of EM. In patients with disseminated rashes phenytoin administration should be discontinued immediately and intravenous steroid treatment should be given and if necessary sympthomatic and supportive treatment should be started similiar to that given to patients with burns.\n\nFig. 1 Preoperative sagital MRI scan showing left temporal lobe glioblastome multiforme.\nFig. 2 A : The maculo-pappular eruptions (smooth skin rash or redness covered by elevated bumps) on the neck, face, trunk and extremities. B : The maculo-pappular rashes on the extremities.\n==== Refs\n1 Ahmed I Reichenberg J Lucas A Shehan JM Erythema multiforme associated with phenytoin and cranial radiation therapy : a report of three patients and review of the literature Int J Dermatol 2004 43 67 73 14693027 \n2 Arif H Buchsbaum R Weintraub D Koyfman S Salas-Humara C Bazil CW Comparison and predictors of rash associated with 15 antiepileptic drugs Neurology 2007 68 1701 1709 \n3 Baba M Karakaş M Aksungur VL Homan S Yücel A Acar MA The anticonvulsant hypersensitivity syndrome J Eur Acad Dermatol Venereol 2003 17 399 401 12834448 \n4 Barbosa LA Teixeira CR Erythema multiforme associated with prophylactic use of phenytoin during cranial radiation therapy Am J Health Syst Pharm 2008 65 1048 1050 18499877 \n5 Lin MS Dai YS Pwu RF Chen YH Chang NC Risk estimates for drugs suspected of being associated with Stevens-Johnson syndrome and toxic epidermal necrolysis : a case-control study Intern Med J 2005 35 188 190 15737140 \n6 Mamon HJ Wen PY Burns AC Loeffler JS Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy Epilepsia 1999 40 341 344 \n7 Man CB Kwan P Baum L Yu E Lau KM Cheng AS Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese Epilepsia 2007 48 1015 1018 17509004 \n8 Micali G Linthicum K Han N West DP Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies Pharmacotherapy 1999 19 223 227 10030773 \n9 Mockenhaupt M Messenheimer J Tennis P Schlingmann J Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics Neurology 2005 64 1134 1138 15824335 \n10 Oner Dincbas F Yörük S Demirkesen C Uzel O Koca S Toxic epidermal necrolysis after cranial radiotherapy and phenytoin treatment Onkologie 2004 27 389 392 15347896 \n11 Pelekanos J Camfield P Camfield C Gordon K Allergic rash due to antiepileptic drugs : clinical features and management Epilepsia 1991 32 554 559 1831121 \n12 Roujeau JC Kelly JP Naldi L Rzany B Stern RS Anderson T Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis N Engl J Med 1995 333 1600 1607 7477195 \n13 Rzany B Correia O Kelly JP Naldi L Auquier A Stern R Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy : a case-control study Lancet 1999 353 2190 2194 10392983 \n14 Welykyj S Gradini R Nakao J Massa M Carbamazepine-induced eruption histologically mimicking mycosis fungoides J Cutan Pathol 1990 17 111 116 2140116 \n15 Wöhrl S Loewe R Pickl WF Stingl G Wagner SN EMPACT syndrome J Dtsch Dermatol Ges 2005 3 39 43 16353748\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1225-8245", "issue": "58(2)", "journal": "Journal of Korean Neurosurgical Society", "keywords": "Cranial Radiotherapy; Erythema Multiforme; Phenytoin", "medline_ta": "J Korean Neurosurg Soc", "mesh_terms": null, "nlm_unique_id": "101467054", "other_id": null, "pages": "163-6", "pmc": null, "pmid": "26361537", "pubdate": "2015-08", "publication_types": "D002363:Case Reports", "references": "17502552;10030773;18499877;10080516;10392983;15737140;15347896;2140116;16353748;7477195;17509004;12834448;14693027;15824335;1831121", "title": "Phenytoin Induced Erythema Multiforme after Cranial Radiation Therapy.", "title_normalized": "phenytoin induced erythema multiforme after cranial radiation therapy" }

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{ "abstract": "Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab.\n\n\n\nThis is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805.\n\n\n\nBetween July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related.\n\n\n\nPyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy.\n\n\n\nJiangsu Hengrui Medicine and National Key R&D Program of China.\n\n\n\nFor the Chinese translation of the abstract see Supplementary Materials section.", "affiliations": "National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].;The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.;National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.;Fudan University Cancer Hospital, Shanghai, China.;Jiangsu Cancer Hospital, Nanjing, China.;Hunan Cancer Hospital, Changsha, China.;Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.;Beijing Cancer Hospital, Beijing, China.;Harbin Medical University Cancer Hospital, Harbin, China.;Liaoning Cancer Hospital & Institute, Shenyang, China.;Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China.;The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.;Jilin Cancer Hospital, Changchun, China.;The First Bethune Hospital of Jilin University, Changchun, China.;The First Bethune Hospital of Jilin University, Changchun, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.;Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.;Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, China.;Wuhan Union Hospital, Wuhan, China.;The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.;Cancer Centre of Jinling Hospital, Nanjing, China.;Sun Yat-Sen University Cancer Center, Guangzhou, China.;Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China.;Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China.;Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.;Zhejiang Cancer Hospital, Hangzhou, China.;The Third Hospital of Nanchang, Nanchang, China.;West China Hospital, Sichuan University, Chengdu, China.;The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Jiangxi Cancer Hospital, Nanchang, China.;Shandong Tumor Hospital, Jinan, China.;Jiangsu Hengrui Medicine, Shanghai, China.;Jiangsu Hengrui Medicine, Shanghai, China.;Jiangsu Hengrui Medicine, Shanghai, China.", "authors": "Xu|Binghe|B|;Yan|Min|M|;Ma|Fei|F|;Hu|Xichun|X|;Feng|Jifeng|J|;Ouyang|Quchang|Q|;Tong|Zhongsheng|Z|;Li|Huiping|H|;Zhang|Qingyuan|Q|;Sun|Tao|T|;Wang|Xian|X|;Yin|Yongmei|Y|;Cheng|Ying|Y|;Li|Wei|W|;Gu|Yuanting|Y|;Chen|Qianjun|Q|;Liu|Jinping|J|;Cheng|Jing|J|;Geng|Cuizhi|C|;Qin|Shukui|S|;Wang|Shusen|S|;Lu|Jinsong|J|;Shen|Kunwei|K|;Liu|Qiang|Q|;Wang|Xiaojia|X|;Wang|Hong|H|;Luo|Ting|T|;Yang|Jin|J|;Wu|Yudong|Y|;Yu|Zhiyong|Z|;Zhu|Xiaoyu|X|;Chen|Chunxia|C|;Zou|Jianjun|J|;|||", "chemical_list": "D000178:Acrylamides; D000634:Aminoquinolines; C000622954:pyrotinib; D000077341:Lapatinib; D000069287:Capecitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2", "country": "England", "delete": false, "doi": "10.1016/S1470-2045(20)30702-6", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2045", "issue": "22(3)", "journal": "The Lancet. Oncology", "keywords": null, "medline_ta": "Lancet Oncol", "mesh_terms": "D000178:Acrylamides; D000328:Adult; D000634:Aminoquinolines; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077341:Lapatinib; D008875:Middle Aged; D011379:Prognosis; D018719:Receptor, ErbB-2; D015996:Survival Rate", "nlm_unique_id": "100957246", "other_id": null, "pages": "351-360", "pmc": null, "pmid": "33581774", "pubdate": "2021-03", "publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.", "title_normalized": "pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of her2 positive metastatic breast cancer phoebe a multicentre open label randomised controlled phase 3 trial" }

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{ "abstract": "Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for the active phase of moderate to severe Graves' orbitopathy (GO). However, acute and severe liver damage has been reported during and after IVMP therapy. In this retrospective study, we investigated risk factors for liver dysfunction during and after IVMP therapy based on 175 Japanese patients with moderate to severe GO and treated at our center between 2003 and 2011. The results showed that seven patients developed severe liver dysfunction with elevated serum alanine aminotransferase (ALT > 300 U/L). Mild (40-100 U/L) and moderate (100-300 U/L) increases of ALT occurred in 62 patients (35%) and 10 patients (6%), respectively. Liver dysfunction was more frequently observed in males, in patients receiving high-dose methylprednisolone, and patients aged over 50 years. Preexistent viral hepatitis was significantly associated with liver dysfunction (65% in patients positive for hepatitis B core antibody and patients positive for hepatitis C virus antibodies). Our study confirmed the association of liver dysfunction with IVMP during and after treatment. It suggests that, in patients with GO, evaluation of preexisting risk factors-including viral hepatitis-and careful weekly monitoring of liver function during IVMP therapy and monthly thereafter for 12 months are warranted.", "affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.;Department of Ophthalmology, Kurume University School of Medicine, Kurume 830-0011, Japan.;Department of Ophthalmology, Kurume University School of Medicine, Kurume 830-0011, Japan.;Division of Biostatistics Center, Kurume University, Kurume 830-0011, Japan.;Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.", "authors": "Eguchi|Hiroyuki|H|;Tani|Junichi|J|;Hirao|Saori|S|;Tsuruta|Munehisa|M|;Tokubuchi|Ichiro|I|;Yamada|Kentaro|K|;Kasaoka|Masataka|M|;Teshima|Yasuo|Y|;Kakuma|Tatsuyuki|T|;Hiromatsu|Yuji|Y|", "chemical_list": null, "country": "Egypt", "delete": false, "doi": "10.1155/2015/835979", "fulltext": "\n==== Front\nInt J EndocrinolInt J EndocrinolIJEInternational Journal of Endocrinology1687-83371687-8345Hindawi Publishing Corporation 10.1155/2015/835979Clinical StudyLiver Dysfunction Associated with Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy Eguchi Hiroyuki \n1\nTani Junichi \n1\nHirao Saori \n1\nTsuruta Munehisa \n1\nTokubuchi Ichiro \n1\nYamada Kentaro \n1\nKasaoka Masataka \n2\nTeshima Yasuo \n2\nKakuma Tatsuyuki \n3\nhttp://orcid.org/0000-0002-0415-5005Hiromatsu Yuji \n1\n\n*\n1Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan2Department of Ophthalmology, Kurume University School of Medicine, Kurume 830-0011, Japan3Division of Biostatistics Center, Kurume University, Kurume 830-0011, Japan*Yuji Hiromatsu: [email protected] Editor: Carlo Cappelli\n\n2015 28 6 2015 2015 83597931 12 2014 5 5 2015 7 5 2015 Copyright © 2015 Hiroyuki Eguchi et al.2015This 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.Intravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for the active phase of moderate to severe Graves' orbitopathy (GO). However, acute and severe liver damage has been reported during and after IVMP therapy. In this retrospective study, we investigated risk factors for liver dysfunction during and after IVMP therapy based on 175 Japanese patients with moderate to severe GO and treated at our center between 2003 and 2011. The results showed that seven patients developed severe liver dysfunction with elevated serum alanine aminotransferase (ALT > 300 U/L). Mild (40–100 U/L) and moderate (100–300 U/L) increases of ALT occurred in 62 patients (35%) and 10 patients (6%), respectively. Liver dysfunction was more frequently observed in males, in patients receiving high-dose methylprednisolone, and patients aged over 50 years. Preexistent viral hepatitis was significantly associated with liver dysfunction (65% in patients positive for hepatitis B core antibody and patients positive for hepatitis C virus antibodies). Our study confirmed the association of liver dysfunction with IVMP during and after treatment. It suggests that, in patients with GO, evaluation of preexisting risk factors—including viral hepatitis—and careful weekly monitoring of liver function during IVMP therapy and monthly thereafter for 12 months are warranted.\n==== Body\n1. Introduction\nIntravenous methylprednisolone (IVMP) pulse therapy is the first-line treatment for patients with active-phase moderate to severe Graves' orbitopathy (GO) [1]. IVMP is widely used because it is more effective and better tolerated than oral steroids [2, 3]. However, acute and severe liver damage has been reported after pulse therapy, with a roughly estimated morbidity and mortality of 0.8% and 0.3%, respectively [4]. The cumulative dose of IVMP in four patients with fatal liver failure was 8.3–15 g [4, 5] but slightly higher in three patients who died (10.8 ± 3.6 g) than in four patients who recovered (7.9 ± 2.9 g) [4]. Therefore, the European Group of Graves' Orbitopathy (EUGOGO) now recommends that the cumulative dose of MP should be less than 8 g [1, 6].\n\nThe causes of IVMP-associated liver damage are incompletely understood. Thus, the aim of the present study was to investigate the risk factors for liver dysfunction during and after IVMP pulse therapy for GO.\n\n2. Materials and Methods\n2.1. Study Population\nThis was a retrospective study of 175 Japanese patients with moderate to severe GO who were treated in one center from 2003 to 2013. The mean age of the 118 females and 57 males was 51.7 ± 15.5 years. They had been admitted to our university hospital for GO and were treated with an intravenous injection of 1 g of MP daily for 3 consecutive days per week, repeated for three to six cycles, and followed by a tapering dose of oral prednisolone (20 mg/day for 4 weeks, 15 mg/day for 2 weeks, 10 mg/day for 2 weeks, 5 mg/day for 2 weeks, and 5 mg/2 days for 2 weeks). The daily dose of MP was reduced to 0.5 g except in cases with optic neuropathy after the recommendation by EUGOGO in 2008 [1]. Heart rate and ECG were monitored during the intravenous infusion of MP, administered every 2-3 h. In addition, 100 of the 175 patients were treated with orbital irradiation therapy (2 Gy/day, 10 times; total dose = 20 Gy) either during or after IVMP pulse therapy. All patients were given artificial tear drops to protect the cornea. Histamine receptor 2 antagonists or proton pump inhibitors were administered for all the cases. Bisphosphonates were administered in 82 patients to protect steroid-induced osteoporosis.\n\n2.2. Biochemical Examination and Diagnosis of Thyroid Diseases\nThyroid diseases were diagnosed by measuring serum-free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroglobulin, anti-thyroglobulin antibody, anti-thyroid peroxidase antibody, and anti-thyrotropin receptor antibodies (TRAbs). TRAbs were measured using three commercial kits: TRAb 1st generation (TRAb Cosmic III, Cosmic, Tokyo, Japan), TRAb 2nd generation, human TRAb (Yamasa, Tokyo, Japan) and TSAb (Yamasa TSAb kit), and thyroid 123I uptake on 123I scintigraphy. Orbitopathy was estimated by ophthalmologists using a modified NOSPECS classification [7] and the clinical activity score (CAS) [1]. Magnetic resonance imaging was also performed before and after pulse therapy, as previously reported [8]. Graves' disease was detected in 139 patients, 29 patients were euthyroid without a history of Graves' disease, and 7 patients had hypothyroidism without a history of Graves' disease. Orbitopathy with NOSPECS class VI was determined in 8 patients, class V in 3 patients, class IV in 139 patients, class III in 23 patients, and class II in 2 patients.\n\nLiver function tests were performed once a week during pulse therapy and repeated at every visit thereafter for 1 year. Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and hepatitis C virus antibody (HCVAb) were measured before pulse therapy. The one patient who was HBsAg-positive consulted with a hepatologist, who prescribed 0.5 mg of entecavir, during and after pulse therapy. In addition, 43 patients were HBcAb-positive and 17 were HCVAb-positive. They likewise consulted with hepatologists before pulse therapy. Serum HBV-DNA was not detected in any patient. HBV-DNA and HCV-RNA were also monitored. Liver dysfunction was classified based on serum alanine aminotransferase (ALT) and total bilirubin levels as mild (ALT: 40–100 U/L), moderate (ALT: 100–300 U/L), or severe (ALT > 300 U/L or total bilirubin: >3 mg/dL).\n\n2.3. Clinical Characteristics of Patients with GO\nFemale and male GO patients significantly differed with respect to age, body mass index (BMI), smoking habits, alcohol habits, and HBcAb positivity before pulse therapy (Table 1). Human TRAb and TSAb levels were significantly higher in female than in male patients before IVMP pulse therapy.\n\n2.4. Statistical Analysis\nStatistical analysis was performed using JMP Pro software (version 11.0.0, SAS Institute, USA). Data are expressed as the mean ± standard deviation. Statistical comparisons were performed using Student's t-test, one-way ANOVA, or Mann-Whitney U test for the analysis of continuous variables. The χ\n2 test or Fisher's exact probability test was used to analyze 2 × 2 or 2 × 4 tables. Multivariate logistic regression analyses were carried out to evaluate the risk factors for liver dysfunction, using exact method (LogXact, Cytel Inc., USA). In all tests, a P value < 0.05 was considered to indicate significance.\n\n3. Results\n3.1. Liver Dysfunction\nIncreases of ALT during and/or after pulse therapy were detected in 79 patients (45%) (Table 2). Mild (ALT 40–100 U/L), moderate (ALT 100–300 U/L), and severe (ALT > 300 U/L) increases of serum ALT were measured in 62 patients (35%), 10 patients (6%), and 7 patients (4%), respectively. All patients with severe liver dysfunction were female and most of them were female. Two were HBcAb positive and one of them developed jaundice with ALT 945 U/L, one day after the cessation of IVMP. Her total bilirubin 8 weeks after the cessation of IVMP was 18.45 mg/dL. Single and cumulative doses of IVMP were 0.5 g and 3.5 g, respectively. HBV-DNA was not detected in patients with severe liver dysfunction. Anti-nuclear and anti-single-stranded DNA antibodies were also negative, as were anti-smooth muscle antibody, and anti-double-stranded DNA antibody in those patients. The HBV carrier taking entecavir prescribed by the hepatologist did not show the elevation of ALT.\n\n3.2. Factors Associated with Liver Dysfunction during or after Pulse Therapy for GO\nLiver dysfunction occurred more frequently in male patients (P < 0.0012) and in patients over the age of 50 years (P < 0.0009). BMI was significantly higher in patients with mild liver dysfunction than in those without liver dysfunction (23.3 ± 4.33 kg/m2 versus 22.0 ± 3.39 kg/m2, Student's t-test, P = 0.043, data not shown). Liver dysfunction was not associated with smoking or alcohol habit but it was associated with a high dose of MP (cumulative dose >8 g versus <8 g, 2 × 2 table, χ\n2 = 6.280, P = 0.0122). Preexistent viral hepatitis was significantly associated with liver dysfunction during and after pulse therapy (P = 0.0035). HBcAb was positive in 43 GO patients (25%) before pulse therapy. In 28 of them (65%), ALT was significantly increased (P = 0.01125), although in most the increase was mild. HCVAb was positive in 17 GO patients (10%) before pulse therapy. In this group, 11 patients (65%) had increased ALT levels (P = 0.01132).\n\n3.3. Multivariate Logistic Regression Analysis\nMultivariate logistic regression analysis showed that age, gender, and cumulative MP dose (>8 g) were associated with liver dysfunction (Table 2).\n\n4. Discussion\nAlthough IVMP pulse therapy is widely used as the first-line treatment for active moderate-to-severe orbitopathy, severe related side effects have been reported, the most common of which is hepatotoxicity. In the recent review by Zang et al. [9], the morbidity and mortality of GO patients treated with IVMP pulse therapy were 6.5% and 0.6%, respectively. Fatal hepatotoxicity was reported to be associated with a cumulative dose of IVMP > 8 g. In two studies, the cumulative doses were 8.3–15 g [4, 5]. EUGOGO now recommends that the cumulative dose of IVMP does not exceed 8 g [1].\n\nIn our series of 175 patients, seven patients (4.0%) developed severe liver dysfunction. The rate of morbidity was similar to the previous report [9]. The cumulative doses of MP were more than 8 g in 5 out of seven patients. However, single and cumulative doses of IVMP in a patient with jaundice were 0.5 g and 3.5 g, respectively.\n\nKoga et al. [10] reported two fatal cases of HBV carriers after corticosteroid therapy, and the frequent reactivation of HBV after immune suppressive therapy, such as with rituximab, was noted [11]. Therefore, in GO patients during IVMP therapy, the reactivation of HBV leading to acute liver failure remains a concern, although its occurrence is rare [4, 9, 12, 13]. Indeed, in the series of Le Moli et al. [12], none of the 27 patients with GO suffered serious liver damage. Wichary and Gasińska [13] concluded that the risk of HBV reactivation is low, based on their experience with 30 patients treated with IVMP. Those studies suggest that it is difficult to predict who will develop severe liver failure, such that it is important to carefully monitor patients during and after IVMP therapy.\n\nOur study identified risk factors for mild to moderate liver dysfunction during and after IVMP therapy for GO. Among male patients, a mild elevation of ALT was associated with a cumulative dose of IVMP > 8 g; in female patients, a moderate elevation of ALT was associated with age over 50 years. A history of HBV and HCV infection also contributed to a high prevalence of hepatotoxicity, as approximately 25% of our GO patients were HBcAb-positive and 10% were HCVAb-positive before pulse therapy. Within this group, 65% had increased ALT levels during and/or after pulse therapy. Multivariate logistic regression analysis showed that gender, age, and cumulative dose of MP were associated with liver dysfunction. Our study in Japanese patients suggests that viral hepatitis, gender, age, and cumulative dose are predisposing risk factors for hepatotoxicity during and after IVMP therapy. The current study also supports recommendations of a cumulative dose of MP < 8 g. However, as even this dose may not be completely safe, careful monitoring of GO patients receiving IVMP is recommended both during and 12 months after therapy.\n\nAlthough the mechanisms of mild to severe hepatotoxicity remain unclear, reactivation of viral hepatitis [4, 10, 11], a direct toxicity of MP [12–14], and exacerbation of autoimmune hepatitis have been suggested [15, 16]. Le Moli et al. [12] reported that mild elevations in liver enzymes following IVMP were dose dependent. The toxic effect of glucocorticoids on hepatocytes, leading to drug-induced steatohepatitis, is thought to involve mitochondrial injury because of the impaired β-oxidation of fatty acids, with subsequent generation of reactive oxygen species and ATP depletion [17].\n\nSalvi et al. [15] and Marinò et al. [16] reported the exacerbation of autoimmune hepatitis with severe liver dysfunction during IVMP therapy. In our series, two patients were positive for antinuclear and anti-smooth muscle antibodies but in both cases liver dysfunction was mild.\n\nThe drug-drug interaction may be another possible mechanism of liver dysfunction [18]. None of patients received aspirin in combination of Ramipril or clopidogrel.\n\nThere were several limitations to this study. First, it was retrospective in design. However, it allowed us to assess the effect of single and cumulative doses of IVMP, because in line with the EUGOGO's recommendation we reduced the single dose of IVMP from 1 g to 0.5 g. Another limitation of the study was the small number of patients, which prevented definite conclusions because of the low incidence of severe liver dysfunction. Additionally, no histopathological examinations were done and the effectiveness of IVMP for GO was not evaluated. Therefore, further prospective studies are indicated to assess the hepatotoxicity of IVMP during and after pulse therapy for GO.\n\nIn conclusion, liver dysfunction is frequently associated with pulse therapy for GO, both during and after treatment. Our study supports the careful evaluation of preexisting risk factors (especially viral hepatitis, age, gender, body mass index, and smoking history) before initiating IVMP therapy in GO patients. In these patients, strict monitoring of liver function once a week during pulse therapy and every month thereafter for the next 12 months is warranted.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nTable 1 Clinical characteristic of patients with Graves' orbitopathy.\n\n\tTotal\tMale\tFemale\tMale versus female\t\n\t\nN = 175\t\nN = 57\t\nN = 118\t\nP value\t\n\n\n\t\nAge (yr)\t51.7 ± 15.5\t55.9 ± 16.3\t49.6 ± 11.9\t0.012\t\n\n\n\t\nBMI (kg/m2)\t22.5 ± 3.7\t23.4 ± 3.8\t22.1 ± 2.7\t0.021\t\n\n\n\t\nHBcAb (+)\t43 (25%)\t21 (37%)\t22 (19%)\t0.0102\t\n\n\n\t\nHCVAb (+)\t17 (10%)\t9 (16%)\t8 (7%)\t0.0677\t\n\n\n\t\nHBcAb (−) HCVAb (−)\t122 (70%)\t31 (54%)\t91 (77%)\t—\t\n\n\n\t\nIVMP > 8 g \t118 (67%)\t40 (70%)\t78 (66%)\t0.5884\t\n\n\n\t\nSmoking (+)\t57 (33%)\t27 (47%)\t30 (25%)\t0.0041\t\n\n\n\t\nAlcohol (+)\t48 (27%)\t28 (49%)\t20 (17%)\t0.0001\t\n\n\n\t\nCAS\t3.1 ± 1.7\t3.2 ± 1.8\t3.0 ± 1.7\t0.8263\t\n\n\n\t\nTRAb (%)\t29.3 ± 27.3\t25.8 ± 26.1\t30.8 ± 27.8\t0.2987\t\n\n\n\t\nhTRAb (IU/L)\t17.7 ± 44.4\t8.10 ± 11.4\t21.9 ± 52.2\t0.0407\t\n\n\n\t\nTSAb (%)\t1262 ± 1480\t931 ± 1229\t1404 ± 1559\t0.0346\t\n\n\n\t\n \t \t \t \t\nMean ± SD\t\nBMI, body mass index; HBcAb, anti-hepatitis B core antibody; HCVAb, anti-hepatitis C virus antibody; IVMP, intravenous injection of methylprednisolone; CAS, clinical activity score; TRAb, anti-thyrotrophin antibody; hTRAb, human TRAb; TSAb, thyroid stimulating antibody.\n\nTable 2 Risk factors associated with liver dysfunction during and/or after intravenous methylprednisolone pulse therapy for Graves' orbitopathy.\n\n\tNumber of patients\t Liver dysfunction\tUnivariate\tMultivariate analysis \t\nALT (IU/L) \t\nFisher's exact probability test\t\nMultinomial logit model for\nan unordered response\t\n<40\t40–100\t100–300\t>300\t95% CI\t2 sided\t\n2 × 4\tLower\tUpper\t\nP value \t\nTotal\t175\t96 (55%)\t62 (35%)\t10 (6%)\t7 (4%)\t \t \t \t \t\n\n\n\t\nMale\t57\t21 (37%)\t31 (54%)\t5 (9%)\t0 (0%)\t\nχ\n2 = 18.34\t \t \t \t\nFemale\t118\t75 (64%)\t31 (26%)\t5 (4%)\t7 (6%)\t\nP = 0.000278\t0.1348\t1.646\t0.01895\t\n\n\n\t\nHBcA b (+)\t43\t15 (35%)\t24 (56%)\t2 (5%)\t2 (5%)\t\nχ\n2 = 11.01\t \t \t \t\n\nP = 0.01125\t \t \t \t\nHCVAb (+)\t17\t6 (35%)\t6 (35%)\t4 (24%)\t1 (6%)\t\nχ\n2 = 11.94\t \t \t \t\n\nP = 0.01132\t \t \t \t\nHBcAb (+) and/or HCVAb (+)\t53\t19 (36%)\t26 (49%)\t5 (9%)\t3 (6%)\t\nχ\n2 = 11.36\n\nP = 0.008867∗\n\t \n\n−0.245\t \n\n1.417\t \n\n0.1846\t\nHBcAb (−) HCVAb (−)\t122\t77 (63%)\t36 (30%)\t5 (4%)\t4 (3%)\t—\t \t \t \t\n\n\n\t\nAge\t \t \t \t \t \t \t \t \t \t\n >50 yr\t95\t41 (43%)\t45 (47%)\t8 (8%)\t1 (1%)\t\nχ\n2 = 20.72\t0.03396\t1.553\t0.03972\t\n ≦50 yr\t80\t55 (69%)\t17 (21%)\t2 (3%)\t6 (8%)\t\nP = 0.00004\t \t \t \t\n\n\n\t\nIVMP\t \t \t \t \t \t \t \t \t \t\n >8 g\t118\t57 (48%)\t47 (40%)\t9 (8%)\t5 (4%)\t\nχ\n2 = 7.187\t0.1012\t1.640\t0.02426\t\n <8 g\t57\t39 (89%)\t15 (26%)\t1 (2%)\t2 (4%)\t\nP = 0.06052\t \t \t \t\n\n\n\t\nSmoking\t \t \t \t \t \t \t \t \t \t\n (+)\t57\t26 (46%)\t24 (42%)\t4 (7%)\t3 (5%)\t\nχ\n2 = 2.969\t \t \t \t\n (−)\t118\t70 (59%)\t38 (32%)\t6 (5%)\t4 (3%)\t\nP = 0.3887\t \t \t \t\n\n\n\t\nAlcohol\t \t \t \t \t \t \t \t \t \t\n (+)\t48\t24 (50%)\t19 (40%)\t3 (6%)\t2 (4%)\t\nχ\n2 = 0.6445\t \t \t \t\n (−)\t127\t72 (57%)\t43 (34%)\t7 (6%)\t5 (4%)\t\nP = 0.9176\t \t \t \t\n\n∗Compared to patients without HBcAb or HCVAb.\n\nALT, alanine aminotransferase; HBcAb, anti-hepatitis B core antibody; HCVAb, anti-hepatitis C virus antibody; IVMP, intravenous injection of methylprednisolone.\n==== Refs\n1 Bartalena L. Baldeschi L. Dickinson A. Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO European Journal of Endocrinology 2008 158 3 273 285 10.1530/eje-07-0666 2-s2.0-40949140917 18299459 \n2 Marcocci C. Bartalena L. Tanda M. L. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study Journal of Clinical Endocrinology and Metabolism 2001 86 8 3562 3567 10.1210/jc.86.8.3562 2-s2.0-17944370142 11502779 \n3 Kahaly G. J. Pitz S. Hommel G. Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in graves' orbitopathy Journal of Clinical Endocrinology and Metabolism 2005 90 9 5234 5240 10.1210/jc.2005-0148 2-s2.0-24344492353 15998777 \n4 Marinól M. Morabito E. Brunetto M. R. Bartalena L. Pinchera A. Marocci C. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves' ophthalmopathy Thyroid 2004 14 5 403 406 10.1089/105072504774193276 2-s2.0-2942614927 15186621 \n5 Weissel M. Hauff W. Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease Thyroid 2000 10 6 p. 521 2-s2.0-0033933033 \n6 Marcocci C. Watt T. Altea M. A. Fatal and non-fatal adverse events of glucocorticoid therapy for Graves' orbitopathy: a questionnaire survey among members of the European Thyroid Association European Journal of Endocrinology 2012 166 2 247 253 10.1530/eje-11-0779 2-s2.0-84856100099 22058081 \n7 Classification of eye changes of Graves' disease Thyroid 1992 2 3 235 236 10.1089/thy.1992.2.235 1422237 \n8 Hiromatsu Y. Kojima K. Ishisaka N. Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy Thyroid 1992 2 4 299 305 10.1089/thy.1992.2.299 2-s2.0-0027048376 1493371 \n9 Zang S. Ponto K. A. Kahaly G. J. Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity The Journal of Clinical Endocrinology and Metabolism 2011 96 2 320 332 10.1210/jc.2010-1962 2-s2.0-79951716568 21239515 \n10 Koga Y. Kumashiro R. Yasumoto K. Two fatal cases of hepatitis B virus carriers after corticosteroid therapy for bronchial asthma Internal Medicine 1992 31 2 208 213 10.2169/internalmedicine.31.208 2-s2.0-0026722143 1600269 \n11 Seto W. K. Chan T. S. Hwang Y. Y. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study Journal of Clinical Oncology 2014 32 3736 3743 25287829 \n12 Le Moli R. Baldeschi L. Saeed P. Regensburg N. Mourits M. P. Wiersinga W. M. Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy Thyroid 2007 17 4 357 362 10.1089/thy.2006.0267 2-s2.0-34248657570 17465867 \n13 Wichary H. Gasińska T. Methylprednisolone and hepatotoxicity in Graves' ophthalmopathy Thyroid 2012 22 1 64 69 10.1089/thy.2010.0158 2-s2.0-84855427170 22029719 \n14 Kaplowitz N. Drug-induced liver injury Clinical Infectious Diseases 2004 38 supplement 2 S44 S48 10.1086/381446 2-s2.0-1542327565 14986274 \n15 Salvi M. Vannucchi G. Sbrozzi F. Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto's thyroiditis: case report Thyroid 2004 14 8 631 634 10.1089/1050725041692927 2-s2.0-4143065899 15320978 \n16 Marinò M. Morabito E. Altea M. A. Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves Journal of Endocrinological Investigation 2005 28 3 280 284 10.1007/bf03345386 2-s2.0-21444443356 15952415 \n17 Farrell G. C. Drugs and steatohepatitis Seminars in Liver Disease 2002 22 2 185 194 10.1055/s-2002-30106 2-s2.0-0036247430 12016549 \n18 Goyal R. K. Srivastava D. Lessnau K.-D. Clopidogrel-induced hepatocellular injury and cholestatic jaundice in an elderly patient: case report and review of the literature Pharmacotherapy 2009 29 5 608 612 10.1592/phco.29.5.608 2-s2.0-66249124628 19397467\n\n", "fulltext_license": "CC BY", "issn_linking": "1687-8337", "issue": "2015()", "journal": "International journal of endocrinology", "keywords": null, "medline_ta": "Int J Endocrinol", "mesh_terms": null, "nlm_unique_id": "101516376", "other_id": null, "pages": "835979", "pmc": null, "pmid": "26221141", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "1600269;14986274;11502779;25287829;15952415;12016549;18299459;17465867;10907999;22058081;1422237;15998777;15186621;21239515;1493371;15320978;22029719;19397467", "title": "Liver Dysfunction Associated with Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy.", "title_normalized": "liver dysfunction associated with intravenous methylprednisolone pulse therapy in patients with graves orbitopathy" }

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LIVER DYSFUNCTION ASSOCIATED WITH INTRAVENOUS METHYLPREDNISOLONE PULSE THERAPY IN PATIENTS WITH GRAVES^ ORBITOPATHY.. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY. 2015;2015:835979 (5 PAGES)", "literaturereference_normalized": "liver dysfunction associated with intravenous methylprednisolone pulse therapy in patients with graves orbitopathy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20150818", "receivedate": "20150818", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11389951, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20151125" } ]

{ "abstract": "This paper describes the association of two unusual side effects of treatment with isotretinoin for severe acne: paronychia and excess granulation tissue in the nails furrows. We report a case of male patient aged 19 years, who in the course of the 36th week of treatment with isotretinoin for acne grade III showed erythema, edema, excess granulation tissue and onychocryptosis in various nail beds of hands and feet, with no history of trauma associated. A literature review revealed few reports of these adverse events, and two clinical patterns of exuberant granulation tissue has been described: one in periungual location and other in lesions of previous acne. The rarity and lack of knowledge on the best treatment for granuloma-like reactions make this theme a considerable challenge.", "affiliations": "Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.;Instituto Materno Infantil Professor Fernando Figueira, Recife, PE, Brazil.", "authors": "Figueiras|Daniela de Almeida|Dde A|;Ramos|Ticiana Batista|TB|;Marinho|Ayana Karla de Oliveira Ferreira|AK|;Bezerra|Milena Soneley Mendonça|MS|;Cauas|Renata Cavalcanti|RC|", "chemical_list": "D015474:Isotretinoin", "country": "Spain", "delete": false, "doi": null, "fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolabdAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20163817Case ReportParonychia and granulation tissue formation during treatment with\nisotretinoin*\n Figueiras Daniela de Almeida 1Ramos Ticiana Batista 1Marinho Ayana Karla de Oliveira Ferreira 1Bezerra Milena Soneley Mendonça 1Cauas Renata Cavalcanti 11 Instituto Materno Infantil Professor Fernando\nFigueira (IMIP) – Recife (PE), Brazil.Mailing address: Daniela de Almeida Figueiras, Rua dos Coelhos,\n300, Boa Vista, 50070-902 - Recife -PE. Brazil Email:\[email protected] 2016 Mar-Apr 2016 91 2 223 225 05 7 2014 04 11 2014 © 2016 by Anais Brasileiros de\nDermatologia2016This is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium provided the original work is properly cited.This paper describes the association of two unusual side effects of treatment\nwith isotretinoin for severe acne: paronychia and excess granulation tissue in\nthe nails furrows. We report a case of male patient aged 19 years, who in the\ncourse of the 36th week of treatment with isotretinoin for acne grade III showed\nerythema, edema, excess granulation tissue and onychocryptosis in various nail\nbeds of hands and feet, with no history of trauma associated. A literature\nreview revealed few reports of these adverse events, and two clinical patterns\nof exuberant granulation tissue has been described: one in periungual location\nand other in lesions of previous acne. The rarity and lack of knowledge on the\nbest treatment for granuloma-like reactions make this theme a considerable\nchallenge.\n\nParonychiaGranulation tissueRetinoids\n==== Body\nINTRODUCTION\nIsotretinoin is effective and widely used in the treatment of nodulocystic acne, acne\nconglobata, acne with risk of permanent scarring and those resistant to the use of\nsystemic antibiotics and topical agents, as indicated in the letter from Kanigsberg\n& Des Groseilliers.1\n\nAdverse events of isotretinoin are well known as teratogenicity, myalgias and\narthralgias, hypertriglyceridemia, hypercholesterolemia and elevated\ntransaminases.\n\nIt is also associated with numerous adverse events including skin cheilitis, facial\ndermatitis, xerosis, rash, conjunctivitis, epistaxis, photosensitivity and dryness\nof mucous membranes. These are commonly observed and generally do not limit its\nuse.\n\nRarely patients may have stimulation of granulation tissue, leading to pyogenic\ngranuloma eruptions of acne lesions in areas of trauma and in nail folds; paronychia\nmay also occur.2,3 Knowing these unusual adverse events is important for the\nclinical management of patients, but its exact pathogenesis remains unclear.\n\nCASE REPORT\nMan, aged 19 years, with acne grade III, without comorbidities, pre-existing nail\nproblems or prior use of medication. He started treatment with isotretinoin at a\ndose of 40 mg/day (0.54 mg/kg/day).\n\nIn the sixth month of treatment, the patient presented edema, erosion and periungual\nerythema with serous discharge in 20 nails and onychocryptosis with excessive\ngranulation tissue on toes. He reported to have undergone treatment with “topic\ncreams” and compresses with boric acid solution prescribed in the emergency\ndepartment, with improvement of the lesions on the hands. Upon returning to our\nservice, the patient showed lesions in the first and second toes bilaterally and on\nthe right toe (Figures 1, 2 and 3).\n\nFigure 1 Paronychia and granulation tissue in feet, secondary to the use of\nisotretinoin\n\n\n\nFigure 2 Pyogenic-like granuloma and paronychia in lateral edge of the first and\nsecond right toes\n\n\n\nFigure 3 Excess of periungueal granulation tissue and paronychia, located in the\nfirst left toe\n\n\n\nTreatment with oral antibiotics was performed, with course of prednisone 40 mg/day,\ncompress with boric acid solution and guidance on the use of appropriate footwear.\nThe isotretinoin was maintained until obtaining a cumulative dose of 120 mg/kg,\ntotaling 7 months.\n\nAfter the end of treatment with isotretinoin, the patient evolved with improvement of\nparonychia and granulation tissue on toes, but with persistence of onychocryptosis\nin hallux valgus. Subsequently, the patient was submitted to matricectomy with\ncomplete resolution of the disease (Figure\n4).\n\nFigure 4 Two months after the completion of matricectomy: patient presented\nresolution of onicocriptosis without recurrence of the lesions on\ntoes\n\n\n\nDISCUSSION\nIsotretinoin was first introduced in the United States in 1982 for the treatment of\nnodulocystic acne, being the only medication that affects all of the major\netiological factors involved in acne. Although isotretinoin is a highly effective\ndrug, its clinical use has always been associated with reports of adverse events\nwith several implications for the patient. It is therefore essential that physicians\nbe aware of the adverse events that may occur during therapy with isotretinoin.\n4\n\nExuberant granulation tissue is described in the literature in patients using\nisotretinoin for acne treatment, but its occurrence is rare with few reports\ndescribed.\n\nThe largest series conducted in 1988 reported 4 cases of paronychia caused by\nexcessive growth of the lateral and distal nail folds, with an excess of granulation\ntissue associated. 5 Multiple\nfingers were involved in all patients and the attempt to restart isotretinoin in one\npatient led to the resurgence of previous lesions, suggesting causality.\n\nThe exact mechanism by which retinoids may lead to the development of granulation\ntissue in skin is not well known. Baran et al suggest that, in susceptible patients,\nexcess retinoids would lead to exacerbation of their functions in epithelial level\nof the nail matrix, generating local exfoliative dermatitis, with accumulation of\nscales in the nail folds. 6 The\nscales would act as foreign bodies, causing inflammation and formation of\ngranulation tissue. The nail fragility may also lead to the formation of nail\nspicules that, when introduced in the periungual tissue, would stimulate the\nappearance of granulation tissue and the ingrown toenail. Finally, the skin\nfragility of the periungual tissue under high doses of retinoids, associated with\ntrauma and/or local bacterial infection, may stimulate the formation of granulation\ntissue.\n\nIsotretinoin is also known to cause exuberant granulation tissue or pyogenic-like\ngranuloma lesions in acne sites between the 3rd and 12th week\nof treatment. 7 Reuben et al.\nsuggest that, according to the characteristics of the treatment group, such event\nmay not be as rare as previously thought. They observed the occurrence of exuberant\ngranulation tissue in 3 patients out of a total of 16 who used the drug.8 Therefore, it is reasonable to\nsuggest that it would cause such changes in other parts of the body.\n\nIn addition, periungual exuberant granulation tissue of both fingers and toes is a\ndocumented adverse event of other retinoids therapies. Campbell et al reported 6\npatients who develop this complication during therapy with etretinate for\npsoriasis.9 These lesions\nappear to be idiosyncratic and unrelated to the daily dose or total cumulative dose.\nSimilar comment can be made regarding our patient who developed the first lesions\nwith 6 months of treatment without having any change in the dosages used.\n\nThus, the knowledge of this unusual adverse event is important for the clinical\nmanagement of patients treated with isotretinoin, and it seems that it is not\nnecessary to discontinue it for the resolution of the lesion. Thus, advantages and\ndisadvantages of discontinuing therapy for this problem should be carefully weighed.\nAccording to the literature, a course of 2-3 weeks of topical steroid and antibiotic\non the occlusion is the first line of treatment for periungual pyogenic granuloma.\n10 In cases where the\nlocal treatment is insufficient, surgical removal becomes necessary.\n\nConflict of Interest: None.\n\nFinancial Support: None.\n\n* Study performed at Instituto Materno Infantil Professor Fernando Figueira (IMIP)\n– Recife (PE), Brazil.\n==== Refs\nREFERENCES\n1 Kanigsberg N DesGroseilliers JP Use of 13-cis-retinoic acid in cystic acne Can Med Assoc J 1983 129 224 224 228 228 6222787 \n2 Exner JH Dahod S Pochi PE Pyogenic granuloma-like acne lesions during isotretinoin\ntherapy Arch Dermatol 1983 119 808 811 6225396 \n3 Brelsford M Beute TC Preventing and managing the side effects of\nisotretinoin Semin Cutan Med Surg 2008 27 197 206 18786498 \n4 Charakida A Mouser PE Chu AC Safety and side effects of the acne drug, oral\nisotretinoin Expert Opin Drug Saf 2004 3 119 129 15006718 \n5 Bigby M Stern RS Adverse reactions to isotretinoin. A report from the Adverse Drug\nReaction Reporting System J Am Acad Dermatol 1988 18 543 552 3280622 \n6 Baran R Etretinate and the nails (study of 130 cases) possible mechanisms\nof some side-effects Clin Exp Dermatol 1986 11 148 152 3720014 \n7 Hagler J Hodak E David M Sandbank M Facial pyogenic granuloma-like lesions under isotretinoin\ntherapy Int J Dermatol 1992 31 199 200 1533205 \n8 Azulay RD Abulafia LA Costa JAN Sodré CT Tecido de granulação exuberante: efeito\ncolateral da terapêutica com\nisotretinoína An Bras Dermatol 1985 60 179 182 \n9 Campbell JP Grekin RC Ellis CN Matsuda-John SS Swanson NA Voorhees JJ Retinoid therapy is associated with excess granulation tissue\nresponses J Am Acad Dermatol 1983 9 708 713 6227639 \n10 Piraccini BM Bellavista S Misciali C Tosti A de Berker D Richert B Periungual and subungual pyogenic granuloma Br J Dermatol 2010 163 941 953 20545691\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0365-0596", "issue": "91(2)", "journal": "Anais brasileiros de dermatologia", "keywords": null, "medline_ta": "An Bras Dermatol", "mesh_terms": "D000152:Acne Vulgaris; D006097:Granulation Tissue; D017789:Granuloma, Pyogenic; D006801:Humans; D015474:Isotretinoin; D008297:Male; D009260:Nail Diseases; D010304:Paronychia; D016896:Treatment Outcome; D055815:Young Adult", "nlm_unique_id": "0067662", "other_id": null, "pages": "223-5", "pmc": null, "pmid": "27192525", "pubdate": "2016-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "15006718;6222787;6225396;6227639;20545691;3280622;1533205;18786498;3720014", "title": "Paronychia and granulation tissue formation during treatment with isotretinoin.", "title_normalized": "paronychia and granulation tissue formation during treatment with isotretinoin" }

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{ "abstract": "Immunoglobulin G4 (IgG4)-related disease is a systemic autoimmune disease that can affect various organs. Corticosteroid therapy is generally an effective treatment; however, IgG4-related aortic lesions pose a risk of aortic rupture related to corticosteroid use. Here, we report a case of IgG4-related periaortitis complicated with a false aneurysm during corticosteroid therapy. Although endovascular repair was successfully performed, autoimmune pancreatitis and sclerosing cholangitis emerged after surgery. The multiple lesions associated with IgG4-related disease were resolved through continuous corticosteroid therapy. Our case suggests that both appropriate surgical intervention and continuous corticosteroid therapy are essential for the treatment of IgG4-related periaortitis.", "affiliations": "Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan. Electronic address: [email protected].;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, Tsukuba Medical Center Hospital, Tsukuba, Japan.;Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba, Japan.", "authors": "Ikeda|Akihiko|A|;Mitomi|Kisato|K|;Konishi|Taisuke|T|;Matsuzaki|Kanji|K|;Jikuya|Tomoaki|T|;Hiramatsu|Yuji|Y|", "chemical_list": "D000305:Adrenal Cortex Hormones; D007074:Immunoglobulin G", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0890-5096", "issue": "29(7)", "journal": "Annals of vascular surgery", "keywords": null, "medline_ta": "Ann Vasc Surg", "mesh_terms": "D000305:Adrenal Cortex Hormones; D000368:Aged; D017541:Aneurysm, False; D001014:Aortic Aneurysm; D001027:Aortography; D001327:Autoimmune Diseases; D019917:Blood Vessel Prosthesis Implantation; D015209:Cholangitis, Sclerosing; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D010195:Pancreatitis; D012185:Retroperitoneal Fibrosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome", "nlm_unique_id": "8703941", "other_id": null, "pages": "1452.e5-9", "pmc": null, "pmid": "26122411", "pubdate": "2015-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Endovascular Repair of a False Aneurysm Developing from IgG4-Related Periaortitis during Corticosteroid Therapy.", "title_normalized": "endovascular repair of a false aneurysm developing from igg4 related periaortitis during corticosteroid therapy" }

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ENDOVASCULAR REPAIR OF A FALSE ANEURYSM DEVELOPING FROM IGG4-RELATED PERIAORTITIS DURING CORTICOSTEROID THERAPY. ANN-VASC-SURG. 2015?29 (7):1452.E5-1", "literaturereference_normalized": "endovascular repair of a false aneurysm developing from igg4 related periaortitis during corticosteroid therapy", "qualification": "3", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20151014", "receivedate": "20151014", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11629747, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" }, { "companynumb": "JP-MYLANLABS-2015M1035484", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "20 MG/DAY", "drugenddate": null, "drugenddateformat": null, "drugindication": "AORTITIS", "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": "4", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "202179", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "5 MG/DAY", "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." } ], "patientagegroup": null, "patientonsetage": null, "patientonsetageunit": null, "patientsex": null, "patientweight": null, "reaction": [ { "reactionmeddrapt": "Vascular pseudoaneurysm", "reactionmeddraversionpt": "19.0", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "IKEDA A, MITOMI K, KONISHI T, MATSUZAKI K, JIKUYA T, HIRAMATSU Y. ENDOVASCULAR REPAIR OF A FALSE ANEURYSM DEVELOPING FROM IGG4-RELATED PERIAORTITIS DURING CORTICOSTEROID THERAPY. ANN-VASC-SURG 2015; 29(7):1452.E5-1.. 2015;29(7):1452.E5-1", "literaturereference_normalized": "endovascular repair of a false aneurysm developing from igg4 related periaortitis during corticosteroid therapy", "qualification": "1", "reportercountry": "JP" }, "primarysourcecountry": "JP", "receiptdate": "20160527", "receivedate": "20151021", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 11650700, "safetyreportversion": 2, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20160815" } ]

{ "abstract": "Radiation necrosis is a potentially debilitating side effect of therapy necessary to treat pediatric central nervous system tumors. Clinical signs of cerebral radiation necrosis (CRN) are similar to symptoms of disease progression and require close monitoring. The case of an infant diagnosed with a malignant rhabdoid tumor is presented to describe the medical and rehabilitation interventions implemented to address CRN. Rehabilitation providers should routinely be consulted in children with CRN as they fill a critical role in treatment, neurological symptom monitoring, and intervention planning to address family-centered functional goals.", "affiliations": "Department of Occupational Therapy, Washington University School of Medicine, St. Louis, Missouri.;Howard Head Sports Medicine, Edwards, Colorado.;Department Radiation Oncology, University of Colorado Anschutz, Aurora, Colorado.;Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado.;Department of Pediatrics, University of Colorado Anschutz, Aurora, Colorado.", "authors": "L'Hotta|Allison J|AJ|0000-0001-7825-2492;Thomas|Kristin M|KM|;Milgrom|Sarah A|SA|;Hemenway|Molly S|MS|;Levy|Jean M Mulcahy|JMM|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/pbc.28705", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "68(1)", "journal": "Pediatric blood & cancer", "keywords": "CNS tumors; neuro-oncology; radiation therapy; rehabilitation", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D016543:Central Nervous System Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D007223:Infant; D011379:Prognosis; D011832:Radiation Injuries", "nlm_unique_id": "101186624", "other_id": null, "pages": "e28705", "pmc": null, "pmid": "32985070", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Medical and rehabilitation interventions in pediatric central nervous system radiation necrosis: A case report.", "title_normalized": "medical and rehabilitation interventions in pediatric central nervous system radiation necrosis a case report" }

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"activesubstancename": "CISPLATIN" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "CISPLATIN." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "THIOTEPA" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": null, "drugbatchnumb": null, "drugcharacterization": "1", 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"drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "ETOPOSIDE." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE SODIUM" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "011719", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "METHOTREXATE SODIUM." }, { "actiondrug": "6", "activesubstance": { "activesubstancename": "VINCRISTINE SULFATE" }, "drugadditional": null, "drugadministrationroute": null, "drugauthorizationnumb": "071484", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "UNK, CYCLIC", "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": "VINCRISTINE SULFATE." } ], "patientagegroup": null, "patientonsetage": "11", "patientonsetageunit": "802", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Respiratory disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Renal disorder", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Radiation necrosis", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pyrexia", "reactionmeddraversionpt": "24.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "L^HOTTA, A.. MEDICAL AND REHABILITATION INTERVENTIONS IN PEDIATRIC CENTRAL NERVOUS SYSTEM RADIATION NECROSIS: A CASE REPORT. PEDIATRIC BLOOD AND CANCER. 2021?68 (1):10.1002/PBC.28705", "literaturereference_normalized": "medical and rehabilitation interventions in pediatric central nervous system radiation necrosis a case report", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20210415", "receivedate": "20210415", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 19140556, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20210717" } ]

{ "abstract": "BACKGROUND\nPolyethylene glycols (PEGs) or macrogols are polyether compounds and are widely used as additives in pharmaceuticals, cosmetics, and food.\n\n\nMETHODS\nWe report on a Caucasian patient experiencing recurrent severe allergic reactions to several drugs. An extensive diagnostic workup including skin prick tests, intradermal tests (IDT) and a double-blind oral challenge was performed to identify the trigger of anaphylaxis. In the present case hypersensitivity to the additive polyethylene glycol was confirmed by an IDT suggesting an Immunoglobulin E-dependent mechanism as a cause of the reaction.\n\n\nCONCLUSIONS\nPotential life-threatening hypersensitivity reactions to hidden molecules like macrogol may be underdiagnosed. Cases of immediate-type PEG hypersensitivity were reported with increasing frequency. The awareness regarding the allergenic potential of PEG should be raised and a proper product labelling is crucial to prevent PEG mediated hypersensitivity.", "affiliations": "Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.;Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.;Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.", "authors": "Wylon|Katharina|K|;Dölle|Sabine|S|;Worm|Margitta|M|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s13223-016-0172-7", "fulltext": "\n==== Front\nAllergy Asthma Clin ImmunolAllergy Asthma Clin ImmunolAllergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology1710-14841710-1492BioMed Central London 17210.1186/s13223-016-0172-7Case ReportPolyethylene glycol as a cause of anaphylaxis Wylon Katharina [email protected] Dölle Sabine [email protected] Worm Margitta [email protected] Klinik für Dermatologie, Venerologie und Allergologie, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany 13 12 2016 13 12 2016 2016 12 6710 6 2016 29 11 2016 © The Author(s) 2016\nOpen 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\nPolyethylene glycols (PEGs) or macrogols are polyether compounds and are widely used as additives in pharmaceuticals, cosmetics, and food.\n\nCase report\nWe report on a Caucasian patient experiencing recurrent severe allergic reactions to several drugs. An extensive diagnostic workup including skin prick tests, intradermal tests (IDT) and a double-blind oral challenge was performed to identify the trigger of anaphylaxis. In the present case hypersensitivity to the additive polyethylene glycol was confirmed by an IDT suggesting an Immunoglobulin E-dependent mechanism as a cause of the reaction.\n\nConclusion\nPotential life-threatening hypersensitivity reactions to hidden molecules like macrogol may be underdiagnosed. Cases of immediate-type PEG hypersensitivity were reported with increasing frequency. The awareness regarding the allergenic potential of PEG should be raised and a proper product labelling is crucial to prevent PEG mediated hypersensitivity.\n\nKeywords\nAnaphylaxisDrug additivesHypersensitivityMacrogolPolyethylene glycolissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\n\nPolyethylene glycol (PEG) or macrogol is a polyether compound. It is widely used as an additive in pharmaceuticals, cosmetics and food [1]. Different types of macrogol exist according to their molecular weight from 300 g/mol to 10,000,000 g/mol [2]. Anaphylactic reactions to macrogol are rarely reported. However, in recent years more reports appeared in the literature with macrogol induced hypersensitivities due to drugs, personal hygiene products, dental products, lozenges and lubricants [3, 4]. Here we report on a female with a history of three immediate type reactions triggered by macrogol 3350.\n\nCase report\nA 46-year-old Caucasian female with no known allergies received an intraarticular injection with a local anesthetic (Xylonest®: prilocaine, sodium chloride, sodium hydroxide/hydrochloric acid 7%). Eight hour after the injection she experienced nausea and a generalized pruritus. The symptoms resolved the next day without any medical treatment. One day later the patient was given an injection with medroxyprogesteronacetate (Clinovir®: medroxyprogesteronacetate, methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate, macrogol 3350, polysorbate 80, sodium chloride) from her gynecologist. Five minutes after the injection she developed generalized pruritus, sneezing, nausea and tachycardia. Previous injections with medroxyprogesteronacetate and prilocaine were well tolerated.\n\nOne year later the patient received an injection to treat a lumbar intervertebral disc prolapse containing lidocaine, bupivacaine hydrochloride, triamcinolone acetonide (Triamhexal®: triamcinolonacetonide, benzyl alcohol, macrogol 4000, sodium chloride, sodium dihydrogen phosphate-dihydrate, sodium hydrogen carbonate, polysorbate 80). Within 5 min the patient developed systemic anaphylactic symptoms, including pruritus, nausea, tachycardia and flush.\n\nThe patient presented to our outpatient clinic 4 months after the first incident and 3 days after the third reaction. We initiated an allergological work-up including skin prick tests with macrogol, Clinovir®, latex, benzyl alcohol, paraben mix, sodium-benzoate, p-hydroxybenzate acid, sodium-metabisulfite, local anesthetics (procaine 1%, lidocaine 1%, bupivacaine 0.5%, prilocaine 1%, articaine 1%, mepivacaine 1%, scandicaine 1%, xylocaine 1%, ultracaine 1%, novocaine 1%), glucocorticosteroids (dexamethasone, prednisolone, triamcinolone, methylprednisolone) which were negative for all tested substances (Table 1). A negative control (sodium chloride 0.9%) and a positive control (histamine 10 mg/ml) were included. Total immunoglobulin E (IgE) was 93.5 kU/l and tryptase was 1.8 µg/l. A double-blind, placebo-controlled oral challenge with the additives which are in the preparations of Clinovir® and Triamhexal® (sodium-benzoate 250 mg and p-hydroxybenzoic acid 250 mg) was negative (Table 2). An intradermal test was performed with local anesthetics and additives of the suspected trigger substances (1% macrogol 3350, 10% macrogol 3350, polysorbate 80, scandicaine, xylocaine, ultracaine, bupivacaine, prilocaine, novocaine). After injecting 1% macrogol 3350 intradermal a 6 mm wheel was seen. 15 min later we carried out a second intradermal test with 10% macrogol 3350 which showed a 6 mm wheel diameter (Table 3). Consecutively the patient developed a systemic reaction with generalized pruritus and a generalized urticaria. The wheel diameter enlarged up to 12 mm, 5 min after the application.Table 1 Skin prick test (interpretation after 15 min)\n\nNegative control\tSodium chloride 0.9%\t0 mm\t\nPositive control\tHistamine\t4 mm\t\nLocal anesthetics\tProcaine 1%, lidocaine 1%, bupivacaine 0,5%, prilocaine 1%, articaine 1%, mepivacaine 1%, scandicaine 1%, xylocaine 1%, ultracaine 1%, novocaine 1%\t0 mm\t\nGlucocorticosteroids\tDexamethasone, prednisolone, triamcinolone, methylprednisolone \t0 mm\t\nOthers\tMacrogol 3350 1%, macrogol 3350 10%, Depot Clinovir®, latex, benzyl alcohol 1%, paraben mix 16%, sodium-benzoate 5%, p-hydroxybenzate acid, sodium-metabisulfite\t0 mm\t\nPositive test result: wheel diameter >3 mm\n\n\nTable 2 Double-blind oral challenge\n\nAdditives\tNa-benzoate 250 mg, p-hydroxybenzoic acid 250 mg\tNegative\t\n\nTable 3 Intradermal test (interpretation after 15 min)\n\nNegative control\tNaCl\t0 mm\t\nPositive control\tHistamine\t4 mm\t\nAdditives\tMacrogol 3350 1%\t6 mm\t\n\tMacrogol 3350 10%\t6 mm\t\n\tPolysorbate 80 1%\t0 mm\t\nLocal anesthetics\tScandicaine 1%, xylocaine 1%, ultracaine 1%, bupivacaine 0,5%, prilocaine 1%, novocaine 1%\t0 mm\t\nPositive test result: wheel diameter >3 mm\n\n\n\n\nBased on the history and the obtained skin test results our patient was diagnosed with an immediate type reaction to macrogol. We suspect that the first severe allergic reaction our patient experienced was not solely induced by prilocaine but another local anesthetic or an unknown additive containing macrogol. We prescribed an emergency kit containing an epinephrine auto-injector, a glucocorticosteroid and an antihistamine. The patient received an allergy pass and was instructed to avoid PEG analogues when taking new, over-the-counter drugs prescription drugs, personal hygiene products, dental products and other potentially PEG containing products.\n\nTwo years after the diagnosis of the hypersensitivity to macrogol the patient ingested WICK Medinait® (paracetamol, dextromethorphan hydrobromide, doxylaminsuccinate, sucrose, glycerol, macrogol 6000, sodium citrate, sodium benzoate, potassium sorbate) treating a common cold. Again, she developed dyspnea and a generalized rash.\n\nConclusions\nHowever, data from the European anaphylaxis-registry with currently 7935 registered anaphylactic cases only three were induced by macrogol. These findings may imply that polyethylene glycol hypersensitivity is potentially life-threatening but probably underdiagnosed as many drugs and food items contain macrogol [4–6]. Handling patients with macrogol hypersensitivity can be challenging because of the extensive allergologic work up, the necessity of the physician’s expertise and the limited avoidance options because many drugs, including those used for the treatment of allergic reactions such as antihistamines may contain macrogol as an additive [5]. Therefore, specific product labeling and awareness is required. Patients should be educated about drugs which may contain PEGs, but also other products like lubricants or ultrasound gels. Our case indicated the need for an increased patient and physician awareness to the allergic potential of macrogol.\n\nConcerning the mechanism of anaphylaxis mediated by PEGs different mechanisms have been proposed. Our case supports the assumption of cross-reactivity between PEGs of different molecular weights and polyethylene glycol analogues [7, 8]. Like other authors have previously shown, the positive intradermal test suggests an IgE-dependent mechanism, although no control tests were performed on healthy individuals to rule out unspecific reactivity [9]. However, even after a 1:10 dilution a positive intradermal test was observed. Other methods besides an oral challenge test to confirm the diagnosis may be by basophil activation test or western blot to show specific IgE binding [9].\n\nIn conclusion, cases of immediate-type PEG hypersensitivity are reported with increasing frequency, therefore, awareness of PEG’s allergenic potential should be raised and better product labeling should be discussed.\n\nAbbreviations\nIgEimmunoglobulin E\n\nIDTintradermal test\n\nPEGpolyethylene glycol\n\nAuthors’ contributions\nKW collected the data and wrote the manuscript. SD provided and analyzed the data from the anaphylaxis registry. MW coordinated and edited the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAvailability of data and materials\nAll data is stored and available in the patients case files and may be requested to see a copy at any stage.\n\nConsent for publication\nWritten and oral informed consent for publication has been obtained from the patients and stored in the case files and may be requested to see a copy at any stage.\n\nEthics approval and consent to participate\nWritten and oral informed consent to participate has been obtained from the patients and stored in the case files and may be requested to see a copy at any stage.\n\nFunding\nThe publication fee will be funded by NORA eV (Network for Online-Registration of Anaphylaxis).\n==== Refs\nReferences\n1. Pizzimenti S Heffler E Gentilcore E Raie A Bussolino C Nebiolo F Macrogol hypersensitivity reactions during cleansing preparation for colon endoscopy J Allergy Clin Immunol Pract 2014 2 3 353 354 10.1016/j.jaip.2014.01.017 24811032 \n2. Jakasa I Verberk MM Esposito M Bos JD Kezic S Altered penetration of polyethylene glycols into uninvolved skin of atopic dermatitis patients J Invest Dermatol 2007 127 1 129 134 10.1038/sj.jid.5700582 17039242 \n3. Bordere A Stockman A Boone B Franki AS Coppens MJ Lapeere H A case of anaphylaxis caused by macrogol 3350 after injection of a corticosteroid Contact Dermat 2012 67 6 376 378 10.1111/j.1600-0536.2012.02104.x \n4. Wenande E Garvey LH Immediate-type hypersensitivity to polyethylene glycols: a review Clin Exp Allergy 2016 46 7 907 922 10.1111/cea.12760 27196817 \n5. Hyry H Vuorio A Varjonen E Skytta J Makinen-Kiljunen S Two cases of anaphylaxis to macrogol 6000 after ingestion of drug tablets Allergy 2006 61 8 1021 10.1111/j.1398-9995.2006.01083.x 16867059 \n6. Schuman E Balsam PE Probable anaphylactic reaction to polyethylene glycol electrolyte lavage solution Gastrointest Endosc 1991 37 3 411 10.1016/S0016-5107(91)70761-X 2071010 \n7. Fisher AA Immediate and delayed allergic contact reactions to polyethylene glycol Contact Dermat 1978 4 3 135 138 10.1111/j.1600-0536.1978.tb03759.x \n8. Yamasuji Y Higashi Y Sakanoue M A case of anaphylaxis caused by polyethylene glycol analogues Contact Dermat 2013 69 183 185 10.1111/cod.12084 \n9. Wenande EC Inhibition of polyethylene glycol-induced histamine release by monomeric ethylene and diethylene glycol: a case of probable polyethylene glycol allergy Allergy Clin Immunol 2013 131 1425 10.1016/j.jaci.2012.09.037\n\n", "fulltext_license": "CC BY", "issn_linking": "1710-1484", "issue": "12()", "journal": "Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology", "keywords": "Anaphylaxis; Drug additives; Hypersensitivity; Macrogol; Polyethylene glycol", "medline_ta": "Allergy Asthma Clin Immunol", "mesh_terms": null, "nlm_unique_id": "101244313", "other_id": null, "pages": "67", "pmc": null, "pmid": "27999603", "pubdate": "2016", "publication_types": "D002363:Case Reports", "references": "27196817;23151193;668343;23228247;23948038;17039242;24811032;2071010;16867059", "title": "Polyethylene glycol as a cause of anaphylaxis.", "title_normalized": "polyethylene glycol as a cause of anaphylaxis" }

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POLYETHYLENE GLYCOL AS A CAUSE OF ANAPHYLAXIS. ALLERG-ASTH-CLIN-IMMUNOL. 2016?1267", "literaturereference_normalized": "polyethylene glycol as a cause of anaphylaxis", "qualification": "3", "reportercountry": "DE" }, "primarysourcecountry": "DE", "receiptdate": "20180319", "receivedate": "20180319", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14657333, "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": "Reporting of adverse incidents is mandatory in Denmark. All reported adverse incidents are made anonymously, and stored in an encrypted database. It is the purpose of this descriptive study to describe the severity of adverse medication incidents caused by oral anticoagulants in hospitals. All moderate, severe and fatal reports concerning non-vitamin K antagonist oral anticoagulants were analyzed from date of marketing until July 8 2014. The data collection for warfarin was from January 1 2014 until July 8 2014. Three independent specialists in clinical pharmacology evaluated the severity of incident outcomes. A total of 147 adverse medication incidents were analyzed, and showed that de facto or potentially fatal and serious incidents were most frequently associated with sector change (admission to or discharge from hospital, or undergoing surgery) and resulted from insufficient or excess dosing. Physicians should be aware when prescribing and changing anticoagulant therapy to avoid severe or fatal incidents.", "affiliations": "Department of Clinical Pharmacology Aarhus University Hospital Aarhus Denmark.;Department of Clinical Pharmacology Aarhus University Hospital Aarhus Denmark.;Unit for Quality and Patient Safety Capital Region of Denmark Copenhagen Denmark.;Department of Clinical Pharmacology Aarhus University Hospital Aarhus Denmark.", "authors": "Henriksen|Jakob Nørgaard|JN|0000-0003-0784-3206;Nielsen|Lars Peter|LP|;Hellebek|Annemarie|A|;Poulsen|Birgitte Klindt|BK|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/prp2.307", "fulltext": "\n==== Front\nPharmacol Res PerspectPharmacol Res Perspect10.1002/(ISSN)2052-1707PRP2Pharmacology Research & Perspectives2052-1707John Wiley and Sons Inc. Hoboken 10.1002/prp2.307PRP2307Original ArticleOriginal ArticlesMedication errors involving anticoagulants: Data from the Danish patient safety database J. N. Henriksen et al.Henriksen Jakob Nørgaard http://orcid.org/[email protected] \n1\nNielsen Lars Peter \n1\nHellebek Annemarie \n2\nPoulsen Birgitte Klindt \n1\n1 Department of Clinical PharmacologyAarhus University HospitalAarhusDenmark2 Unit for Quality and Patient SafetyCapital Region of DenmarkCopenhagenDenmark* Correspondence\n\nJakob Nørgaard Henriksen, Department of Clinical Pharmacology, Aarhus University Hospital, Wilhelm Meyers Alle 4, DK‐8000 Aarhus C, Denmark.\n\nTel: +4540438804; Fax: +4586128804;\n\nE‐mail: [email protected]\n03 4 2017 6 2017 5 3 10.1002/prp2.2017.5.issue-3e0030713 2 2017 14 2 2017 © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nReporting of adverse incidents is mandatory in Denmark. All reported adverse incidents are made anonymously, and stored in an encrypted database. It is the purpose of this descriptive study to describe the severity of adverse medication incidents caused by oral anticoagulants in hospitals. All moderate, severe and fatal reports concerning non‐vitamin K antagonist oral anticoagulants were analyzed from date of marketing until July 8 2014. The data collection for warfarin was from January 1 2014 until July 8 2014. Three independent specialists in clinical pharmacology evaluated the severity of incident outcomes. A total of 147 adverse medication incidents were analyzed, and showed that de facto or potentially fatal and serious incidents were most frequently associated with sector change (admission to or discharge from hospital, or undergoing surgery) and resulted from insufficient or excess dosing. Physicians should be aware when prescribing and changing anticoagulant therapy to avoid severe or fatal incidents.\n\nAdverse incidentsanticoagulant therapyclinical pharmacologyDanish patient safety database source-schema-version-number2.0component-idprp2307cover-dateJune 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.1.0 mode:remove_FC converted:02.06.2017\n\n\nJ. N. \nHenriksen \n, \nL. P. \nNielsen \n, \nA. \nHellebek \n, \nB. K. \nPoulsen \n. Medication errors involving anticoagulants: Data from the Danish patient safety database , Pharma Res Per , 5 (3 ), 2017 , e00307, doi: 10.1002/prp2.307\n==== Body\nAbbreviations\nDPSDDanish Patient Safety Database\n\nINRinternational normalized ratio\n\nNOACnon‐vitamin K antagonist oral anticoagulant\n\nTTRtherapeutic range\n\nIntroduction\nAnticoagulant drugs are widely used for both treatment and prophylaxis of thrombotic diseases (Adelborg et al. 2016), and are some of the drugs that most frequently cause medication errors, as demonstrated by previous data (Runciman et al. 2003; Hardmeier et al. 2004). These drugs often cause serious or fatal events (Runciman et al. 2003; Hardmeier et al. 2004; Saedder et al. 2014), and are therefore considered to be high risk medication (Danish Medicines Agency 2011). In particular, when patients are transferred from one sector to the other, unintended incidents related to medication can happen (Bell et al. 2011).\n\nWarfarin was one of the first anticoagulant drugs on the market, and has been available since 1964 (Mercury Pharma Group Ltd 2016). In 2014, a total of 88.158 patients were treated with warfarin in Denmark (Sundhedsdatastyrelsen 2016). In March 2008, the first non‐vitamin K antagonist oral anticoagulant (NOAC), Pradaxa® (dabigatran), was released (Boehringer Ingelheim 2016). Three more NOACs have since been introduced to the market; Xarelto® (rivaroxaban) in September 2008, Eliquis® (apixaban) in May 2011 and Lixiana® (edoxoban) in June 2015 (Bayer Pharma AG 2015; Bristol‐Myers Squibb/Pfizer EEIG 2016; Daiichi Sankyo Europe BmgH 2016). As of 2014 in Denmark, a total of 23.466 patients were treated with dabigatran, 16.085 patients with rivaroxaban and 8.024 patients with apixaban (Sundhedsdatastyrelsen 2016).\n\nThe Danish Patient Safety Database (DPSD) is a national database containing all reported adverse incidents in Danish Health Care since 2004, when it was made mandatory for all health care personnel in the hospital sector to report adverse incidents (Ministry of Health/Jens Kristian Gøtrik 2003). The definition of an adverse incident is an incident or error that is unassociated to the patient's disease, but could have or, in fact, has caused harm to the patient (Government Agency of Patient Safety 2016). The reported adverse incidents are made anonymously and filed in an encrypted database, the DPSD. The purpose of this database is to generate information and provide learning objectives, thereby identifying ways to improve medication safety. Strict policy regarding the anonymity of the person making the report is formulated (Government Agency of Patient Safety 2016), and access to the information in the database is restricted.\n\nWe chose anticoagulant drugs because of an increasing use and the association with serious adverse medication incidents. Unlike earlier reports (Zaidenstein et al. 2002; Fanikos et al. 2004; Piazza et al. 2011), our data material contained NOACs as well as warfarin. It is the purpose of this study to describe the severity rather than the extent of adverse medication incidents and the circumstances that led to them, in order to provide learning objectives.\n\nMaterials and Methods\nDesign\nDescriptive study.\n\nSetting and data source\nReports to the Patient Safety Database are free‐text fields with no minimum amount of information required to complete the reporting process.\n\nAccess to the database was obtained on July 8 2014. On this date, one abstracter manually retrieved all adverse incidents reported as moderate, serious or fatal from the hospital sector concerning dabigatran, rivaroxaban and apixaban, and manually transcribed them to a Microsoft Excel®‐file in anonymous form. The marketing date of these three drugs therefore became the first possible entry point into the database. For warfarin, all reported moderate, serious and fatal adverse incidents from January 1 2014 until July 8 2014 were collected. As warfarin has been marketed for several years and by far is the most commonly used anticoagulant in Denmark, adverse incidents reporting was assumed to be stable, and therefore no reports were included before January 2014. We did, however, add fatal cases concerning warfarin prior to 2014 not to miss valuable information. This added though only two more reports. Reports on incidents occurring in primary care were excluded. In some reports more than one anticoagulant was reported.\n\nClassification of adverse medication incidents\nWe sorted available information for every adverse incident into categories consisting of gender (male, female or unknown), age (0–50, 50–75, >75 or unknown), reported drug (warfarin, dabigatran, rivaroxaban, apixaban or unknown), medication process (prescribing, administering, dispensing or unknown), type of problem (excess dose, insufficient dose, other1 or unknown), hospitalization process (admission, in hospital, discharge, surgery, unknown) and specific clinical situation (bridging, medication review, monitoring and other; see Table 2 for definitions).\n\nThis supported analysis of the involved drug, the specific process of medication and the situation during hospitalization, where the adverse incidents were most harmful. Incidents that did not fit into a category were labeled unknown.\n\nAnalysis\nEvery adverse incident was graded according to severity by three independent specialists in Clinical Pharmacology. They graded incidents with both known and unknown outcomes according to the definitions in Table 1.\n\nTable 1 Definitions of severity of the adverse incidents\n\nCategory\tKnown outcome (Government Agency of Patient Safety 2016)\tUnknown outcome (Lisby et al. 2005)\t\nNo harm/mild/potentially nonsignificant\tNo harm/minor harm that does not require additional treatment or care.\tMedication error that is judged without clinical risk for the patient.\t\nModerate/potentially significant\tTransient harm that requires admission to hospital, treatment by a physician, increased level of care or additional treatment for hospitalized patients.\tMedication error that is judged to pose a potential clinical risk of being inconvenient to the patient, without permanently harming the patient.\t\nSerious/potentially serious\tPermanent harm that requires admission to hospital, treatment by a physician, increased level of care or additional treatment for hospitalized patients. This includes harms that require acute, life‐saving treatment.\tMedication error that is judged to be able to cause a potential clinical risk of harming the patient.\t\nFatal/potentially fatal\tFatal\tMedication error that is judged to pose a potential clinical risk of leading to a fatal outcome.\t\nJohn Wiley & Sons, LtdAdverse medication incidents with a known outcome (an actual harm to the patient) was described as a “de facto” harm, whereas adverse medication incidents with an unknown outcome (and a potential for harming the patient) was described as a potential harm. If grading differed among the clinical pharmacologists, the reported adverse incident was reviewed again by the group to achieve consensus. We chose to pool both de facto and potentially nonsignificant, significant, serious or fatal to increase the strength of the data.\n\nThus, an adverse incident with a known outcome described in the database as “A 48‐year old woman with known systemic lupus erythematosus and antiphospholipid antibody syndrome had previously been switched from warfarin to dabigatran due to compliance problems. She was admitted due to bleeding and dabigatran was discontinued. This was not reinstated upon discharge. Seven days later, the patient was admitted to hospital with pulmonary embolism” would be categorized as follows: (1) Age = 48; (2) gender = female; (3) reported drug = dabigatran; (4) medication process = prescribing; (5) type of problem = no anticoagulant therapy; (6) location in the health care sector = discharge; (7) specific clinical situation = medication review; (8) outcome = 7 days later admitted with a lung embolus. This case was judged by the clinical pharmacologists as serious.\n\nAn adverse incident with an unknown outcome described in the database as “An 88‐year old woman was admitted with suspected deep vein thrombosis. The ultrasound was negative. She was discharged with both dabigatran and low molecular weight heparin” would be categorized as follows: (1) Age = 88; (2) gender = female; (3) reported drug = dabigatran; (4) medication process = prescribing; (5) type of problem = excess anticoagulant therapy; (6) location in the health care sector = discharge; (7) specific clinical situation = medication review; (8) outcome = unknown. This case was judged by the clinical pharmacologists to be potentially serious.\n\nResults\nA total of 148 adverse incidents were included in the study. One was omitted due to lack of information, and was therefore not possible to grade. Of the remaining 147, the outcome was known in 65 incidents (44%) and unknown in 82 (56%). In total, there were (de facto or potentially) seven fatal, 83 serious, 52 significant and five nonsignificant adverse medication incidents (Fig. 1).\n\nFigure 1 Reported drug and associated severity. Direct comparisons between individual drugs should be avoided, as the basis for data could be different.\n\nIn the medication process, an adverse medication incident occurred during prescription in 115 of the total 147 incidents (78%). All the seven fatal adverse medication incidents occurred in this part of the medication process and also accounted for 70 of the total 83 serious adverse medication incidents (84%). Vice versa, there were no fatal incidents due to administration and dispensation, and only one and six, respectively, were graded as serious.\n\nExcess or insufficient dosing was associated with all the seven fatal adverse medication incidents in our data material, with most being caused by excess doses (5 of 7). In the subcategories of excess or insufficient dosing, 33 (40%) and 23 (28%), respectively, of a total of 83 were graded as de facto or potentially serious.\n\nIn the hospitalization process, described as sector change (admission, discharge and surgery) was associated with a total of 116 of 147 adverse medication incidents (79%) as well as all the fatal (100%) and 68 out of the total 83 serious (82%) adverse medication incidents.\n\nImportant parts of the physician's task when handling patients during sector change (bridging, monitoring and medication review) was associated with all seven fatal (100%) and 70 of 83 serious adverse medication incidents (84%). Two of these 70 serious adverse medication incidents were thus not related to sector change (3%).\n\nCompared to admission and surgery, the discharge phase of the hospitalization process was associated with more adverse medication incidents (63 of 147 = 43%) than the two others (22 and 31 of 147 respectively = 15 and 21%). Only three of the 147 adverse medication incidents (2%) in the category “hospitalisation process” did not contain sufficient information to fit into a subcategory. It therefore became the most reliable category in terms of amount of data therein.\n\nWhere information in the reports about dosing errors was available, the adverse medication incident in the admission phase was due to excess anticoagulant in seven of 11 incidents (64%) and insufficient anticoagulant in the remaining four (36%). During surgery, the adverse medication incident was due to excess anticoagulant in 17 of the 28 incidents (61%) with insufficient anticoagulant accounting for the remaining 11 (39%). During discharge, the numbers were 19 of 43 (44%) and 24 of 43 (56%), respectively (results not shown Fig. 2).\n\nFigure 2 The situation in which the adverse incident happened related to severity of outcome.\n\nDiscussion\nOur data showed that all fatal and almost all serious adverse medication incidents were associated with the prescribing phase of the medication process. Unlike an American study looking at reported adverse incidents over a 3‐year period in the national database (Santell et al. 2003), we did not find a similar association with neither administering nor dispensing. This indicates a problem related to physicians rather than the nursing staff. It poses a question whether better decision‐making support, more education or other actions are necessary when trying to minimize adverse medication incidents. In some regions of Denmark, the electronic patient chart allows the physician to use a function called “anticoagulation” to evaluate international normalized ratio (INR) values and warfarin given while the patient is in hospital. This helps to regulate anticoagulant therapy with warfarin while the patient is hospitalized. However, this feature only includes patients treated with warfarin and no information about doses prior to admission is given.\n\nThis leads to our second major finding. Sector change (i.e., admission, discharge and surgery) was associated with the highest number of serious and fatal adverse medication incidents. This is supported by the adverse medication incidents related to prescribing situations such as bridging, critical evaluation of the patients' medication in a medication review and monitoring anticoagulant therapy. During admission and surgery, prescribing excess anticoagulant was the most frequent problem. During discharge, the reverse was true with prescribing insufficient anticoagulant being the most frequent problem.\n\nWith recent data showing no increased benefit of bridging low to moderate risk patients on warfarin, but instead an increased risk of bleeding (Douketis et al. 2015), fewer patients are expected to be offered bridging with low molecular weight heparin and thereby reducing the risk of adverse medication incidents.\n\nWe know there is an increased risk of unintended discontinuation of evidence‐based therapy in patients admitted to hospital (Bell et al. 2011), and it has also been demonstrated, that among the five categories of drugs studied, anticoagulant therapy had the highest adjusted odds ratio of unintended discontinuation (Bell et al. 2011). Likewise, it has been documented, that adverse incidents related to medication increase with a patient's admittance to hospital for any reason (Cornish et al. 2005). Work is being done to implement an electronic information system showing a patient's current medication that is accessible to physicians in both primary care and hospitals. However, it is not yet fully implemented among all general practitioners and is not yet fully equipped to handle information about varying doses of warfarin for example.\n\nWhile it has been shown that anticoagulant therapy along with cardiovascular and antiasthmatic therapy were the most frequent medications to cause fatalities among hospitalized patients (Ebbesen et al. 2001), there were no fatalities among hospitalized patients in our data set.\n\nOur data was not able to support NOACs being associated with different risk patterns compared with warfarin, and data were too limited to report on their own. This was not only due to the low number of events for NOACs, but also because of the quality of the reported incidents. In almost all the reports, we had no information about who prescribed the medication, the time in therapeutic range (TTR) for warfarin, patients' co‐morbidity and co‐medication. An attempt to do a head to head comparison between warfarin and NOACs would only be associated with a strong possibility of misinterpretation without bringing clinically relevant data. The data on NOACs merely confirm that the risk of harming patients with anticoagulants is increased in specific clinical situations such as sector change, particularly during discharge.\n\nA major challenge in our data material proved to be the level of information contained in the reports. When reporting an adverse incident to the Patient Safety Database, a health care person is prompted to choose either a known or an anticipated degree of severity as well as to provide information regarding the location and time of the incident. The options for harm are none, mild, moderate, serious or fatal (Table 1). Although a description of events prior to the adverse incident is required, there are no requirements about the quality or extent of the description. The level of information regarding the patient and the incident therefore varies significantly between reports. Therefore, we were unable to fully characterise all adverse incidents according to predefined categories. Naturally, this inconsistency of information, tended to inflict and to some degree incapacitate the severity analysis.\n\nFurthermore, more than half the incidents had an unknown outcome, and analysis depended on anticipation of a certain outcome rather than on a factual outcome.\n\nDue to these limitations, we were not able to distinguish between the different classes of drugs in terms of severity or to draw any conclusions about the individual drugs and the individual characteristics about the problem (for example, which drugs were insufficiently dosed, did the patient have renal impairment or when were INR‐values insufficiently handled). Concerning warfarin, though, we know that from a combined retrospective and prospective Danish study that disease and drug‐drug interactions were the two most common reasons for patients treated with warfarin being admitted to hospital due to elevated INR‐values with or without an active bleeding (Meegaard et al. 2012).\n\nAlthough reporting of serious adverse effects as well as adverse medication incidents are mandatory in Denmark, we must assume some degree of underreporting. In a randomized controlled trial of patients with atrial fibrillation for example, 2,71% and 3,36% of patients on dabigatran and warfarin, respectively experienced a major bleeding event per year as an adverse effect of their treatment (Connolly et al. 2009). However, postmarketing reporting of these adverse effects is much lower. When comparing the presumed annual major bleeding events rate in patients on warfarin using the data from the above‐mentioned trial with actual reporting to the Federal Drug Administration in the United States, only about a third of these events are reported (Moore and Bennett 2012). Therefore, the full scope of adverse medication incidents with anticoagulants might very well be larger than our data indicate.\n\nWe chose not to look at the extent but rather the severity of the adverse medication incidents, and therefore only included adverse incidents related to warfarin from January 2014 until July 2014 with the addition of two, fatal incidents before that. This created a longer period for adverse incidents to be recorded for NOACs relative to warfarin. However, warfarin was up until July 2014 still used substantially more than NOACs (Sundhedsdatastyrelsen 2016) and the relative longer time span of possible reported adverse incidents with NOACs is likely balanced by the much higher consumption of warfarin. We have attempted to highlight this in Table 2. Whether a change in the type and severity of adverse incidents has changed in the years leading up to 2014 is unknown, but since warfarin has been marketed for decades, this would not seem likely.\n\nTable 2 Number of adverse incidents divided into categories, subcategories as well as severity\n\nCategories\tTotal number within the subgroup (%)\tDe facto or potentially fatal (%)\tDe facto or potentially serious (%)\tDe facto or potentially significant+nonsignificant (%)\t\nGender\t\nMale\t55 (37%)\t3 (6%)\t31 (56%)\t21 (38%)\t\nFemale\t62 (42%)\t2 (3%)\t40 (65%)\t20 (32%)\t\nUnknown\t30 (21%)\t2 (7%)\t12 (40%)\t16 (53%)\t\nAge\t\n0–50\t9 (6%)\t0\t5 (56%)\t4 (44%)\t\n51–75\t43 (29%)\t1 (3%)\t26 (60%)\t16 (37%)\t\n75+\t60 (41%)\t4 (7%)\t37 (62%)\t19 (31%)\t\nUnknown\t35 (24%)\t2 (6%)\t16 (46%)\t17 (48%)\t\nReported drug\t\nWarfarin\t96 (65%)\t4 (4%)\t50 (52%)\t42 (44%)\t\nDabigatran\t30 (21%)\t2 (7%)\t19 (63%)\t9 (30%)\t\nHeparin\t11 (7%)\t1 (9%)\t8 (73%)\t2 (18%)\t\nRivaroxaban\t6 (4%)\t0\t5 (83%)\t1 (17%)\t\nUnknown\t4 (3%)\t0\t1 (25%)\t3 (75%)\t\nMedication process\t\nPrescribing\t115 (78%)\t7 (6%)\t70 (61%)\t38 (33%)\t\nAdministering\t4 (3%)\t0\t1 (25%)\t3 (75%)\t\nDispensing\t16 (11%)\t0\t6 (38%)\t10 (62%)\t\nUnknown\t12 (8%)\t0\t6 (50%)\t6 (50%)\t\nType of problem\t\t\t\t\t\nExcess anticoagulant\t51 (35%)\t5 (10%)\t33 (65%)\t13 (25%)\t\nInsufficient anticoagulant\t50 (34%)\t2 (4%)\t23 (46%)\t25 (50%)\t\nOthera\n\t9 (6%)\t0\t6 (67%)\t3 (33%)\t\nUnknown\t37 (25%)\t0\t21 (57%)\t16 (43%)\t\nHospitalization process\t\nAdmission\t22 (15%)\t3 (14%)\t14 (64%)\t5 (22%)\t\nIn hospital\t28 (19%)\t0\t12 (43%)\t16 (57%)\t\nDischarge\t63 (43%)\t2 (3%)\t36 (57%)\t25 (40%)\t\nSurgery\t31 (21%)\t2 (6%)\t18 (58%)\t11 (36%)\t\nUnknown\t3 (2%)\t0\t3 (100%)\t0\t\nSpecific clinical situation\t\nBridgingb\n\t25 (17%)\t2 (8%)\t16 (64%)\t7 (28%)\t\nMedication reviewc\n\t61 (41%)\t2 (3%)\t36 (59%)\t23 (38%)\t\nMonitoringd\n\t22 (15%)\t3 (14%)\t18 (82%)\t1 (4%)\t\nOthere\n\t39 (27%)\t0\t13 (33%)\t26 (67%)\t\nThe numerals state the number of adverse incidents in the listed category. Percentages in the second column from the left are percent within the category. Percentages in the third, fourth and fifth column from the left are percentages in the subcategory.\n\na I.e. Patient given one anticoagulant, but should have been given another or not giving antidote to warfarin with a high INR.\n\nb Bridging was defined as changing anticoagulant therapy for a short while (i.e. during surgery) from one anticoagulant to another.\n\nc Medication review consisted of: Physician's review and prescribing of patient's medicine at admission, during hospital stay or discharge.\n\nd Monitoring was defined as reacting to an international normalized ratio (INR)‐value.\n\ne Missing or incorrect information in the electronic patient chart, lack of compliance or dispensing error.\n\nJohn Wiley & Sons, LtdInstead of highlighting differences between the drugs, our data showed anticoagulants as a whole to be associated with serious and fatal harm to patients during sector change, particularly during discharge. Our data showed that the fatal and serious problems were with prescribing rather than administering and dispensing the drugs.\n\nWith the purpose of providing learning points to the health care system, the Danish Patient Safety Database should support extra careful attention when prescribing anticoagulants and caring for patients treated with them during admission, discharge and surgery.\n\nConclusion\nAdverse incidents on anticoagulant therapy are associated with serious and even fatal harm to patients. In our dataset, we identified two main areas that caused serious and fatal outcomes. First of all, the prescription phase of the medication process proved to be the clinically most important in causing harm. We did not find similar relationship to administering and dispensing phases. Secondly, sector transfer, that is, admission, discharge and surgery, was associated with the majority of fatal and serious incidents. Our data do not support that the introduction of NOACs has influenced this significantly.\n\nIn all, anticoagulants have to be considered as risk medication in general, and patients treated with such drugs warrant increased attention.\n\nDisclosure\nDr. Henriksen reports nonfinancial support from LEO Pharma, outside the submitted work.\n\nAcknowledgements\nThe staff at “Learning” and “The Advisory council on Medication” under the Danish Patient Safety Authority for devising the project and granting access to the Danish Patient Safety Database.\n==== Refs\nReferences\n\n\nAdelborg \nK \n, \nGrove \nEL \n, \nSundboll \nJ \n, \nLaursen \nM \n, \nSchmidt \nM \n (2016 ). Sixteen‐year nationwide trends in antithrombotic drug use in denmark and its correlation with landmark studies . Heart \n102 : 1883 –1889 .27406838 \n\n\nBayer \nPharma AG \n (2015 ) Summary of product characteristics, xarelto [homepage on the Internet] . 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Pharmacoepidemiol Drug Saf \n11 : 235 –238 .12051123\n\n", "fulltext_license": "CC BY", "issn_linking": "2052-1707", "issue": "5(3)", "journal": "Pharmacology research & perspectives", "keywords": "Adverse incidents; Danish patient safety database; anticoagulant therapy; clinical pharmacology", "medline_ta": "Pharmacol Res Perspect", "mesh_terms": null, "nlm_unique_id": "101626369", "other_id": null, "pages": "e00307", "pmc": null, "pmid": "28603628", "pubdate": "2017-06", "publication_types": "D016428:Journal Article", "references": "11606147;24671697;12856391;15668306;12051123;19717844;14660523;15738372;26095867;23086541;21862745;15611888;27406838;22293053;28603628;15325949;22114827", "title": "Medication errors involving anticoagulants: Data from the Danish patient safety database.", "title_normalized": "medication errors involving anticoagulants data from the danish patient safety database" }

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PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-034431", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "48", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Haemorrhage", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" }, { "reactionmeddrapt": "Pulmonary embolism", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NIELSEN L, HELLEBEK A, POULSEN B. MEDICATION ERRORS INVOLVING ANTICOAGULANTS: DATA FROM THE DANISH PATIENT SAFETY DATABASE. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2017;5(3):E00307.", "literaturereference_normalized": "medication errors involving anticoagulants data from the danish patient safety database", "qualification": "5", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170628", "receivedate": "20170628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13699340, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20170830" }, { "companynumb": "DK-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-035327", "fulfillexpeditecriteria": "1", "occurcountry": "DK", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DABIGATRAN ETEXILATE MESYLATE" }, "drugadditional": "3", "drugadministrationroute": "065", "drugauthorizationnumb": "022512", "drugbatchnumb": null, "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": null, "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": "PRADAXA" } ], "patientagegroup": null, "patientonsetage": "68", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Thrombosis", "reactionmeddraversionpt": "20.0", "reactionoutcome": "6" } ], "summary": null }, "primarysource": { "literaturereference": "NIELSEN P, HELLEBEK A, POULSEN K. MEDICATION ERRORS INVOLVING ANTICOAGULANTS: DATA FROM THE DANISH PATIENT SAFETY DATABASE. PHARMACOLOGY RESEARCH AND PERSPECTIVES. 2017;5:3:E00307.", "literaturereference_normalized": "medication errors involving anticoagulants data from the danish patient safety database", "qualification": "5", "reportercountry": "DK" }, "primarysourcecountry": "DK", "receiptdate": "20170628", "receivedate": "20170628", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "2", "safetyreportid": 13699255, "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": "Although poisoning with calcium channel blocking agents is frequent, to our knowledge no cases involving amlodipine have been published. We describe here a case of amlodipine intoxication, in which protracted hypotension did not respond to vasopressor therapy alone. After the addition of continuous calcium chloride and glucagon infusion, blood pressure was restored and vasopressor therapy could be tapered off substantially. When calcium and glucagon were interrupted because of severe hypercalcemia and hyperglycemia, the patient developed irreversible hypotension and died. Either glucagon or calcium or both, and to some extent vasopressors, seem to have constituted effective treatment of hypotension in this case.", "affiliations": "Department of Intensive Care, University Hospital, Ghent, Belgium.", "authors": "Koch|A R|AR|;Vogelaers|D P|DP|;Decruyenaere|J M|JM|;Callens|B|B|;Verstraete|A|A|;Buylaert|W A|WA|", "chemical_list": "D017311:Amlodipine; D010076:Oxazepam", "country": "United States", "delete": false, "doi": "10.3109/15563659509017993", "fulltext": null, "fulltext_license": null, "issn_linking": "0731-3810", "issue": "33(3)", "journal": "Journal of toxicology. Clinical toxicology", "keywords": null, "medline_ta": "J Toxicol Clin Toxicol", "mesh_terms": "D017311:Amlodipine; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007022:Hypotension; D008875:Middle Aged; D010076:Oxazepam", "nlm_unique_id": "8213460", "other_id": null, "pages": "253-6", "pmc": null, "pmid": "7760451", "pubdate": "1995", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Fatal intoxication with amlodipine.", "title_normalized": "fatal intoxication with amlodipine" }

[ { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03023", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "065", "drugauthorizationnumb": "078925", "drugbatchnumb": "UNKNOWN", "drugcharacterization": "1", "drugcumulativedosagenumb": null, "drugcumulativedosageunit": null, "drugdosageform": null, "drugdosagetext": "70 MG, 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": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE BESYLATE." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "1", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Shock", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Bradycardia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Arrhythmia", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Toxicity to various agents", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" }, { "reactionmeddrapt": "Hypotension", "reactionmeddraversionpt": "21.0", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KOCH AR, VOGALAERS DP, DECRUYENAERE JM, CALLENS B AND ET. AL.. FATAL INTOXICATION WITH AMLODIPINE. CLIN TOXICOL.. 1995?33:253?256", "literaturereference_normalized": "fatal intoxication with amlodipine", "qualification": "3", "reportercountry": "US" }, "primarysourcecountry": "US", "receiptdate": "20180516", "receivedate": "20180516", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 14900086, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": 1, "transmissiondate": "20180711" }, { "companynumb": "BE-LUPIN PHARMACEUTICALS INC.-2015-03589", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": "078043", "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": "70", "drugstructuredosageunit": "003", "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "AMLODIPINE" }, { "actiondrug": null, "activesubstance": { "activesubstancename": "OXAZEPAM" }, "drugadditional": null, "drugadministrationroute": "048", "drugauthorizationnumb": null, "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": null, "drugrecurrence": null, "drugseparatedosagenumb": null, "drugstartdate": null, "drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "OXAZEPAM." } ], "patientagegroup": null, "patientonsetage": "63", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Completed suicide", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Overdose", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiac arrest", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" }, { "reactionmeddrapt": "Cardiogenic shock", "reactionmeddraversionpt": "18.1", "reactionoutcome": "5" } ], "summary": null }, "primarysource": { "literaturereference": "KOCH A, VOGELAERS D, DECRUYENAERE J, CALLENS B, VERSTRAETE A, BUYLAERT W. FATAL INTOXICATION WITH AMLODIPINE. CLINICAL TOXICOLOGY. 1995?33 (3):253-256.", "literaturereference_normalized": "fatal intoxication with amlodipine", "qualification": "1", "reportercountry": "BE" }, "primarysourcecountry": "BE", "receiptdate": "20151117", "receivedate": "20151117", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "3", "safetyreportid": 11745090, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": 1, "seriousnessdisabling": null, "seriousnesshospitalization": null, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20160304" } ]

{ "abstract": "Anti-synthetase syndrome is an autoimmune disorder characterized by the presence of autoantibodies against aminoacyl transfer RNA (tRNA) synthetases, and myositis, interstitial lung disease (ILD), arthritis, fever and Raynaud's phenomenon (RP). We present a 54-year-old woman, who complained of fatigue, low-grade fever, myalgias, arthralgias, RP and dyspnoea on exertion. Chest CT scan revealed features of interstitial lung disease. Due to rapid deterioration of her lung function, she required oxygen support. The patient did not respond to empiric treatment with antibiotics. Autoantibody testing was remarkable for ANA positivity (1/160) and high-titre anti-Jo1 positivity. A diagnosis of anti-synthetase syndrome was made and the patient was placed on high-dose corticosteroids and rituximab with significant improvement. At 1-year follow up, she remains in good condition, without the need for oxygen supplementation.", "affiliations": "Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.;Department of Respiratory Medicine, University General Hospital of Larissa, Faculty of Medicine, University of Thessaly, Larissa, Greece.;Department of Respiratory Medicine, University General Hospital of Larissa, Faculty of Medicine, University of Thessaly, Larissa, Greece.;Department of Rheumatology and Clinical Immunology.;Department of Rheumatology and Clinical Immunology.", "authors": "Kourkouni|Evangelia|E|;Mitsogiannis|Georgios|G|;Simopoulou|Theodora|T|;Liaskos|Christos|C|;Katsiari|Christina G|CG|;Daniil|Zoi|Z|;Gourgoulianis|Konstantinos|K|;Bogdanos|Dimitrios P|DP|;Sakkas|Lazaros I|LI|", "chemical_list": null, "country": "Greece", "delete": false, "doi": "10.31138/mjr.30.3.186", "fulltext": "\n==== Front\nMediterr J Rheumatol\nMediterr J Rheumatol\nMJR\nMediterranean Journal of Rheumatology\n2529-198X The Mediterranean Journal of Rheumatology (MJR) \n\n10.31138/mjr.30.3.186\nMJR-30-3-186\nCase Report\nInterstitial Lung Disease in Anti-Synthetase Syndrome\nKourkouni Evangelia 1 Mitsogiannis Georgios 1 Simopoulou Theodora 1 Liaskos Christos 1 Katsiari Christina G. 1 Daniil Zoi 2 Gourgoulianis Konstantinos 2 Bogdanos Dimitrios P. 1 Sakkas Lazaros I. 1 1 Department of Rheumatology and Clinical Immunology;\n2 Department of Respiratory Medicine, University General Hospital of Larissa, Faculty of Medicine, University of Thessaly, Larissa, Greece\nCorresponding Author: Lazaros I. Sakkas, Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41110, Greece, Tel.: +302413502813, Fax: +202413501014, E-mail:[email protected]\n9 2019 \n30 9 2019 \n30 3 186 189\n12 4 2019 25 6 2019 09 7 2019 © 2019 The Mediterranean Journal of Rheumatology (MJR)2019This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Anti-synthetase syndrome is an autoimmune disorder characterized by the presence of autoantibodies against aminoacyl transfer RNA (tRNA) synthetases, and myositis, interstitial lung disease (ILD), arthritis, fever and Raynaud’s phenomenon (RP). We present a 54-year-old woman, who complained of fatigue, low-grade fever, myalgias, arthralgias, RP and dyspnoea on exertion. Chest CT scan revealed features of interstitial lung disease. Due to rapid deterioration of her lung function, she required oxygen support. The patient did not respond to empiric treatment with antibiotics. Autoantibody testing was remarkable for ANA positivity (1/160) and high-titre anti-Jo1 positivity. A diagnosis of anti-synthetase syndrome was made and the patient was placed on high-dose corticosteroids and rituximab with significant improvement. At 1-year follow up, she remains in good condition, without the need for oxygen supplementation.\n\nanti-synthetase syndromeanti-Jo1interstitial lung diseaseRaynaud’s phenomenon\n==== Body\nINTRODUCTION\nAnti-synthetase syndrome (aSS) is a rare autoimmune disorder characterized by the presence of antibodies against aminoacyl-transfer RNA synthetase (ARS) and a variable constellation of manifestations; most commonly interstitial lung disease (ILD), myositis, and arthritis. These manifestations occur in 60–95% of cases, whereas other, less common manifestations occurring in ∼40% of cases include Raynaud’s phenomenon (RP), fever and mechanic’s hands.1 By far the most common ARS antibody is anti-Jo1, which targets histidyl-tRNA synthetase (histidyl-RS) and occurs in 73% of aSS patients.2 Other less common ARS antibodies are against PL-12 (alanyl-RS) (in 14% of patients), PL-7 (threonyl-RS) (in 9% of patients), OJ (isoleucyl-RS), and EJ (glycyl-RS), KS (asparaginyl-RS), Zo (phenylalanyl-RS), and YRS/Tyr (tyrosyl-RS).3 Patients with anti-synthetase syndrome often suffer from severe and rapidly progressive ILD. In fact, life expectancy is curtailed in aSS and the major cause of death is ILD and pulmonary hypertension. The 5-year survival is 90% in anti-Jo-1-positive patients and 75% in non-Jo-1-positive patients but the 5-year survival can be as low as 31%.4 Thus, it is important to recognize the syndrome early and promptly institute immunosuppressive treatment. Herein, we describe a patient with anti-synthetase syndrome with rapidly progressive and severe ILD.\n\nCASE PRESENTATION\nA 54-year-old Caucasian woman presented to a private physician with a twenty days history of fatigue, low grade fever, myalgias, arthralgias, Raynaud’s phenomenon and dyspnoea on exertion. She was initially treated with 20mg of methylprednisolone as undifferentiated arthritis, and symptoms were improved. Attempts to taper down steroids led to relapse of manifestations. A new chest X-ray revealed increased lineal markings in lower lung fields (Figure 1) and a chest CT scan showed linear markings, ground glass opacities and mild bronchiectasis (Figure 2). Laboratory tests were remarkable for increased inflammation indices (CRP 3.5mg/dL [normal, <0.5 mg/dL], ESR 42 mm]), mild creatinine kinase elevation (CPK 185 U/L, normal, <145) and a positive ANA test (1/160, normal <1:80). Methylprednisolone was discontinued and empiric antibiotics (clarithromycin, moxifloxacin), antiviral (oseltamivir) and bronchodilators were prescribed, for presumed respiratory infection, without benefit.\n\nFigure 1. Chest x-rays showing increased markings in lower lung fields.\n\nFigure 2. Chest CT scan showing thickened linear markings, ground glass opacities, and mild bronchiectasis.\n\nShe was referred to the Emergency department of our Hospital and admitted to the Department of Rheumatology and Clinical Immunology for further evaluation and treatment.\n\nOn admission, she had mild hypoxia with reduced arterial oxygen saturation (SaO2 saturation, 90%–92%, pO2 65 mmHg on FiO2 21%), and arterial blood pressure was normal. The patient had low-grade fever up to 38° C (two spikes per day). Inflammation markers were elevated (CRP 2.2 mg/dL, ESR 23mm). The rest of the basic laboratory work-up is shown in Table 1. Pulmonary function tests revealed mildly restricted pattern with forced vital capacity (FVC) 74%, forced expiratory volume in 1s (FEV1) 73%, and FEV1/FVC 100%.\n\nTable 1. Laboratory tests during hospital stay.\n\nTest\tAt admission\tAt exit\t\nHaematocrit (%)\t40\t39\t\nWBC (×103/μL)\t8800\t14300\t\nPLT (×103/μL)\t367\t364\t\nCRP (mg/dL, normal <0,5)\t2,2\t0,7\t\nESR (mm)\t35\t23\t\nLactate dehydrogenase (IU/L, normal <245)\t377\t273\t\nCreatine phosphokinase (U/L, normal <145)\t241\t88\t\nDifferential diagnosis of diffuse pulmonary infiltrates, fever, hypoxia and elevated inflammatory markers included respiratory infections, and autoimmune pulmonary/rheumatic diseases. The latter included hypersensitivity pneumonitis, sarcoidosis, systemic lupus erythematosus, Sjögren syndrome, systemic sclerosis, rheumatoid arthritis, vasculitis, and myositis. An autoantibody panel with RF, anti-CCP, ANCA, and ANA was ordered.\n\nLegionella and Pneumococcal antigen urinary tests, serological tests for EBV, CMV, HIV, Parvo B19, myco-plasma and brucellosis, and Mantoux skin test were negative. Blood and urine cultures were sterile. The patient could not provide sputum for culture or immunofluorescence for Pneumocystis jirovecii. Beta D-glucan test for fungal infection was not available as a routine test in the microbiology laboratory of the hospital. The patient was empirically treated with broad spectrum antibiotics (intravenous piperacillin-tazobactam) without response. She progressively deteriorated with dyspnoea, tachypnoea, low pO2 (49 mmHg) requiring nasal oxygen supplementation, and rising CRP (6.3 mg/dl). Pulmonary embolism and acute heart failure were ruled out. Pneumocystis jirovecii pneumonia could not be excluded, and empirical treatment with co-trimoxazole (15 mg/kg/day) plus prednisone according to the treatment guidelines was initiated. Initially, the patient’s clinical status and laboratory findings (CRP 0.7 mg/dl) were improved, but with prednisolone tapering, fever reappeared, and oxygen supplementation was again needed. Therefore, the possibility of an ILD associated with immune-mediated rheumatic diseases was very likely. Systemic sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, and vasculitis were unlikely, since there was no other feature of these diseases. Rheumatoid arthritis was still a possibility, but anti-synthetase syndrome became the most likely diagnosis. In our department, we perform an autoantibody profile for myositis-anti-synthetase syndrome by line immunoassay (Figure 3). This multiplex test revealed very strong positivity for anti-Jo-1 (82 Arbitrary units, AU, cut off, 10) and anti-Ro52 antibodies (101 AU, cut off, 10). Antibodies against Mi-2 alpha, Mi-2 beta, TIF1γ, MDA5, NXP2, SAE1, Ku, PM-Scl100, PM-Scl75, SRP, PL-7, PL-12, EJ, and OJ) were all negative. Serum creatine phosphokinase (CPK) levels and electromyography were normal. Therefore, a diagnosis of anti-synthetase syndrome was made on the basis of ILD, fever, arthralgias, RP, and anti-Jo1 autoantibodies. High dose prednisolone was initiated along rituximab (1g on day 0 and day 15). The patient exhibited a quick improvement which continued during the following months with tapering of corticosteroids. At 1-year follow up, the patient is on 5 mg of prednisolone per day and rituximab (day 0–day 15) every six months. She is in good health, without the need of oxygen, and has started her work again. Chest x-rays and pulmonary function tests were normal.\n\nFigure 3. Line immunoblot assay showing positivity for Jo-1 and Ro52 autoantibodies.\n\nDISCUSSION\nOur case highlights the need for early recognition and treatment of aSS-ILD. Although aSS is associated with myositis, a patient may initially present with no myositis.1 On the other hand, ILD is the most prevalent manifestation of aSS occurring in 86–95% of patients.5,6 ILD frequently dominates the clinical picture at presentation and may rapidly progress to pulmonary failure. In fact, aSS-ILD is more prevalent and severe rather than myositis-associated ILD.4 ILD is more severe in anti-PL12/PL7 patients rather than anti-Jo-1 patients.4 In fact, patients with anti-PL12/PL7 antibodies have predominant ILD, often without muscle involvement, whereas patients with anti-Jo-1 antibodies have more diffuse phenotype.2,5 The presence of anti-Ro52 antibody in patients with aSS may be associated with rapidly progressive ILD6,7 and cancer.7 It should be noted that patients with ILD should also be tested for associated anti-signal recognition particle antibodies, including anti-MDA-5 (RNA helicase) and anti-Mi-2 (nuclear helicase). CT findings of aSS-ILD mostly include areas of ground glass opacities and reticulation, predominantly in lower lung lobes, and peribronchial lesions. Less frequently (∼35%) there is organizing pneumonia with fibrosis.8 Patients with aSS may also have myocarditis and pulmonary hypertension.4 Myocarditis occurs in 34% of aSS patients and may be asymptomatic or present with acute/subacute heart failure.9\n\nNo randomized control trials have been conducted in aSS, current therapy is off-label and based on case series and case reports, and includes corticosteroids along with an immunosuppressant, such as azathioprine, mycophenolate mofetil, calcineurin inhibitors (tacrolimus), rituximab and cyclophosphamide.4 Rituximab seems to be a very effective option with marked improvement in FVC in patients with connective tissue disease and ILD, who have anti-Jo1 antibodies.10 Significant improvement after treatment with rituximab is noted more frequently in anti-Jo1 antibody-positive compared to anti-Jo1 antibody-negative patients with inflammatory myopathies. In our case, an improvement in CT imaging features, as well as at FVC and DLCO tests, was observed over time. It must be noted that the greatest benefit was seen at the 3-year follow-up.\n\nIn conclusion, early recognition of aSS and investigation for major organ involvement is required for the optimal outcome of patients with this syndrome.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest.\n==== Refs\nREFERENCES\n1. Bartoloni E Gonzalez-Gay MA Scirè C Castaneda S Gerli R Lopez-Longo FJ \nClinical follow-up predictors of disease pattern change in anti-Jo1 positive anti-synthetase syndrome: Results from a multicenter, international and retrospective study\n. Autoimmun Rev \n2017 ;16 (3 ):253 –7\n. [10.1016/j.autrev.2017.01.008 ] [PMID: ]28147261 \n2. Pinal-Fernandez I Casal-Dominguez M Huapaya JA Albayda J Paik JJ Johnson C \nA longitudinal cohort study of the anti-synthetase syndrome: increased severity of interstitial lung disease in black patients and patients with anti-PL7 and anti-PL12 autoantibodies\n. Rheumatology (Oxford) \n2017 ;56 (6 ):999 –1007\n. [10.1093/rheumatology/kex021 ] [PMID: ] [PMCID: ]28339994 \n3. Gallay L Gayed C Hervier B \nAntisynthetase syndrome pathogenesis: knowledge and uncertainties\n. Curr Opin Rheumatol \n2018 ;30 :664 –73\n. [10.1097/BOR.0000000000000555 ] [PMID: ]30239350 \n4. Witt LJ Curran JJ Strek ME \nThe Diagnosis and Treatment of Anti-synthetase Syndrome\n. Clin Pulm Med \n2016 ;23 (5 ):218 –26\n. [10.1097/CPM.0000000000000171 ] [PMID: ] [PMCID: ]27594777 \n5. Hervier B Devilliers H Stanciu R Meyer A Uzunhan Y Masseau A \nHierarchical cluster and survival analyses of antisynthetase syndrome: phenotype and outcome are correlated with anti-tRNA synthetase antibody specificity\n. Autoimmun Rev \n2012 ;12 (2 ):210 –7\n. [10.1016/j.autrev.2012.06.006 ] [PMID: ]22771754 \n6. Shi J Li S Yang H Zhang Y Pang Q Lu X Wang G \nClinical Profiles and Prognosis of Patients with Distinct Antisynthetase Autoantibodies\n. J Rheumatol \n2017 ;44 (7 ):1051 –7\n. [10.3899/jrheum.161480 ] [PMID: ]28461650 \n7. Marie I Hatron PY Dominique S Cherin P Mouthon L Menard JF \nShort-term and long-term outcome of anti-Jo1-positive patients with anti-Ro52 antibody\n. Sem Arthritis Rheum \n2012 ;41 (6 ):890 –9\n. [10.1016/j.semarthrit.2011.09.008 ] [PMID: ]22078416 \n8. Waseda Y Johkoh T Egashira R Sumikawa H Saeki K Watanabe S \nAntisynthetase syndrome: Pulmonary computed tomography findings of adult patients with antibodies to aminoacyl-tRNA synthetases\n. Eur J Radiol \n2016 ;85 :1421 –26\n. [10.1016/j.ejrad.2016.05.012 ] [PMID: ]27423682 \n9. Dieval C Deligny C Meyer A Cluzel P Champtiaux N Lefevre G \nMyocarditis in Patients With Antisynthetase Syndrome: Prevalence, Presentation, and Outcomes\n. Medicine \n2015 ;94 (26 ):e798 . [10.1097/MD.0000000000000798 ] [PMID: ] [PMCID: ]26131832 \n10. Doyle TJ Dhillon N Madan R Cabral F Fletcher EA Koontz DC \nRituximab in the Treatment of Interstitial Lung Disease Associated with Antisynthetase Syndrome: A Multicenter Retrospective Case Review\n. J Rheumatol \n2018 ;45 (6 ):841 –50\n. [10.3899/jrheum.170541 ] [PMID: ] [PMCID: ]29606668\n\n", "fulltext_license": "CC BY", "issn_linking": "2529-198X", "issue": "30(3)", "journal": "Mediterranean journal of rheumatology", "keywords": "Raynaud’s phenomenon; anti-Jo1; anti-synthetase syndrome; interstitial lung disease", "medline_ta": "Mediterr J Rheumatol", "mesh_terms": null, "nlm_unique_id": "101730166", "other_id": null, "pages": "186-189", "pmc": null, "pmid": "32185363", "pubdate": "2019-09", "publication_types": "D002363:Case Reports", "references": "22078416;27423682;26131832;27594777;22771754;29606668;28461650;28147261;30239350;28339994", "title": "Interstitial Lung Disease in Anti-Synthetase Syndrome.", "title_normalized": "interstitial lung disease in anti synthetase syndrome" }

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"drugstartdateformat": null, "drugstructuredosagenumb": null, "drugstructuredosageunit": null, "drugtreatmentduration": null, "drugtreatmentdurationunit": null, "medicinalproduct": "PREDNISOLONE." } ], "patientagegroup": null, "patientonsetage": "54", "patientonsetageunit": "801", "patientsex": "2", "patientweight": null, "reaction": [ { "reactionmeddrapt": "Drug ineffective", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" }, { "reactionmeddrapt": "Off label use", "reactionmeddraversionpt": "22.1", "reactionoutcome": "1" } ], "summary": null }, "primarysource": { "literaturereference": "KOURKOUNI E, MITSOGIANNIS G, SIMOPOULOU T, LIASKOS C, KATSIARI CG, DANIIL Z ET.AL. INTERSTITIAL LUNG DISEASE IN ANTI-SYNTHETASE SYNDROME.. MEDITERRANEAN J. RHEUMATOLOGY. 2019?30(3):186-9", "literaturereference_normalized": "interstitial lung disease in anti synthetase syndrome", "qualification": "1", "reportercountry": "GR" }, "primarysourcecountry": "GR", "receiptdate": "20200115", "receivedate": "20200115", "receiver": { "receiverorganization": "FDA", "receivertype": "6" }, "reporttype": "1", "safetyreportid": 17274414, "safetyreportversion": 1, "sender": { "senderorganization": "FDA-Public Use", "sendertype": "2" }, "serious": 1, "seriousnesscongenitalanomali": null, "seriousnessdeath": null, "seriousnessdisabling": null, "seriousnesshospitalization": 1, "seriousnesslifethreatening": null, "seriousnessother": null, "transmissiondate": "20200409" } ]

{ "abstract": "Giant cell arteritis is a common systemic vasculitis affecting the elderly, with maximum prevalence in the 7th decade of age, targeting aortic derived medium and large vessels of the neck and head. Diagnosis is established on a biopsy specimen of the temporal artery wall, through pathological confirmation of panarteritis, typically characterized by mononuclear cell infiltrate, with the 1990 ACR criteria often used in clinical practice. We present the case of a patient with a new onset headache and systemic inflammation, who did not fulfil the classical diagnostic criteria, nor did the temporal artery biopsy (TAB) provide a positive result. However, the ultrasonographical features, clinical evolution and response to corticosteroid therapy confirmed the diagnosis. This patient had bilateral presence of the halo sign on color duplex ultrasonography (CDUS), cited as a highly specific feature, when compared to the ACR criteria as a standard reference. We employed its positive likelihood-ratio (LR+) of 43 as previously estimated, while considering a low pre-test probability for a positive diagnosis (15%), to calculate a post-test probability of 88%, leading to our decision to treat him as having giant cell arteritis. Remission of the headache and rebound phenomena when tapered off steroid therapy substantially contributed to the positive diagnosis, underlining the importance of future studies needing to use clinical evolution as a reference standard.", "affiliations": "Colentina Clinical Hospital, Department of Neurology, Bucharest, Romania.;Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest, Romania.;Carol Davila University of Medicine and Pharmacy Bucharest, Bucharest, Romania.", "authors": "Chiriac|Andra|A|;Badea|Camelia|C|;Băicuș|Cristian|C|", "chemical_list": "D000893:Anti-Inflammatory Agents; D011241:Prednisone", "country": "Germany", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1220-4749", "issue": "57(4)", "journal": "Romanian journal of internal medicine = Revue roumaine de medecine interne", "keywords": "compression sign; giant cell arteritis; halo sign; ultrasonography", "medline_ta": "Rom J Intern Med", "mesh_terms": "D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents; D013700:Giant Cell Arteritis; D006801:Humans; D008297:Male; D011241:Prednisone; D014463:Ultrasonography", "nlm_unique_id": "9304507", "other_id": null, "pages": "341-344", "pmc": null, "pmid": "31120860", "pubdate": "2019-12-01", "publication_types": "D002363:Case Reports", "references": null, "title": "Will imaging change the diagnosis and management of giant cell arteritis?", "title_normalized": "will imaging change the diagnosis and management of giant cell arteritis" }

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{ "abstract": "Acute liver failure (ALF) in neonates is rare. Although the incidence is reported to be rare, neonatal hemochromatosis (NH) has to be considered as one of the causes of neonatal ALF. We present a pair of dichorionic twin who had a diverse clinical presentation of NH. One twin passed away despite medical treatment with exchange transfusion and intravenous immunoglobulin (IVIg), whereas the other twin suffered from only mildly deranged liver function, which normalized spontaneously. Early identification of liver failure and clinical awareness of this disease entity are essential to its timely diagnosis and treatment. Antenatal management using IVIg prevents the recurrence of NH in subsequent pregnancies.", "affiliations": "Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong.;Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong.;Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong.", "authors": "Chee|Yee Yuet|YY|;Wong|Siu Chun Mabel|SCM|;Wong|Ming Sum Rosanna|MSR|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1055/s-0038-1675335", "fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0038-1675335180007Case ReportHeterogeneous Presentation of Neonatal Hemochromatosis in Dichorionic Twins Chee Yee Yuet FHKAM1Wong Siu Chun Mabel FHKAM1Wong Ming Sum Rosanna FHKAM11 Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong KongAddress for correspondence Yuet Yee Chee, FHKAM Department of Paediatrics and Adolescent MedicineUniversity of Hong Kong, 102 Pokfulam Road, Queen Mary Hospital, Hong KongHong [email protected] 2018 20 11 2018 8 4 e332 e334 31 1 2018 19 6 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.Acute liver failure (ALF) in neonates is rare. Although the incidence is reported to be rare, neonatal hemochromatosis (NH) has to be considered as one of the causes of neonatal ALF. We present a pair of dichorionic twin who had a diverse clinical presentation of NH. One twin passed away despite medical treatment with exchange transfusion and intravenous immunoglobulin (IVIg), whereas the other twin suffered from only mildly deranged liver function, which normalized spontaneously. Early identification of liver failure and clinical awareness of this disease entity are essential to its timely diagnosis and treatment. Antenatal management using IVIg prevents the recurrence of NH in subsequent pregnancies.\n\nKeywords\nneonatal hemochromatosisgestational alloimmune liver diseaseliver failure\n==== Body\nCase Report\nClinical Presentation\nA dichorionic diamniotic male twin was born at 35 weeks of gestation with a birth weight of 1.6 kg (small for gestational age). The baby presented with recurrent hypoglycemia shortly after birth. Blood tests on the second day of life showed cholestasis (up to 145 umol/L), hypoalbuminemia, hyperammonemia (up to 453 umol/L), and coagulopathy, which progressively worsened throughout the first week of life. Work-up for neonatal liver failure was negative for metabolic disease, and surgical and infective causes.\n\n\nFerritin level was elevated at 8,397 umol/L. Biopsy of the liver and buccal mucosa was performed. This demonstrated hepatic and extrahepatic iron deposition (\nFig. 1\n) and confirmed the diagnosis of neonatal hemochromatosis (NH; likely due to gestational alloimmune liver disease, GALD). Medical treatment was given with exchange transfusion and intravenous immunoglobulin (IVIg). However, he failed to respond to medical treatment and developed worsening liver failure. Liver transplantation was considered but deemed not an option due to the low body weight and unavailability of living-related liver donor. After extensive discussion with the parents, the decision for redirection of care was made. The baby was electively extubated and eventually succumbed on day 33 of life.\n\n\nFig. 1 \nLiver biopsy showing hepatocellular siderosis (left) and abnormal iron deposition in salivary gland (right), demonstrating iron in blue by Perl's stain.\n\n\nOn the contrary, the other twin girl was born with a birth weight of 2.4 kg and suffered only from mildly deranged liver function only. Her liver function test showed mildly elevated liver enzymes (peak aspartate aminotransferase [AST] of 371 U/L and alanine aminotransferase [ALT] of 162 U/L at around 3 weeks of life) and conjugated bilirubin (11 umol/L), with normal ammonia level and clotting profile all along. Metabolic, surgical, and infective work-ups were negative. Ferritin level was high at 9,801 umol/L. Liver function test subsequently normalized spontaneously upon follow-up.\n\nFamily was counseled on the importance of antenatal treatment with IVIg in future pregnancies to prevent the recurrence of NH.\n\nDiscussion\n\nAlthough neonatal liver failure is rarely encountered, one of the most important diagnoses to consider is NH. NH is a rare condition. The exact incidence of the disorder is unknown. Fetal liver injury causes disturbed fetal iron homeostasis, resulting in fetal iron overload. NH is characterized by severe liver injury with the accumulation of iron in hepatic and extrahepatic tissues. The most common cause of fetal liver injury leading to the NH phenotype is a gestational alloimmune disorder called GALD.\n1\n2\nIt results from the transplacental transfer of maternal immunoglobulin G (IgG) directed against an antigen on the fetal hepatocyte, with fetal complement activation and formation of membrane attack complex, resulting in fetal hepatocyte injury and death (with congenital cirrhosis and siderosis of extrahepatic tissues). Once a woman has become sensitized, transplacental passage of IgG can occur in subsequent pregnancy, causing immune-mediated liver injury in the fetus.\n\n\n\nDiagnosis of NH is by the demonstration of iron accumulation in the extrahepatic tissues, usually through the biopsy of oral mucosal salivary glands or using T2-weighed magnetic resonance imaging (MRI) demonstrating the accumulation of iron in the pancreas, heart, or adrenal glands.\n1\nAntibodies to C5b-9 complex, a neoantigen created during the activation of terminal complement cascade, are used to demonstrate the accumulation of membrane attack complex in liver biopsy.\n2\nHowever, this immunohistochemical staining for C5b-9 complex is not available in our locality.\n\n\n\nTreatment for NH includes exchange transfusion (by removing existing reactive antibodies) and IVIg (blocking antibody action and interfering with complement activation).\n3\n4\nSurvival with medical treatment (without liver transplantation) is reported to be at around 75%.\n4\nIf medical treatment fails, liver transplantation remains to be the last therapeutic option.\n\n\n\nNH presentation could be quite heterogeneous, as shown in this pair of twins. The twin boy was being affected antenatally with growth restriction and early presentation with hypoglycemia within few hours after birth followed by liver failure. Without the frank presentation of liver failure in one of the index twin, the other twin would have been managed as a case of neonatal hepatitis, and the diagnosis of NH would be missed. With antenatal IVIg treatment, outcome of future pregnancy in our index family is expected to be good.\n5\n6\n\n\n\nTable 1\nsummarizes the clinical characteristics of published cases of twins pregnancy affected by NH in the literature.\n7\n8\n9\n10\n11\n\n\nTable 1 Summary of twins pregnancy affected by NH\n\tNormal values\tTwin set 1 (index)\t\t\nTwin set 2\n7\n\t\t\nTwin set 3\n8\n\t\t\nTwin set 4\n9\n\t\nTwin set 5\n9\n\t\t\nTwin set 6\n10\n\t\t\nTwin set 7\n11\n\t\t\n Twin set 8\n11\n\t\t\n\t\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin B\tTwin A\tTwin B\t\n\nPregnancy\n\t\tDCDA\tDCDA\tMC\tMC\tMC\tMC\tN/A\tMCDA\tMCDA\tMC\tMC\tDCDA\tDCDA\tDCDA\tDCDA\t\n\nGender\n\t\tMale\tFemale\tMale\tMale\tFemale\tFemale\tMale\tMale\tMale\tMale\tMale\tMale\tFemale\tFemale\tFemale\t\n\nGestational age (weeks)\n\t\t35\t35\t37\t37\t34\t34\t27\t26\t26\t33\t33\t35\t35\t37\t37\t\n\nBirth weight (kg)\n\t\t1.6\t2.4\t2.49\t2.5\t1.83\t1.95\t0.92\t0.82\t0.9\t2.4\t2.1\tAGA\tAGA\tAGA\tAGA\t\n\nTotal bilirubin (umol/L)\n\t<24\t368\t169\t154\t197\t36\tN/A\t149\t71\t476\t–\tN/A\t231\t67\t91\t238\t\n\nDirect bilirubin (umol/L)\n\t<10\t145\t11\t32\t21\t19\tN/A\tN/A\tN/A\tN/A\t–\tN/A\t113\t9\t7\t80\t\n\nAST (U/L)\n\t<60\t146\t371\t502\t133\t34\tN/A\tN/A\tN/A\tN/A\t–\tN/A\tN/A\tN/A\tN/A\tN/A\t\n\nALT (U/L)\n\t<53\t56\t162\t78\t23\t101\tN/A\t98\t25\t306\t–\t5\t27\t41\t21\t38\t\n\nINR\n\t<2\t4.5\t1.2\t2.8\t1.5\t3\tN/A\t1.5\t1.2\t1.6\t–\t1.37\t4.7\t1\t2.2\t3.4\t\n\nFerritin (pmol/L)\n\t275–831\t8,397\t9,801\t62,115\t5,643\t3,596\tN/A\t2,663\t5,443\t6,625\t–\t1,180\t2,609\t1,539\t3,762\t8,865\t\n\nNH Treatment\n\t\tIVIG, ET\tNot required\tIVIG\tNot required\tAntioxidant–chelation therapy\tN/A\tAntioxidant therapy\tNot required\tAntioxidant therapy\t–\tAntioxidant therapy\tAntioxidant–chelation therapy\tAntioxidant therapy\tAntioxidant–chelation therapy\tAntioxidant–chelation therapy\t\n\nOutcome\n\t\tDied on day 33 of life\tHealthy at 10 mo\tHealthy at 1.5 y\tHealthy at 1.5 y\tHealthy at 1 y\tDied on day 12 of life\tAlive\tAlive\tAlive\tIUD\tHealthy at 6 mo\tHealthy at 1 y\tHealthy at 1 y\tHealthy at 10 mo\tHealthy at 10 mo\t\nAbbreviations: AGA, appropriate for gestational age; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCDA, dichorionic–diamniotic; ET, exchange transfusion; INR, international normalized ratio; IUD, intrauterine demise; IVIG, intravenous immunoglobulin; MC, monochorionic; MCDA, monochorionic-diamniotic; N/A, not available; NH, neonatal hemochromatosis .\n\nConclusion\nIn conclusion, a high index of suspicion of NH in babies presenting with cholestasis and deranged liver function is important so as to facilitate its early diagnosis and management. It has a high recurrence in subsequent pregnancies, and antenatal IVIg treatment can greatly reduce this chance.\n\nConflicts of Interest All contributing authors declare no conflicts of interest.\n==== Refs\nReferences\n1 Whitington PF Gestational alloimmune liver disease and neonatal hemochromatosis Semin Liver Dis 2012 32 04 325 332 23397533 \n2 Heissat S Collardeau-Frachon S Baruteau J Neonatal hemochromatosis: diagnostic work-up based on a series of 56 cases of fetal death and neonatal liver failure J Pediatr 2015 166 01 66 73 25444000 \n3 Lopriore E Mearin ML Oepkes D Devlieger R Whitington PF Neonatal hemochromatosis: management, outcome, and prevention Prenat Diagn 2013 33 13 1221 1225 24030714 \n4 Rand EB Karpen SJ Kelly S Treatment of neonatal hemochromatosis with exchange transfusion and intravenous immunoglobulin J Pediatr 2009 155 04 566 571 19560784 \n5 Whitington PF Hibbard JU High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis Lancet 2004 364 (9446):1690 1698 15530630 \n6 Whitington PF Kelly S Outcome of pregnancies at risk for neonatal hemochromatosis is improved by treatment with high-dose intravenous immunoglobulin Pediatrics 2008 121 06 e1615 e1621 18474533 \n7 Midorikawa H Mizuochi T Okada JI Hisano T Disparate clinical findings in monochorionic twins with neonatal hemochromatosis Pediatr Int 2017 59 11 1215 1216 29359379 \n8 Korkmaz L Baştuğ O Daar G Doğanay S Deniz K Kurtoğlu S Neonatal hemochromatosis in monochorionic twins J Neonatal Perinatal Med 2015 8 04 413 416 26836824 \n9 Isa HM Mohamed AM Neonatal hemochromatosis. Case series from Bahrain Saudi Med J 2013 34 12 1274 1280 24343468 \n10 Vanden Eijnden S Hassoun M Donner C Iron overload in gestational alloimmune liver disease: still more questions than answers Prenat Diagn 2012 32 08 810 812 22566027 \n11 Ekong UD Kelly S Whitington PF Disparate clinical presentation of neonatal hemochromatosis in twins Pediatrics 2005 116 06 e880 e884 16291733\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2157-7005", "issue": "8(4)", "journal": "AJP reports", "keywords": "gestational alloimmune liver disease; liver failure; neonatal hemochromatosis", "medline_ta": "AJP Rep", "mesh_terms": null, "nlm_unique_id": "101569862", "other_id": null, "pages": "e332-e334", "pmc": null, "pmid": "30464860", "pubdate": "2018-10", "publication_types": "D002363:Case Reports", "references": "29359379;24030714;25444000;26836824;22566027;24343468;15530630;19560784;18474533;23397533;16291733", "title": "Heterogeneous Presentation of Neonatal Hemochromatosis in Dichorionic Twins.", "title_normalized": "heterogeneous presentation of neonatal hemochromatosis in dichorionic twins" }

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